Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19](Br)=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[N:35][NH:36][CH:37]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19]([C:33]4[CH:34]=[N:35][NH:36][CH:37]=4)=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(Br)c2n1C
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(-c3cn[nH]c3)c2n1C
Temperature: 140 °C
Yield: 19.4 %

Procedure:
A mixture of 4-Amino-6-[(S)-1-(7-bromo-6-fluoro-1-methyl-1H-benzoimidazol-2-yl)ethylamino]-pyrimidine-5-carbonitrile, (0.10 g, 0.26 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.065 g, 0.33 mmol), tetrakis(triphenylphosphine)palladium(0) (0.015 g, 0.01 mmol) and caesium carbonate (0.17 g, 0.51 mmol) in dioxane (3 mL) and water (1.5 mL) was placed in a sealed tube and degassed with nitrogen for 5 minutes, then heated for 40 minutes at 140° C. by microwave irradiation. 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.10 g, 0.52 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.015 g, 0.01 mmol) were added and the resultant mixture heated for 80 minutes at 140° C. by microwave irradiation. The resulting mixture was loaded onto an Isolute® SCX-2 cartridge then washed with MeOH and the product eluted with 2M NH3/MeOH then concentrated in vacuo. The residue was purified by chromatography eluting with (SiO2, 0-10% (2M ammonia in methanol) in DCM) then by preparative HPLC (Phenomenex Gemini 5 μm C18 on a 78 min gradient 20-98% 0.1% HCO2H in acetonitrile/water) to give 428 as a white solid (0.019 g, 20%). LCMS (Method K): RT 2.23 min [M+H]+ 378.0. 1H NMR (DMSO-d6, 400 MHz): δ 13.10 (1H, s), 8.28 (1H, s), 8.04 (1H, s), 7.83 (1H, s), 7.66-7.64 (1H, m), 7.60 (1H, dd, J=8.74, 4.77 Hz), 7.31 (2H, s), 7.12-7.06 (1H, m), 5.66-5.61 (1H, m), 3.66 (3H, s), 1.57 (3H, d, J=6.73 Hz)
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].C([O-])(=O)C.[Pb+4:17].[Br:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:28])=[C:23](B(O)O)[CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].[Br:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:28])=[C:23]([Pb+3:17])[CH:24]=1
Reactant: OB(O)c1cc(Br)ccc1Cl
Reactant: [Pb+4]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Clc1ccc(Br)cc1[Pb+3]
Temperature: 40 °C
Yield: 91.8 %

Procedure:
To a mixture of lead tetraacetate (26.83 g, 61 mmol) and mercuric diacetate (0.77 g, 2.4 mmol), thoroughly flushed with nitrogen, is added anhydrous chloroform (50 ml) and the reaction mixture is stirred and heated to 40° C. 5-Bromo-2-chlorophenylboronic acid (11.39 g, 48 mmol) is added in one portion, and the reaction mixture is stirred at 40° C. for 4 hours. After cooling to room temperature potassium carbonate (3.34 g) is added, the mixture stirred vigorously for 5 minutes and then filtered. The filtrate is concentrated in vacuo to give 5-bromo-2-chlorophenyllead triacetate (25.33 g), used without further purification in the next step.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]2[CH2:20][CH2:19][C@@:13]3([NH:17][C:16](=[O:18])[O:15][CH2:14]3)[CH2:12]2)=[CH:7][CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:40][O:41][C:42]1[CH:43]=[C:44](O)[CH:45]=[CH:46][CH:47]=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>C1COCC1>[CH3:40][O:41][C:42]1[CH:47]=[C:46]([CH:45]=[CH:44][CH:43]=1)[O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C@@H:11]2[CH2:20][CH2:19][C@@:13]3([NH:17][C:16](=[O:18])[O:15][CH2:14]3)[CH2:12]2)=[CH:9][CH:10]=1
Reactant: COc1cccc(O)c1
Reactant: O=C1N[C@@]2(CC[C@@H](c3ccc(CCCO)cc3)C2)CO1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cccc(OCCCc2ccc([C@@H]3CC[C@]4(COC(=O)N4)C3)cc2)c1
Yield: 70.8 %

