Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([CH3:21])=[CH:18][CH:19]=3)[N:14]([CH:22]([CH3:24])[CH3:23])[C:13](=[O:25])[N:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[Br:26]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([CH2:21][Br:26])=[CH:18][CH:19]=3)[N:14]([CH:22]([CH3:23])[CH3:24])[C:13](=[O:25])[N:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Oc1cccc(-c2nc(=O)n(C(C)C)c3cc(C)ccc23)c1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Oc1cccc(-c2nc(=O)n(C(C)C)c3cc(CBr)ccc23)c1
Temperature: 25 °C

Procedure:
A mixture of 14 g of 4-(3-acetoxyphenyl)-1-isopropyl-7-methyl-2(1H)-quinazolinone, 20 g of N-bromosuccinimide, and 600 ml of carbon tetrachloride is irradiated with infrared light for 15 minutes in a 1000 ml flat-bottom flask while stirring and refluxing. After cooling to room temperature with an ice bath, the mixture is washed successively with 500 ml and 100 ml of water in a 2 liter separatory funnel. Each water phase is washed with an additional 100 ml of carbon tetrachloride. The combined carbon tetrachloride phase is evaporated to dryness. The resulting residue is dissolved in 200 ml of methanol and evaporated to dryness to obtain crude 4-(3-acetoxyphenyl)-7-bromomethyl-1-isopropyl-2(1H)-quinazolinone. A thin-layer chromatogram on Silica Gel GE with ethyl acetate as the mobile phase shows the presence of the desired monobrominated product and dibrominated by-product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:11][OH:12])[CH:5]=[C:6]([Br:10])[C:7]=1[CH2:8]Br.BrCC1C=C(Cl)C(CC2C=C(C(C)C)[C:23](=O)[NH:24]N=2)=C(Cl)C=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:11][OH:12])[CH:5]=[C:6]([Br:10])[C:7]=1[CH2:8][C:23]#[N:24]
Reactant: CC(C)c1cc(Cc2c(Cl)cc(CBr)cc2Cl)n[nH]c1=O
Reactant: OCc1cc(Br)c(CBr)c(Br)c1
Product: N#CCc1c(Br)cc(CO)cc1Br
Yield: 78 %

Procedure:
This compound was prepared by a similar method to that described in Example 14, Step 5 except that (3,5-dibromo-4-bromomethyl-phenyl)-methanol (58) was used in place 6-(4-bromomethyl-2,6-dichloro-benzyl)-4-isopropyl-pyridazin-3-one (54). The product was purified by flash chromatography using silica gel eluted with a gradient of 3:1 to 1:1 hexanes:ethyl acetate. The desired fractions were collected and concentrated under vacuum to afford a solid which was dried under high vacuum to afford 2,6-dibromo-4-hydroxymethyl-phenyl)-acetonitrile (59) (78%) as a yellow solid; EI(+)-HRMS m/z calcd for C9H7Br2NO (M+) 302.8894, found 302.8881. MW=304.9702, Exact Mass=302.8894
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[Cl:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14].CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:13](=[O:14])[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[Cl:10])=[N:6][CH:7]=1
Reactant: NNc1ccc(F)cn1
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NNc1ccc(F)cn1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of (5-fluoro-pyridin-2-yl)-hydrazine (for reference procedure see WO 2010/022076, which is incorporated herein by reference; 1.0 g, 7.87 mmol) and 2-chloro-benzoyl chloride (1 mL, 7.87 mmol) in DCM (50 mL) was added dropwise DIPEA (2.74 mL, 15.75 mmol). The reaction mixture was stirred at RT for 1 h then washed with water. The organic layer was dried through a phase separator and then concentrated in vacuo to afford the title compound (1.95 g, 93%) as a brown solid. LCMS (Method 3): Rt 2.82 min, m/z 266 [MH+].
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].Br[CH2:6][C:7]([N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1)=[O:8]>O>[CH2:6]1[C:17]2=[C:18]3[C:13](=[CH:14][CH:15]=[CH:16]2)[CH2:12][CH2:11][CH2:10][N:9]3[C:7]1=[O:8]
Reactant: O=C(CBr)N1CCCc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: O=C1Cc2cccc3c2N1CCC3
Temperature: 200 °C
Reaction time: 0.5 h

