Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([CH:19]=O)=[C:9]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])[C:10]=1[CH3:11])=[O:5])C.[CH3:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26](=[O:31])[CH2:25]2.[OH-].[K+]>N1CCCCC1.C(O)C>[C:14]([CH2:13][CH2:12][C:9]1[C:10]([CH3:11])=[C:6]([C:4]([OH:3])=[O:5])[NH:7][C:8]=1[CH:19]=[C:25]1[C:24]2[C:28](=[CH:29][CH:30]=[C:22]([CH3:21])[CH:23]=2)[NH:27][C:26]1=[O:31])([OH:16])=[O:15]
Reactant: CCOC(=O)CCc1c(C=O)[nH]c(C(=O)OCC)c1C
Reactant: Cc1ccc2c(c1)CC(=O)N2
Agent: [K+]
Agent: [OH-]
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1ccc2c(c1)C(=Cc1[nH]c(C(=O)O)c(C)c1CCC(=O)O)C(=O)N2
Temperature: 95 °C
Yield: 70.3 %

Procedure:
5-Formyl-4-(2-ethoxycarbonylethyl)-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (560 mg), 5-methyl-2-oxindole (300 mg), and piperidine (4 drops) in ethanol (4 mL) were stirred at 90° C. for 2 hours. Potassium hydroxide (537 mg) was added to the mixture and it was then stirred at 95° C. for an additional hour. The reaction mixture was cooled and concentrated. The residue was dissolved into water and acidified with 2 N hydrochloric acid to pH 2. The precipitate was filtered, washed with water, and dried in a vacuum oven overnight to give 496 mg of 4-(2-carboxyethyl)-3-methyl-5-(5-methyl -2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:3][CH:2]=1.C([O-])=O.[NH4+]>C(O)C.O.[C].[Pd]>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccncc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)CCc1ccncc1
Yield: 65.1 %

Procedure:
tert-Butyl (E)-3-(4-Pyridyl)acrylate (0.88 g, 4.3 mmol) was dissolved in ethanol (10 ml), and 10% palladium-carbon (0.17 g) and a solution of ammonium formate (1.4 g, 21.4 mmol) in water (2.5 ml) were added thereto. The reaction mixture was refluxed for 3 hrs. Palladium-carbon was filtered off. The reaction mixture was combined with water, concentrated under reduced pressure to the half amount and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel (20 g) column chromatography. The fractions eluted with hexane-ethyl acetate (3:1, v/v) were collected and concentrated to give the titled compound (0.58 g, 65%).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][C:9]2[C:10]3[CH2:31][NH:30][CH2:29][CH2:28][C:11]=3[N:12]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][N:24]=[C:23]4[CH3:27])=[CH:18][CH:17]=3)[N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>>[CH:1]1([CH2:7][CH2:8][C:9]2[C:10]3[CH2:31][N:30]([C:32](=[O:34])[CH3:33])[CH2:29][CH2:28][C:11]=3[N:12]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][N:24]=[C:23]4[CH3:27])=[CH:18][CH:17]=3)[N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(CCC4CCCCC4)n2)CNCC3)cc1
Product: CC(=O)N1CCc2nc(Nc3ccc(-n4ccnc4C)cc3)nc(CCC3CCCCC3)c2C1
Yield: 26 %

Procedure:
1-(4-(2-Cyclohexylethyl)-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (51 mg, 26%) was synthesised from 4-(2-cyclohexylethyl)-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (Example 54a) and acetic anhydride according to the general procedure for N-acetylation. MS (ES+) m/z 459.4 (M+H)+
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:12]([NH:14][CH2:15][C:16](NC)=[O:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33].NC[C@@H](O)[CH2:37][OH:38].CN1CCOCC1>>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:12]([NH:14][CH2:15][C@@H:16]([OH:17])[CH2:37][OH:38])=[O:13])[CH:5]=[N:4][C:3]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33]
Reactant: CNC(=O)CNC(=O)c1ccc(C)c(-n2cnc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Reactant: NC[C@@H](O)CO
Solvent: CN1CCOCC1
Product: Cc1ccc(C(=O)NC[C@@H](O)CO)cc1-n1cnc(OCc2ccc(F)cc2F)c(Br)c1=O
Yield: 40 %