Procedure:
To a solution of (5R,7R)-7-(4-(3-hydroxypropyl)phenyl)-3-oxa-1-azaspiro[4.4]nonan-2-one (5.2 g, 18.89 mmol) in THF (150 mL) was added PS-triphenylphosphine 3 mmol/g (7.43 g, 28.3 mmol) followed by 3-methoxyphenol (2.457 mL, 22.66 mmol). After about 10 minutes a solution of di-tert-butylazodicarboxylate (5.22 g, 22.66 mmol) in THF (10 mL) was added. After about 4 hours the reaction mixture was filtered, rinsing with DCM and EtOAc. The filtrate was concentrated in vacuo and purified by chromatography on silica gel (DCM/EtOAc) to provide (5R,7R)-7-(4-(3-(3-methoxyphenoxy)propyl)phenyl)-3-oxa-1-azaspiro[4.4]nonan-2-one (5.1 g, 13.37 mmol, 70.8% yield) as a colorless solid.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[OH-].[Na+].Cl[C:17]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:18]=1[C:19]#[N:20].O>CS(C)=O>[CH3:1][N:2]([CH3:13])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:17]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:18]=2[C:19]#[N:20])=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: CN(C)S(=O)(=O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CN(C)S(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])cc2C#N)cc1
Temperature: 60 °C
Yield: 79.9 %

Procedure:
To a solution of 6.37 g (0.0317 moles) of N,N-dimethyl-4-hydroxybenzenesulfonamide in 150 ml of DMSO was added 1.27 g (0.0317 moles) of NaOH. The mixture was heated to 60° C. and 5.26 g (0.288 moles) of 2-chloro-5-nitrobenzonitrile added and the mixture heated at 75° C. for 21/2 hrs. The reaction mixture was cooled and poured into a solution of 400 ml of 2 N aqueous NaOH and 300 ml of water. The product was collected by filtration, washed well with water and dried to obtain 8.8 g of product (88% yield). Recrystallization from a mixture of ethanol and dimethylformamide afforded purified N,N-dimethyl-4-(2-cyano-4-nitrophenoxy)benzenesulfonamide, mp 221.5°-223° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[CH:11][CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:18]([O:20][C:21](=[O:31])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=1)[CH3:19]>>[CH2:18]([O:20][C:21](=[O:31])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:15]([C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:14]=2)=[O:17])[CH:25]=1)[CH3:19]
Reactant: O=C(O)c1cccc(-c2cc(Cl)cc(Cl)c2)n1
Reactant: CCOC(=O)COc1cccc(N)c1
Product: CCOC(=O)COc1cccc(NC(=O)c2cccc(-c3cc(Cl)cc(Cl)c3)n2)c1