Procedure:
To a flask containing 30 g. of aluminum chloride is added 20.5 g. of 1-(bromoacetyl)-1,2,3,4-tetrahydroquinoline. After a vigorous initial reaction, the mixture is heated to 200° C. After 30 minutes, the reaction mixture is poured on cold water and the resulting oil is extracted with methylene chloride, dried, and the solvent removed under reduced pressure. The resultant oil is dissolved in ether, the solution cooled and the precipitate sublimed to yield 1,2,5,6-tetrahydro-4H-pyrrolo-(3,2,1-ij)quinolin-2-one, m.p. 90°-93° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[C:12]([Br:14])[CH:11]=[C:10]2[C:5]=1[N:6]=[C:7]([O:17][CH3:18])[C:8]([O:15][CH3:16])=[N:9]2.C(N(CC)CC)C.[Cl-].[CH2:27]([O:29][C:30](=[O:34])[C:31](O)=[O:32])[CH3:28]>C1COCC1>[CH2:27]([O:29][C:30](=[O:34])[C:31]([NH:2][CH2:3][C:4]1[CH:13]=[C:12]([Br:14])[CH:11]=[C:10]2[C:5]=1[N:6]=[C:7]([O:17][CH3:18])[C:8]([O:15][CH3:16])=[N:9]2)=[O:32])[CH3:28]
Reactant: COc1nc2cc(Br)cc(CN)c2nc1OC
Reactant: CCOC(=O)C(=O)O
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)NCc1cc(Br)cc2nc(OC)c(OC)nc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
300 mg (1 mmol) of 5-aminomethyl-7-bromo-2,3-dimethoxyquinoxaline hydrochloride are suspended in 10 ml of THF and the suspension is cooled to 0° C. 0.183 ml (1.3 equiv.) of triethylamine is added and then 0.123 ml (1.1 equiv.) of oxalic acid monoethyl ester chloride is added dropwise in the course of 30 minutes. The mixture is stirred at 0° C. for 2 hours, then at 20° C. for 16 hours and is concentrated by evaporation. The residue is stirred in diethyl ether, and the solid is filtered off, washed with water and diethyl ether and dried.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:8]([C:12]([NH:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:13])=[C:7]([Cl:22])[CH:6]=[CH:5][C:4]=2[N:3]=1.[N:23]1([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[Cl:22][C:7]1[C:8]([C:12]([NH:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:13])=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:26]1[CH2:25][CH2:24][N:23]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:28][CH2:27]1)[CH:11]=[CH:10]2
Reactant: O=C(NCC1CCCCC1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: CCOC(=O)CN1CCNCC1
Product: CCOC(=O)CN1CCN(c2ccc3c(C(=O)NCC4CCCCC4)c(Cl)ccc3n2)CC1

Procedure:
Prepared according to the method of example 30, using 2,6-dichloro-N-(cyclohexylmethyl)-5-quinolinecarboxamide Example 43(a)) (200 mg) and 1-piperazineacetic acid, ethyl ester (500 mg) to afford the subtitle compound as a solid (200 mg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12]([N:14]1[CH2:17][CH:16]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=2[OH:25])[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[CH2:26]([C:28]([CH3:30])=O)[CH3:27]>>[C:7]([O:11][C:12]([N:14]1[CH2:15][CH:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:30][C:28]3[CH:9]=[CH:7][CH:8]=[CH:27][CH:26]=3)=[CH:20][C:19]=2[O:25][CH2:16][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:17]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc(O)cc2O)C1
Reactant: CCC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CC(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)C1

Procedure:
In a 25 ml round-bottomed flask, 1.35 g of potassium carbonate are added in small portions to a solution of 0.86 g of 3-(2,4-dihydroxyphenyl)azetidine-1-carboxylic acid tert-butyl ester (Example 1) in 9 ml of methyl ethyl ketone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][CH:34]=1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[N:15]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][CH:34]=4)[N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cn2nc3c(-c4ccc(Cl)cc4)c(-c4ccc(Cl)cc4)cnn3c2=O)cc1
Temperature: 75 °C
Yield: 31.4 %