Procedure:
The title compound was prepared by a procedure similar to the one described for 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methyl-N-{1-[(methylamino)carbonyl]methyl}benzamide using (R)-(+)-3-amino-1, 2-propanediol (0.162 g 2.5 mmol) as the amine and without the addition of a second equivalent of N-methylmorpholine. After reverse phase HPLC purification, the organic extracts were concentrated under reduced pressure and dried in vacuo to afford the desired product (374.5 mg, 40%) as beige solid. 1H-NMR (CD3OD, 400 MHz) δ 8.32 (s, 1H), 7.92 (dd, 1H, J=2 Hz), 7.77 (d, 1H, J=2 Hz), 7.62 (m, 1H), 7.55 (d, 1H, J=8.4 Hz), 7.04 (m, 2H), 5.60 (q, 2H, J=12.4 Hz), 3.80 (m, 1H), 3.53 (m, 3H), 3.39 (m, 1H), 2.19 (s, 3H); ES-HRMS m/z 524.0649 (M+H C22H21BrF2N3O5 requires 524.0627).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[C:6]([C:16]2([C:27]#[N:28])[CH2:25][CH2:24][C:23]3[N:22]=[CH:21][NH:20][C:19](=[O:26])[C:18]=3[CH2:17]2)=[CH:5][CH:4]=1.Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[C:27]([C:16]1([C:6]2[C:7]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[O:9][C:8]=3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:25][CH2:24][C:23]2[N:22]=[CH:21][N:20]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:19](=[O:26])[C:18]=2[CH2:17]1)#[N:28]
Reactant: COc1ccc(C2(C#N)CCc3nc[nH]c(=O)c3C2)c2c1oc1ccccc12
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cnc2c(c1=O)CC(C#N)(c1ccc(OC)c3oc4ccccc4c13)CC2

Procedure:
To a solution of the compound obtained in example 13 (170 mg, 0.46 mmol) in 5 ml of dry DMF was added ethyl bromoacetate (84.5 mg, 0.5 mmol) and cesium carbonate (195.6 mg, 0.6 mmol) at room temperature for 1 hr. Once the reaction has completed, the reaction mass was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, followed by brine, and concentrated under vacuum. The crude product was purified by column chromatography to get 175 mg (83.2% yields) of the product. MP-106.2-125.1° C.
Reaction SMILES: [C:1]1([S:7]([OH:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:11][C:12]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=[O:15].[N+:22]([O-])([OH:24])=[O:23]>>[C:1]1([S:7]([OH:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:11][C:12]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[C:16]([N+:22]([O-:24])=[O:23])[C:13]=1[CH:14]=[O:15]
Reactant: O=[N+]([O-])O
Reactant: COc1cccc(C=O)c1O
Agent: O=S(=O)(O)c1ccccc1
Product: COc1ccc([N+](=O)[O-])c(C=O)c1O
Temperature: 15 °C
Reaction time: 0.5 h

Procedure:
2-Hydroxy-3-methoxybenzaldehyde benzenesulfonate (200 g, 0.685 mole) was added to 90% nitric acid (400 mL) with the temperature maintained at 0°±2° over a period of one-half to one hour. The reaction mixture was stirred an additional 0.5 hour and poured over ice (2.5 L) with stirring. After standing several hours, the solid was collected by filtration and washed with water (500 mL). The solid was then suspended in acetone (1.25 L) and the mixture was heated to reflux for 0.5 hour, concentrated to 500 mL and cooled to 15° C. The resultant solid was collected by filtration and washed with cold acetone (125 mL) to provide the title compound, 138.5 g (60%), mp 151°-155° C.
Reaction SMILES: [I-].[CH:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:4])[CH3:3].C([Li])CCC.[Br:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH:40]=O>O1CCCC1.CCCCCC>[Br:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH:40]=[C:2]([CH3:4])[CH3:3]
Reactant: O=CCCCCCCCCCCBr
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)=CCCCCCCCCCCBr
Temperature: -40 °C