Procedure:
Carboxylic acid (131) (50 mg, 0.19 mmol) was coupled to aniline (64) (40 mg, 0.21 mmol) using Method D. The residue was triturated with TBME (3 ml) to give the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[S:6][C:7]=1[CH2:8]Cl.[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([NH2:26])(=[O:25])=[O:24])([O-:16])=[O:15].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:26]1[CH2:2][C:3]2[CH:4]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[S:6][C:7]=2[CH2:8]1)(=[O:24])=[O:25])([O-:16])=[O:15]
Reactant: NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: COC(=O)c1cc(CCl)c(CCl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1cc2c(s1)CN(S(=O)(=O)c1ccccc1[N+](=O)[O-])C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of methyl 4,5-bis(chloromethyl)thiophene-2-carboxylate (4.106 g, 17.17 mmol) and 2-nitrobenzenesulfonamide (3.825 g, 18.92 mmol) in acetone (40 mL) was added 2.5 M of potassium carbonate in water (20 mL, 50 mmol). The resulting biphasic mixture was stirred at room temperature for 1 hour then further heated at 45° C. overnight resulting in formation of precipitate. The reaction mixture was cooled to room temperature and the precipitate was collected by vacuum filtration. The solid obtained was washed with water followed by cold methanol and dried under vacuum to afford an off white solid (3.352 g, 53%). LCMS (FA) ES+ 369; 1H NMR (400 MHz, DMSO) δ 8.02 (ddd, J=7.8, 4.9, 1.4 Hz, 2H), 7.90 (td, J=7.7, 1.5 Hz, 1H), 7.84 (td, J=7.7, 1.4 Hz, 1H), 7.63 (s, 1H), 4.79 (t, J=2.9 Hz, 2H), 4.60 (t, J=2.9 Hz, 2H), 3.80 (s, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].[CH:16]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:16]([N:19]1[CH2:24][CH2:23][N:22]([CH2:2][CH2:3][CH2:4][N:5]2[C:9](=[O:10])[C:8]3=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]3[C:6]2=[O:15])[CH2:21][CH2:20]1)([CH3:18])[CH3:17]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: CC(C)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)N1CCN(CCCN2C(=O)c3ccccc3C2=O)CC1
Reaction time: 4 h
Yield: 122.8 %

Procedure:
To the solution of N-(3-bromopropyl)phthalimide (30.1 g) in acetone (200 ml) were added 1-isopropyl piperazine (23.0 g) and potassium carbonate (41.4 g). The resulting mixture was refluxed with stirring for 4 hours. The reaction maxture was cooled and then filtered. The filter cake was washed with acetone. The filtrate and washing were combined and evaporated under reduced pressure to give an oil of N-[3-(4-isopropyl-1-piperazinyl)propyl]phthalimide (43.5 g).
Reaction SMILES: [F:1][CH:2]([F:38])[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH3:37])=[CH:10][C:11]=2[CH:13]([O:15][CH2:16][C:17]2([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:22][CH2:21][N:20]([C:23](OC(C)(C)C)=O)[CH2:19][CH2:18]2)[CH3:14])[CH:6]=[N:5]1.C([BH3-])#N.[Na+].C=O>FC(F)(F)C(O)=O.C(O)(=O)C>[F:38][CH:2]([F:1])[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH3:37])=[CH:10][C:11]=2[CH:13]([O:15][CH2:16][C:17]2([C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]2)[CH3:14])[CH:6]=[N:5]1
Reactant: Cc1cc(C(C)OCC2(c3ccc(F)cc3)CCN(C(=O)OC(C)(C)C)CC2)c2c(cnn2CC(F)F)c1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: Cc1cc(C(C)OCC2(c3ccc(F)cc3)CCN(C)CC2)c2c(cnn2CC(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(±)-tert-Butyl 4-((1-(1-(2,2-difluoroethyl)-5-methyl-1H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (10 mg, 0.02 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 1 mL) and stirred at room temperature for 1 h. The reaction was concentrated, loaded onto a strong cation exchange cartridge in methanol, and flushed with several volumes of methanol which were discarded. The crude secondary amine was eluted in 2 M ammonia in methanol and concentrated. The resulting residue was dissolved in acetonitrile (1 mL), cooled to 0° C., and treated with sodium cyanoborohydride (5.9 mg, 0.01 mmol) and formalin (0.52 mL). After 5 min, the reaction was treated with a few drops of acetic acid. The ice bath was removed and stirring continued for 1 h. The reaction was concentrated and purified by column chromatography (10% methanolic ammonia/methylene chloride) to afford 4 mg (47%) as a clear oil. LC/MS (HPLC method 1): tR=2.35 min, 446.56(MH)+.
Reaction SMILES: C([N:3]1CC[CH:6](C(O)=O)[CH2:5][CH2:4]1)C.[CH2:12]([O:14][C:15]([CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])[CH3:13].C(#N)C=C>C(O)(C)C>[CH2:12]([O:14][C:15]([CH:17]1[CH2:22][CH2:21][N:20]([CH2:6][CH2:5][C:4]#[N:3])[CH2:19][CH2:18]1)=[O:16])[CH3:13]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CCN1CCC(C(=O)O)CC1
Solvent: CC(C)O
Solvent: C=CC#N
Product: CCOC(=O)C1CCN(CCC#N)CC1
Yield: 101.5 %