Procedure:
A solution of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (192 mg, 0.54 mmol), prepared as described in Example 1, K2CO3 (90 mg), and α-bromo-p-toluonitrile (127 mg, 0.645 mmol) in DMF (2 mL) was heated at 75° C. for 1 h. After this time, the solution was concentrated under redcued pressure. The resulting crude product was purified by reverse phase HPLC to provided the title compound, 4-((7,8-bis-(4-chlorophenyl)-3-oxo-[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl)methyl)benzonitrile (80 mg) as a yellow solid. MS M+H=472; 1H NMR (CDCl3): δ 8.17 (s, 1H), 7.63 (d, J=8.4 Hz, 2H), 7.49 (d, J=8.3 Hz, 2H), 7.33 (m, 2H), 7.25 (m, 2H), 7.24 (m, 2H), 7.09 (m, 2H), 5.25 (2H).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([CH2:12][C:13]([NH:15][C:16]2[S:20][C:19]3[CH2:21][CH2:22][CH2:23][CH2:24][C:18]=3[C:17]=2[C:25](O)=[O:26])=[O:14])[N:4]=1.N=C=N.[CH2:33]([NH2:35])[CH3:34]>C(Cl)Cl.CN(C=O)C>[CH2:33]([NH:35][C:25]([C:17]1[C:18]2[CH2:24][CH2:23][CH2:22][CH2:21][C:19]=2[S:20][C:16]=1[NH:15][C:13](=[O:14])[CH2:12][N:5]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[C:3]([C:2]([F:28])([F:1])[F:29])=[N:4]1)=[O:26])[CH3:34]
Reactant: CCN
Reactant: O=C(Cn1nc(C(F)(F)F)c2c1CCCC2)Nc1sc2c(c1C(=O)O)CCCC2
Agent: N=C=N
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCNC(=O)c1c(NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)sc2c1CCCC2
Yield: 6.4 %