Procedure:
Isopropyltriphenylphosphonium iodide (6 g, 14 mmoles) was suspended in tetrahydrofuran (120 ml), stirred at -40° C. and treated with n-butyllithium (14 mmoles) dissolved in hexane (2.5M). The mixture was stirred at -40° C. for 15 minutes, cooled to -75° C. and treated with a solution of 1-bromo-11-oxoundecane (2.8 g, 11.5 mmoles) in tetrahydrofuran (30 ml). The mixture was stirred at -75° C. for 15 minutes, allowed to warm to 25° C. and concentrated in vacuo. The residue was triturated with hexane, filtered and the filtrate concentrated in vacuo. The residue was chromatographed on silica gel eluted with hexane to afford 1-bromo-12-methyl-11-tridecene.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:10]=[C:11]([N:22]2[CH2:26][C@H:25]([CH2:27][NH:28][C:29](=O)[O:30]C(C)(C)C)[O:24][C:23]2=[O:36])[CH:12]=[CH:13][C:14]=1[N:15]1[CH:20]=[CH:19][C:18](=[O:21])[CH2:17][CH2:16]1.[Cl:37][CH:38]([Cl:44])C(OCC)=O>ClC(Cl)C>[Cl:37][CH:38]([Cl:44])[C:29]([NH:28][CH2:27][CH:25]1[O:24][C:23](=[O:36])[N:22]([C:11]2[CH:12]=[CH:13][C:14]([N:15]3[CH:20]=[CH:19][C:18](=[O:21])[CH2:17][CH2:16]3)=[C:9]([F:8])[CH:10]=2)[CH2:26]1)=[O:30]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CN(c2ccc(N3C=CC(=O)CC3)c(F)c2)C(=O)O1
Reactant: CCOC(=O)C(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C1C=CN(c2ccc(N3CC(CNC(=O)C(Cl)Cl)OC3=O)cc2F)CC1
Reaction time: 1.5 h

Procedure:
TFA (0.75 mL) is added to a solution of the carbamate from Step 6 of Example 3 (100 mg, 0.247 mmol) in dichloroethane (3.0 mL). This solution is stirred for 1.5 h., and the solvent is removed under vacuum. The residue is dissolved in MeOH (4.0 mL). TEA (105 mg, 1 mmol) is added to the mixture, followed by adding ethyl dichloroacetate (77 mg, 0.49 mmol). The mixture is stirred at r.t. for 16 h. Solvent is removed under vacuum, and the crude product purified by silica gel column chromatography (gradient 1% to 2% MeOH in DCM). MS (m/z): 417 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ 9.17 (t, J=5.5 Hz, 1H), 7.79 (d, J=14.3 Hz, 1H), 7.69–7.48 (m, 3 H), 6.67 (s, 1H), 5.17 (d, J=7.7 Hz, 1H), 5.05–4.99 (m, 1H), 4.35 (t, J=9.1 Hz, 1H), 4.06 (t, J=7.7 Hz, 3H), 3.93 (dd, J=6.0 and 9.3 Hz, 1H), 3.74–3.72 (m, 2H), 3.51–3.49 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[C:29]([S:31][CH3:32])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:24]([O-:26])=[O:25])=[C:9]([CH:23]=1)[O:10][C:11]1[CH:22]=[CH:21][CH:20]=[CH:19][C:12]=1[O:13][CH2:14][C:15]([O:17][CH3:18])=[O:16].ClC1C=C(C=CC=1)C(OO)=[O:38].C(OCC)(=O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:30]=[C:29]([S:31]([CH3:32])=[O:38])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:24]([O-:26])=[O:25])=[C:9]([CH:23]=1)[O:10][C:11]1[CH:22]=[CH:21][CH:20]=[CH:19][C:12]=1[O:13][CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)COc1ccccc1Oc1cc(Oc2ccc(SC)cc2Cl)ccc1[N+](=O)[O-]
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)COc1ccccc1Oc1cc(Oc2ccc(S(C)=O)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
A solution of methyl {o-{5-[2-chloro-4-(methylthio)phenoxy]-2-nitrophenoxy}phenoxy}acetate (4.30 g, 0.009 mol) in methylene chloride is cooled to 0° C. and treated with 3-chloroperoxybenzoic acid (1.73 g, 0.010 mol). The reaction mixture is warmed to room temperature, stirred overnight, quenched with triethylamine (1.4 mL) and concentrated in vacuo. The residue is dissolved into ethyl acetate and the organic solution is washed sequentially with water and 2 N hydrochloric acid, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain an amber oil. Column chromatography of the oil using silica gel and ethyl acetate gives the title product as an amber oil (2.6 g) which is identified by NMR spectral analyses.
Reaction SMILES: C(N(CC)CC)C.[C@H:8]12[CH2:14][C@H:11]([NH:12][CH2:13]1)[CH2:10][N:9]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].Cl[C:23]1[N:24]=[N:25][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:27][CH:28]=1>C1(C)C=CC=CC=1>[C:29]1([C:26]2[N:25]=[N:24][C:23]([N:12]3[CH2:13][C@@H:8]4[CH2:14][C@H:11]3[CH2:10][N:9]4[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:28][CH:27]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Clc1ccc(-c2ccccc2)nn1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1ccc(-c2ccccc2)nn1
Temperature: 100 °C