Procedure:
A solution of piperidine-4-carboxylic acid ethyl ester (ethylisonipecotate) (4.7 g, 30 mmol), acrylonitrile (1.7 g, 31 mmol) in isopropyl alcohol (30 ml) was stirred at room temperature for 15 hours, then evaporated to dryness to afford 1-(2-cyano-ethyl)-piperidine-4-carboxylic acid ethyl ester as an oil (6.4 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:17](=[O:20])(=[O:19])[NH2:18])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([OH:7])=[O:6].[CH2:21](I)[CH2:22][CH2:23][CH3:24].O>C(O)CCC>[CH2:21]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:17](=[O:20])(=[O:19])[NH2:18])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([O:7][CH2:3][CH2:2][CH2:10][CH3:9])=[O:6])[CH2:22][CH2:23][CH3:24]
Reactant: CCCCI
Reactant: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1-c1ccccc1
Solvent: O
Solvent: CCCCO
Product: CCCCNc1cc(C(=O)OCCCC)cc(S(N)(=O)=O)c1-c1ccccc1

Procedure:
A solution of 3-amino-4-phenyl-5-sulfamylbenzoic acid (1.46 g) and n-butyl iodide (1.5 ml) in n-butanol (20 ml) is refluxed for 3-4 days under such conditions, that the water formed during the reaction is separated. After 12, 24, 36 and 48 hours, additional amounts of n-butyl iodide (each time 0.75 ml) are added. The resulting solution is evaporated in vacuo, and the obtained crude n-butyl 3-n-butylamino-4-phenyl-5-sulfamylbenzoate is saponified by heating with 2 N sodium hydroxide (20 ml) for 30 minutes. After cooling, the resulting solution is acidified with 4 N hydrochloric acid (12 ml) to precipitate 3-n-butylamino-4-phenyl-5-sulfamylbenzoic acid, which is collected by filtration, washed with water and dried. After recrystallization from aqueous ethanol, the acid is obtained with a melting point of 134°-136° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])(C)(C)C.C(O[C:30](=[O:53])[CH2:31][C:32](=O)[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[S:40][CH:41]=[C:42]([CH2:44][O:45]C3CCCCO3)[N:43]=2)[CH:34]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:45][CH2:44][C:42]1[N:43]=[C:39]([C:35]2[CH:34]=[C:33]([C:32]3[CH2:31][C:30](=[O:53])[NH:23][C:9]4[CH:10]=[C:11]([C:19]([F:20])([F:21])[F:22])[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:13][C:8]=4[N:7]=3)[CH:38]=[CH:37][CH:36]=2)[S:40][CH:41]=1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2nc(COC3CCCCO3)cs2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3nc(CO)cs3)c1)=N2

Procedure:
The title compound was prepared from [2-amino-5-(methyl-propyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (0.17 g) (Example J35) and 3-oxo-3-[3-[4-(tetrahydro-pyran-2-yloxymethyl)-thiazol-2-yl]-phenyl]-propionic acid tert-butyl ester (Example K27) (0.23 g) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (0.06 g).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:5]=1[CH2:6][NH:7][C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][N:11]=[C:10](Cl)[N:9]=1.[F:23][C:24]1[CH:25]=[CH:26][C:27]([N+:31]([O-:33])=[O:32])=[C:28]([CH:30]=1)[NH2:29]>C1COCC1>[F:3][C:4]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:5]=1[CH2:6][NH:7][C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][N:11]=[C:10]([NH:29][C:28]2[CH:30]=[C:24]([F:23])[CH:25]=[CH:26][C:27]=2[N+:31]([O-:33])=[O:32])[N:9]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1NCc1c(F)cccc1F
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1Nc1ncc([N+](=O)[O-])c(NCc2c(F)cccc2F)n1
Reaction time: 0.5 h
Yield: 11.4 %