Procedure:
2-[2-(3-Trifluoromethyl-4,5,6,7-tetrahydroindazol-1-yl)-acetylamino]-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (20 mg, 0.047 mmol) was dissolved in a solution of DCM (800 μL) and DMF (200 μL). Polymer supported carbodiimide (loading 1.22 mmol/g, 53 mg, 0.064 mmol) was added, followed by ethylamine (2.0 M solution in THF, 94.0 μl, 0.188 mmol). The resultant mixture was heated in a Biotage SmithCreator microwave at 120° C. for 15 min. The resin was filtered off and washed through with MeOH (2×50 mL), EtOAc (2×20 mL) and MeCN (2×20 mL). The combined filtrate was concentrated in vacuo, and the residue obtained purified by preparative reverse phase HPLC to afford the title compound as a white solid (1 mg, 0.003 mmol, 6%).
Reaction SMILES: [Na].CO.Cl.[NH2:5][C:6]([NH2:8])=[NH:7].Cl.[Cl:10][C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH3:22])[CH:20]=2)[N:15]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][N:24]=2)[CH:14]=1)=[O:12]>COCCOC>[ClH:10].[NH:7]([C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH3:22])[CH:20]=2)[N:15]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][N:24]=2)[CH:14]=1)=[O:12])[C:6]([NH2:8])=[NH:5]
Reactant: N=C(N)N
Reactant: Cc1ccc2c(c1)c(C(=O)Cl)cn2-c1nccc2ccccc12
Agent: Cl
Agent: [Na]
Solvent: COCCOC
Solvent: CO
Product: Cc1ccc2c(c1)c(C(=O)NC(=N)N)cn2-c1nccc2ccccc12
Temperature: 20 °C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
0.457 g (19.8 mmol) of sodium is added at 20° C. under an argon atmosphere to 60 cm3 of methanol. After complete dissolution, 1.79 g (18.75 mmol) of guanidine hydrochloride are added. After stirring at 20° C. for 2 hours, the reaction mixture is filtered under an argon atmosphere. The filtrate is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is dissolved in 20 cm3 of 1,2-dimethoxyethane. 1.2 g of 3-chlorocarbonyl-1-(isoquinol-1-yl)-5-methyl-1H-indole hydrochloride, suspended in 40 cm3 of 1,2-dimethoxyethane, are subsequently added at 20° C. under an argon atmosphere. After stirring at 20° C. for 17.5 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is triturated in 20 cm3 of water. After stirring at 22° C. for 1 hour, the suspension is filtered and then dried to give a beige-coloured solid which is purified by flash chromatography [eluent: cyclohexane/ethyl acetate (7/3 by volume) and then dichloromethane/methanol/20% aqueous ammonia (18/3/0.5 by volume)]. After concentrating the fractions under reduced pressure, 1.2 g of a beige-coloured solid are obtained, which solid is triturated in 12 cm3 of N hydrochloric acid for 1 hour. After filtering off, the residue is recrystallised under hot conditions from 80 cm3 of methanol to give 0.885 g of 3-guanidinocarbonyl-1-(isoquinol-1-yl)-5-methyl-1H-indole hydrochloride in the form of beige-coloured crystals melting at 268° C. IR spectrum (KBr): 3350, 3092, 1693, 1625, 1524, 1462, 1406, 1216 and 832 cm−1.
Reaction SMILES: Cl.C(OC([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C@@H:20]2[CH2:22][C@H:21]2[CH3:23])=[O:19])=[CH:13][CH:12]=1)=O)(C)(C)C.C(OCC)C>O1CCOCC1>[CH3:23][C@@H:21]1[CH2:22][C@H:20]1[C:18]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][NH2:9])=[CH:16][CH:15]=1)=[O:19]
Reactant: C[C@@H]1C[C@H]1C(=O)Nc1ccc(CNC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: C[C@@H]1C[C@H]1C(=O)Nc1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
Add 4M hydrogen chloride in dioxane (17.7 mL) to a solution of (±)-trans-N-(tert-butoxycarbonyl)-4-[(2-methyl-cyclopropanecarbonyl)-amino]-benzylamine (1.72 g, 5.65 mmol) in dioxane (35.4 mL). Stir at room temperature overnight, add diethyl ether and concentrate in vacuo several times. Partition the residue between saturated aqueous NaHCO3 (200 mL) and DCM (500 mL). Extract the aqueous phase with DCM/iso-propanol (3:1, 4×200 mL). Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Load the compound into a SCX column (10 g), wash the column with DCM (100 mL), and then elute with 2M ammonia in methanol/DCM (1:1, 100 mL) to afford the title compound (0.935 g, 81%) as a waxy colorless oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[CH2:4][CH2:5][NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([Br:22])[CH:17]=3)[S:12][C:11]=2[C:10]([CH2:23][NH2:24])=[CH:9][CH:8]=1)[CH3:2].[CH3:27][S:28](Cl)(=[O:30])=[O:29].O.[OH-].[Na+]>N1C=CC=CC=1>[CH2:25]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([Br:22])[CH:17]=3)[S:12][C:11]=2[C:10]([CH2:23][NH:24][S:28]([CH3:27])(=[O:30])=[O:29])=[CH:9][CH:8]=1)[CH3:26]
Reactant: CCN(CC)CCNc1ccc(CN)c2sc3ccc(Br)cc3c(=O)c12
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: CCN(CC)CCNc1ccc(CNS(C)(=O)=O)c2sc3ccc(Br)cc3c(=O)c12
Temperature: 25 °C
Yield: 86.5 %