Procedure:
Triethylamine (20 mL) was added to a suspension of t-butyl (S,S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (3.43 g, 17.3 mmol, Aldrich Chemical Company) and 3-chloro-6-phenylpyridazine (3.30 g, 17.3 mmol, Aldrich Chemical Company) in toluene (50 mL) and the mixture was heated under nitrogen at 100° C. for 7 days. The dark mixture was cooled to room temperature, and the resulting precipitate was isolated by filtration, washed with toluene (15 mL) and dried under vacuum to provide the title compound as an off-white solid. The filtrate was concentrated and the residue was purified by column chromatography on silica gel, eluting with ethyl acetate, to provide additional product: MS (DCI/NH3) m/z 353 (M+H)+.
Reaction SMILES: C(N=C=NC(C)C)(C)C.[OH:10][C:11]1[C:12]([C:17]([OH:19])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=1.[F:20][C:21]1[C:26](O)=[C:25]([F:28])[C:24]([F:29])=[C:23]([F:30])[C:22]=1[F:31]>C(Cl)Cl.O>[OH:10][C:11]1[C:12]([C:17]([O:19][C:26]2[C:25]([F:28])=[C:24]([F:29])[C:23]([F:30])=[C:22]([F:31])[C:21]=2[F:20])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)c1ncccc1O
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Solvent: O
Product: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1ncccc1O
Reaction time: 12 h

Procedure:
At 20-25° C. 13 g of N,N′-diisopropylcarbodiimide (DIC) were added dropwise to a solution of 14 g of 3-hydroxypyridine-2-carboxylic acid and 18.5 g of pentafluorophenol in 700 ml of CH2Cl2. After the reaction had ended (about 40 min), the solution was allowed to stand at 20-25° C. for about 12 hours. The solvent was removed, and the residue formed was then taken up in water and the solution was extracted with CH2Cl2. The organic phase gave, after drying and removal of the solvent, 29 g of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:12](OC)(=[O:20])[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[SH:15].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]2[S:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[C:12](=[O:20])[N:9]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(C#N)cc1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(-c2nc(=O)c3ccccc3s2)cc1
Yield: 1.8 %

Procedure:
A mixture of 4-acetylbenzonitrile (2.00 g, 14 mmol), methyl thiosalicylate (4.63 g, 28 mmol), triethylamine (2.79 g, 28 mmol) and toluene (10 ml) was heated and refluxed for 72 hours under a nitrogen flow. The reaction solution was concentrated under reduced pressure and the residue was applied to column chromatography using silica gel (100 g). Fractions eluted with hexane-ethyl acetate (3:1, v/v) were concentrated under reduced pressure. The residue was recrystallized from isopropyl ether to give the title compound (0.07 g, 2%) as crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][CH:12]=[C:13]2[C:17]([CH3:18])=[C:16]([CH3:19])[NH:15][C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[CH2:25][CH:26]=[CH:27][C:28]([F:31])([F:30])[F:29])(=O)=O>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][CH:12]=[C:13]2[C:17]([CH3:18])=[C:16]([CH3:19])[N:15]([CH2:25][CH:26]=[CH:27][C:28]([F:31])([F:30])[F:29])[C:14]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1[nH]c2c(OCc3ccccc3)nncc2c1C
Reactant: CS(=O)(=O)OCC=CC(F)(F)F
Product: Cc1c(C)n(CC=CC(F)(F)F)c2c(OCc3ccccc3)nncc12
Yield: 20.7 %