Procedure:
Under an argon atmosphere, sodium hydride (100 mg) was added to a solution of N-(2,6-difluorobenzyl)-2-chloro-5-nitropyrimidin-4-amine (150 mg) and 5-fluoro-2-nitroaniline (78 mg) in THF (10 mL) at RT. The mixture was stirred for 30 min, quenched via the addition of sat. aq. NH4Cl, extracted with DCM and purified by preparative HPLC to give a low yield of N4-(2,6-difluorobenzyl)-N2-(5-fluoro-2-nitrophenyl)-5-nitropyrimidine-2,4-diamine (75) (24 mg), MH+=421.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[N:11]=[CH:12][N:13]=[C:14]3[C:21]=2[C:20]2[CH2:19][CH2:18][CH2:17][C:16]=2[S:15]3)[CH2:5][CH2:4]1.Cl[CH2:23][C:24]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:25].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][N:2]([CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[N:11]=[CH:12][N:13]=[C:14]3[C:21]=2[C:20]2[CH2:19][CH2:18][CH2:17][C:16]=2[S:15]3)[CH2:5][CH2:4]1)[CH2:23][C:24]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:25]
Reactant: CNC1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Reactant: O=C(CCl)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(CC(=O)N1CCOCC1)C1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.9 %

Procedure:
Note: For the preparation of the starting material compound 1, see Example 147. To a solution of 1-N-methyl-4-N-[7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yl]cyclohexane-1,4-diamine (90 mg, 0.30 mmol, 1.00 equiv) in DMF (10 mL) was added 2-chloro-1-(morpholin-4-yl)ethan-1-one (73.35 mg, 0.45 mmol, 1.50 equiv) and potassium carbonate (83 mg, 0.60 mmol, 2.00 equiv) at room temperature under nitrogen. The resulting solution was stirred overnight at ambient temperature. After completion of the reaction, the solids were removed by filtration and the filtrate was concentrated under vacuum. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (SHIMADZU): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% NH4HCO3 and CH3CN (6.0% CH3CN up to 50.0% in 19 min); Flow rate, 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the desired 2-[methyl[4-([7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yl]amino)cyclohexyl]amino]-1-(morpholin-4-yl)ethan-1-one (30.8 mg) as a white solid. MS (ES, m/z): 430 (M+H+). NMR (400 MHz, CD3OD-do): δ 8.23 (s, 1H), 4.05-4.08 (m, 1H), 3.67-3.68 (m, 6H), 3.59-3.60 (m, 2H), 3.40 (s, 2H), 3.08 (t, 2H), 3.01 (t, 2H), 2.52-2.59 (m, 3H), 2.34 (s, 3H), 2.16-2.19 (m, 2H), 1.93-1.96 (m, 2H), 1.45-1.57 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[N-:10]=[N+:11]=[N-:12].[Na+].C(N(CC)CC)C>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[N:10]=[N:11][NH:12][N:9]=2)[CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cncc(Br)c1
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: Brc1cncc(-c2nn[nH]n2)c1
Temperature: 25 °C