Procedure:
1-[[2-(Diethylamino)ethyl]amino]-4-(aminomethyl)-7-bromothioxanthen-9-one (1 g, 2.3 mmol) in 11.5 mL of dry pyridine under nitrogen was stirred in an ice bath for 15 min and 0.2 mL (2.6 mmol) of methanesulfonyl chloride in chilled pyridine was added dropwise and the mixture was stirred at room temperature. The reaction mixture was poured into 200 mL of water, added 0.19 g of sodium hydroxide in ice/water, and extracted into chloroform. The organic layer was washed with water (2×) and brine, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated in vacuo and the residue was stirred in ether, filtered, and dried to afford 1.02 g of N-[[1-[[2-(diethylamino) ethyl]amino]-7-bromo-9-oxothioxanthen-4-yl]methyl]methanesulfonamide, m.p. 134°-139° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:24]=[C:25]([CH:27]=[CH:28][C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]=4)[N:26]=3)[C:10]([C:13]3[CH:14]=[CH:15][C:16](/[C:19](=[N:22]\[H])/[NH:20][NH2:21])=[N:17][CH:18]=3)=[CH:11][N:12]=2)[CH2:3][CH2:2]1.O.[C:40]([O-])(O)=O.[Na+]>C(O)=O>[N:21]1[NH:20][C:19]([C:16]2[N:17]=[CH:18][C:13]([C:10]3[N:9]4[CH:24]=[C:25](/[CH:27]=[CH:28]/[C:29]5[CH:38]=[CH:37][C:36]6[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=6)[N:30]=5)[N:26]=[C:8]4[C:7]([N:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)=[N:12][CH:11]=3)=[CH:14][CH:15]=2)=[N:22][CH:40]=1
Reactant: O=C([O-])O
Reactant: [H]/N=C(/NN)c1ccc(-c2cnc(N3CCOCC3)c3nc(C=Cc4ccc5ccccc5n4)cn23)cn1
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: C(=C/c1cn2c(-c3ccc(-c4ncn[nH]4)nc3)cnc(N3CCOCC3)c2n1)\c1ccc2ccccc2n1
Temperature: 25 °C
Yield: 19 %

Procedure:
A solution of compound 5a (180 mg, 0.370 mmol) in formic acid (3 mL) was stirred in a 10 mL sealed tube at 100° C. for 2 h. After cooling to rt, water (20 mL) was added, and the pH of the solution was adjusted to 7 with saturated NaHCO3 solution. The resulting solids were collected by filtration and washed with Et2O to obtain the title compound 91 as a yellow solid (37 mg, 19% yield). 1H-NMR (300 MHz, DMSO-d6+D2O) δ (ppm): 8.96 (s, 1H), 8.72 (d, J=8.4 Hz, 1H), 8.38-8.32 (m, 4H), 8.19-8.06 (m, 4H), 8.01-7.91 (m, 1H), 7.74-7.68 (m, 2H), 7.58 (s, 1H), 4.45-4.25 (m, 4H), 3.90-3.70 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C28H23N9O: 502.2 (M+H). Found 502.3.
Reaction SMILES: C1C2C(CO[C:16]([NH:18][C@H:19]([C:44]([NH:46][C:47]3[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:48]=3[O:55][CH3:56])=[O:45])[CH2:20][CH2:21][C:22](=[O:43])[NH:23][C:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:17])C3C(=CC=CC=3)C=2C=CC=1.[OH:57][C:58]1[CH:59]=[C:60]([CH:64]=[CH:65][C:66]=1[OH:67])C(O)=O>>[OH:57][C:58]1[CH:59]=[C:60]([CH:64]=[CH:65][C:66]=1[OH:67])[C:16]([NH:18][C@H:19]([C:44]([NH:46][C:47]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:48]=1[O:55][CH3:56])=[O:45])[CH2:20][CH2:21][C:22](=[O:43])[NH:23][C:24]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:17]
Reactant: O=C(O)c1ccc(O)c(O)c1
Reactant: COc1ccc(OC)c(NC(=O)[C@H](CCC(=O)NC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)OCC2c3ccccc3-c3ccccc32)c1
Product: COc1ccc(OC)c(NC(=O)[C@H](CCC(=O)NC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)c2ccc(O)c(O)c2)c1