Procedure:
The title compound was prepared as pale yellow crystals in 20.7% yield in a similar procedure to that described in Example 41-by using 7-benzyloxy-2,3-dimethylpyrrolo[2,3-d]pyridazine and 4,4,4-trifluoro-2-butenyl methanesulfonate.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.ClC(N(C)C)=C(C)C.[Br:21][C:22]1[C:23]([CH3:29])=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25].CCN(C(C)C)C(C)C>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Br:21][C:22]1[C:23]([CH3:29])=[C:24]([NH:25][C:7](=[O:9])[C:6]2[CH:5]=[CH:4][C:3]([N:2]([CH3:1])[CH3:12])=[CH:11][CH:10]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: Cc1c(N)cccc1Br
Reactant: CN(C)c1ccc(C(=O)O)cc1
Agent: CC(C)=C(Cl)N(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Br)cccc1NC(=O)c1ccc(N(C)C)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.5 %

Procedure:
A suspension of 4-(dimethylamino)benzoic acid (100 mg, 0.605 mmol) in DCM (3 mL) was treated with 1-chloro-N,N,2-trimethylprop-1-en-1-amine (0.120 mL, 0.908 mmol) and the resulting solution was stirred at rt for 1.5 h. 3-Bromo-2-methylaniline (0.053 mL, 0.432 mmol) was added, followed by DIEA (0.264 mL, 1.513 mmol). The mixture was stirred at rt for 1 h, then was diluted with DCM and NaHCO3 (aq). The layers were separated and the organic phase was washed with brine, dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 85:15 to 65:35 hexane-EtOAc) to provide N-(3-bromo-2-methylphenyl)-4-(dimethylamino)benzamide as a light yellow solid (77 mg, 53%). 1H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H) 7.85 (d, J=9.0 Hz, 2H) 7.49 (dd, J=8.0, 1.0 Hz, 1H) 7.30 (dd, J=7.9, 0.9 Hz, 1H) 7.15 (t, J=7.9 Hz, 1H) 6.75 (d, J=9.0 Hz, 2H) 2.99 (s, 6H) 2.25 (s, 3H). Mass spectrum m/z 331, 333 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[C:17]([C:22](=[O:31])[NH:23][CH2:24][C:25](=[O:30])[NH:26][CH:27]([CH3:29])[CH3:28])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH:43]=[CH:44][CH:45]=1)[C:38](=N)OCC>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[C:17]3[C:18](=[CH:19][CH:20]=2)[N:21]=[C:38]([C:37]2[CH:43]=[CH:44][CH:45]=[C:35]([O:34][CH3:33])[CH:36]=2)[N:23]([CH2:24][C:25](=[O:30])[NH:26][CH:27]([CH3:28])[CH3:29])[C:22]3=[O:31])[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOC(=N)c1cccc(OC)c1
Reactant: CC(C)NC(=O)CNC(=O)c1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)ccc1N
Agent: Cl
Solvent: CCO
Product: COc1cccc(-c2nc3ccc(N4CCCN(C(=O)OC(C)(C)C)CC4)cc3c(=O)n2CC(=O)NC(C)C)c1
Yield: 13 %

Procedure:
A mixture of 4-{4-Amino-3-[(isopropylcarbamoylmethyl)carbamoyl]phenyl}perhydro-1,4-diazepine-1-carboxylic acid tert-butyl ester (INTERMEDIATE V.2) (300 mg, 0.69 mmol) and ethyl 3-methoxybenzimidate hydrochloride (INTERMEDIATE II.2) (298 mg, 1.38 mmol) in EtOH (6 mL) was heated at reflux temperature for 16 h. The reaction mixture was cooled, filtered and the filtrate concentrated in vacuo. The crude residue was purified by preparative HPLC to afford 4-[3-(isopropylcarbamoylmethyl)-2-(3-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl]perhydro-1,4-diazepine-1-carboxylic acid tert-butyl ester (INTERMEDIATE VII.1) (50 mg, 0.09 mmol, 13%).
Reaction SMILES: [CH:1]([S:4]([C:7]1[N:11]=[CH:10][NH:9][N:8]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].[CH2:12]([N:15]([CH2:19][CH:20]=[CH2:21])[C:16](Cl)=[O:17])[CH:13]=[CH2:14].O1CCCC1>C(N(CC)CC)C>[CH2:12]([N:15]([CH2:19][CH:20]=[CH2:21])[C:16]([N:9]1[CH:10]=[N:11][C:7]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])=[N:8]1)=[O:17])[CH:13]=[CH2:14]
Reactant: C=CCN(CC=C)C(=O)Cl
Reactant: CC(C)S(=O)(=O)c1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCN(CC=C)C(=O)n1cnc(S(=O)(=O)C(C)C)n1