Procedure:
A solution of 3-bromo-5-cyanopyridine (1 eq), sodium azide (1.2 eq), triethylamine (1.2 eq) and AcOH (1.2 eq) was stirred at 100C for 14 h. The reaction mixture was cooled to rt, diluted with aqueous acetic acid solution and extracted with EtOAc. The organic extracts were washed with brine, dried over MgSO4, filtered and concentrated to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([OH:12])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:16])=O.CN(C)C=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([Cl:16])=[O:12])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)/C=C/c1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)/C=C/c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of (2E)-3-(4-chlorophenyl)prop-2-enoic acid (2.0 g, 11 mmol) in 50 mL methylene chloride was added oxalyl chloride (1.05 mL, 12.1 mmol) and N,N-dimethylformamide (0.05 mL, 0.6 mmol). The resulting mixture was stirred at r.t. for 6 h. The solvent was removed under vacuum. The resulting solid was diluted with hexanes and the solvent removed under vacuum to provide an off-white solid which was used without further purification.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([NH2:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](Cl)(=O)[CH2:18][CH3:19].C(=O)(O)[O-].[Na+]>ClC(Cl)Cl>[CH2:18]([C:19]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[C:9]([C:10](=[O:11])[N:12]=1)=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH3:17]
Reactant: CCC(=O)Cl
Reactant: NC(=O)c1ccccc1Nc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCc1nc(=O)c2ccccc2n1-c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
2.0 g (9.42 mmol) 2-phenylamino-benzamide were dissolved in 30 ml trichloromethane the solution was cooled to 0° C., and 2.61 g (2.44 ml, 28.2 mmol) propionyl chloride was added slowly. The mixture was boiled for 90 minutes and afterwards neutralized with a saturated sodium bicarbonate solution. After evaporation the substance was crystallized from isopropanol.
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][NH:5][CH3:6].C(=O)([O-])[O-].[K+].[K+].[Br:13][C:14]1[CH:18]=[C:17]([C:19]2[O:24][C:23](=[O:25])[C:22]3[CH:26]=[C:27]([N+:31]([O-:33])=[O:32])[CH:28]=[C:29]([CH3:30])[C:21]=3[N:20]=2)[N:16]([C:34]2[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][N:35]=2)[N:15]=1>O.CN(C)C=O>[Br:13][C:14]1[CH:18]=[C:17]([C:19]([NH:20][C:21]2[C:29]([CH3:30])=[CH:28][C:27]([N+:31]([O-:33])=[O:32])=[CH:26][C:22]=2[C:23]([N:4]([CH3:3])[NH:5][CH3:6])=[O:25])=[O:24])[N:16]([C:34]2[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][N:35]=2)[N:15]=1
Reactant: CNNC
Reactant: Cc1cc([N+](=O)[O-])cc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNN(C)C(=O)c1cc([N+](=O)[O-])cc(C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 0.26 g of N,N′-dimethylhydrazine dihydrochloride, 2 ml of water, 0.5 g of potassium carbonate and 10 ml of N,N-dimethylformamide was added 0.20 g of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-8-methyl-6-nitro-4H-3,1-benzoxazine-4-one. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and extracted with ethyl acetate three times. The organic layers were combined, washed successively with water and an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 3-bromo-1-(3-chloro-2-pyridinyl)-N-[2-(N,N′-dimethylhydrazinocarbonyl)-6-methyl-4-nitrophenyl]-1H-pyrazole-5-carboxamide of the formula:
Reaction SMILES: C(C1[CH:18]=[CH:17][C:6]2[O:7][CH2:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11](=[O:12])[C:5]=2[CH:4]=1)#N.Cl.[C:20]([OH:23])(=[O:22])[CH3:21]>O>[O:12]=[C:11]1[C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[CH2:8][O:7][C:6]2[CH:17]=[CH:18][C:21]([C:20]([OH:23])=[O:22])=[CH:4][C:5]1=2
Reactant: CC(=O)O
Reactant: N#Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Agent: Cl
Solvent: O
Product: O=C(O)c1ccc2c(c1)C(=O)c1ccccc1CO2

Procedure:
Reflux 27.3 gm. of 2-cyano-6,11-dihydro-11-oxodibenz[b,e]oxepin in a mixture of 300 cc. of 37% aqueous hydrochloric acid and 300 cc. of glacial acetic acid for 24 hours. Cool, dilute with water and separate the solids by filtration in order to obtain the title product (m.p. 250° C. dec.).