Procedure:
The title compound was prepared from N-[Nα-(9-fluorenylmethoxycarbonyl)-Nδ-trityl-L-glutaminyl]-2,5-dimethoxyaniline (531 mg, 0.7 mmol, example 82, step A) as described for example 82 (step B) using 3,4-dihydroxybenzoic acid (164 mg, 1.1 mmol) instead of caffeic acid. The crude material was purified by flash chromatography using first 10% then 30% EtOAc/CH2Cl2 containing 1% AcOH. The title compound was obtained as yellow crystals (164 mg, 35%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[CH:39]1([C:42](Cl)=[O:43])[CH2:41][CH2:40]1>C(Cl)Cl>[CH:39]1([C:42]([NH:1][C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]4[C:19](=[O:31])[N:20]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:21]([CH3:24])[C:22]=4[CH3:23])=[O:17])=[CH:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)=[O:43])[CH2:41][CH2:40]1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)cc2)c(=O)n(-c2ccccc2)n1C
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)C4CC4)c3)cc2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
To a solution of N-(4-((2-aminopyridin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (200 mg, 0.48 mmol) in DCM (5 mL) was added triethylamine (1 mL), followed by adding cyclopropanecarbonyl chloride (104.5 mg, 0.96 mmol) at 0° C. The reaction mixture was warmed to rt and stirred for 3 hours, then quenched with water (10 mL). The separated organic layer was added saturated aq. Na2CO3 (10 mL) and EtOH (30 mL). The mixture was stirred at rt for 30 minutes and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (v/v)=80/1) to give the title compound as a white solid (130 mg, 56%).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]=[CH:2]2.[C:8]([OH:11])(=[O:10])[CH3:9]>>[C:8]([O:11][C:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2)(=[O:10])[CH3:9]
Reactant: CC(=O)O
Reactant: C1=CC2CCC1C2
Product: CC(=O)OC12CCC(CC1)C2
Reaction time: 5.5 h
Yield: 95 %

Procedure:
To illustrate reaction of a cycloolefin in the process, a mixture of norbornene (bicyclo [2.2.1]-2-heptene) and acetic acid was reacted over HZSM-12 zeolite. The reaction was carried out on a steam bath at about 100° C. for 5.5 hours. The addition product, norbornyl acetate, was formed in about 95% yield.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:17])[C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].CCN(C(C)C)C(C)C.Cl.[NH2:31][CH2:32][CH2:33][C:34]([NH2:36])=[O:35].Cl>C(#N)C>[C:34]([CH2:33][CH2:32][NH:31][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:17])[C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19])(=[O:35])[NH2:36]
Reactant: NCCC(N)=O
Reactant: CN(C(=O)c1ccccc1)c1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN(C(=O)c1ccccc1)c1ccc(NCCC(N)=O)c([N+](=O)[O-])c1
Temperature: 80 °C

Procedure:
N-(4-fluoro-3-nitro-phenyl)-N-methyl-benzamide (1.47 g, 5.37 mmol) was taken up in dry acetonitrile under argon, DIEA (2.08 g, 16.11 mmol, 2.80 ml) and β-alanine amide hydrochloride (1.00 g, 8.06 mmol) were added. The reaction mixture was heated to 80° C. for 48 h. The reaction was poured into 1N HCl and the aqueous layer was extracted 3× with ethyl acetate. The combined organic layers were washed with water, brine and dried over magnesium sulfate. The solution was filtered and the solvent removed under reduced pressure. The residue was triturated twice with cold hexane and dried to give N-[4-(2-carbamoyl-ethylamino)-3-nitro-phenyl]-N-methyl-benzamide. (1.75 g, 95%)
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:60])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si](C(C)(C)C)(C)C)[CH:46]([O:58][CH3:59])[CH2:45]2)[CH:7]([CH3:61])[CH:6]([O:62][Si:63]([C:66]([CH3:69])([CH3:68])[CH3:67])([CH3:65])[CH3:64])[CH2:5][C:4]1=[O:70])[CH3:2].F>C(#N)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:60])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:58][CH3:59])[CH2:45]2)[CH:7]([CH3:61])[CH:6]([O:62][Si:63]([C:66]([CH3:67])([CH3:68])[CH3:69])([CH3:65])[CH3:64])[CH2:5][C:4]1=[O:70])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C)(C)C(C)(C)C)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: F
Solvent: CC#N
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 67.6 %

Procedure:
The product from Step 4A (500 mg) was dissolved in acetonitrile (20 ml) and 100 ml of hydrogen fluoride (48%) was added. The reaction was stirred for 20 minutes at room temperature, quenched with saturated sodium bicarbonate, then extracted with ethyl acetate. Removal of solvent in vacuo followed by chromatography on silica gel (80% ethyl acetate/hexane) gave 300 mg of product (Mass, 1H and 13C NMR data consistent with the title compound.