Procedure:
A mixture of 7.0 g. 3-isopropylsulphonyl-1,2,4-triazole, 7.0 ml. diallylcarbamoyl chloride, 25 ml. dry tetrahydrofuran and 8 ml. dry triethylamine was refluxed for 1 hour under anhydrous conditions. The reaction mixture was worked up as described in Example 1 to give 1-diallylcarbamoyl-3-isopropylsulphonyl-1,2,4-triazole as an oil which was heated under reduced pressure (100° C./0.5 mm.) for 1 hour to remove all traces of volatile material. Refractive index of product nD26 1.5158. Elemental analysis satisfactory.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]1=[O:18])=[O:8].[C:19]([N:27]=[C:28]=[O:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:19]([NH:27][C:28]([N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]([C:7](=[O:8])[CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[C:10]1=[O:18])=[O:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: O=C(Cc1cccs1)C1C(=O)Nc2ccccc21
Product: O=C(NC(=O)N1C(=O)C(C(=O)Cc2cccs2)c2ccccc21)c1ccccc1

Procedure:
N-Benzoyl-3-(2-[2-thienyl]acetyl)-2-oxindole-1-carboxamide was prepared by reaction of 3-(2-[2-thienyl]acetyl)-2-oxindole with benzoyl isocyanate using the method of Example 1.
Reaction SMILES: C[O-].[Na+].[OH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([C:15]([OH:17])=[O:16])=[N:10][CH:9]=[CH:8]2.[Cl:18][C:19]1[CH:24]=[C:23](Cl)[N:22]=[CH:21][N:20]=1>CO.CN(C=O)C>[Cl:18][C:19]1[N:20]=[CH:21][N:22]=[C:23]([O:4][C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][CH:14]=2)[C:11]([C:15]([OH:17])=[O:16])=[N:10][CH:9]=[CH:8]3)[CH:24]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: O=C(O)c1nccc2cc(O)ccc12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(O)c1nccc2cc(Oc3cc(Cl)ncn3)ccc12
Temperature: 10 °C
Reaction time: 14 h

Procedure:
40 ml (20 mMol) of a 0.5 M solution of sodium methylate in MeOH are added to a suspension of 1.9 g (10 mMol) 6-hydroxy-isoquinoline-1-carboxylic acid (CAS 174299-07-1) in 50 ml MeOH and sonicated until a solution is obtained. The solvent is then evaporated off. The residue is dried in high vacuum for 4 h and 100 ml DMF are added. The suspension is cooled to 10° C. and a solution of 1.55 g (10 mMol) 4,6-dichloropyrimidine in 25 ml DMF is added. The reaction mixture is stirred at room temperature for 14 h. The solvent is evaporated off and the mixture is partitioned between H2O/EtOAc. After extraction, the aqueous phase is neutralized with a 1 N solution of HCl. The suspension is extracted with EtOAc, washed with H20 and brine, dried (MgSO4) and concentrated to give a beige powder: 1H-NMR (DMSO-d6): δ ppm 7.60 (s, 1H), 7.68 (dd, J=9.4, 2.3 Hz, 1H), 7.98 (d, J=2.3 Hz, 1H), 8.04 (d, J=5.5 Hz, 1H), 8.59 (d, J=5.9 Hz, 1H), 8.66 (s, 1H), 8.68 (s, 1H).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6](/[C:10](=[N:16]/[O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[N:28]=[C:29]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[O:30][C:31]=3[CH3:32])=[CH:21][CH:20]=2)/[C:11]([O:13]CC)=[O:12])[CH:7]=[CH:8][CH:9]=1.CO.Cl>O1CCCC1>[Br:3][C:4]1[CH:5]=[C:6](/[C:10](=[N:16]/[O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][C:27]3[N:28]=[C:29]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[O:30][C:31]=3[CH3:32])=[CH:23][CH:24]=2)/[C:11]([OH:13])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1cccc(Br)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\C(=O)O)c2cccc(Br)c2)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added to a solution of ethyl Z-2-(3-bromopbenyl)-2-[4(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]acetate (430 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at 40° C. for 2 hours. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain Z-2-(3-bromophenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]acetic acid (370 mg, yield 91%) as colorless crystals. m.p. 181-182° C. (decomposition)