Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([NH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:12])[CH2:4][CH2:3]1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: NC1CCN(CCCC(=O)c2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NC1CCN(CCCC(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Amino-1-(4-phenyl-4-oxobutyl)piperidine (1.23 g. 0.005 m) was suspended in a solution of dichloromethane (10 mls) containing triethylamine (2 mls). Methanesulphonyl chloride (0.570 g, 0.005 m) in dichloromethane (5 mls) was added dropwise over 5 minutes and the reaction stirred overnight at room temperature. The solution was then washed with five aliquots of water and dried over magnesium sulphate. Evaporation yielded the free base in 90% purity. This was triturated in ethyl acetate and warmed. The mother liquor was decanted off and evaporated to yield the title compound m.pt 141.4° C. This was recrystallised from ethanolic HCl as the hydrochloride salt (0.510 g), m.pt 167.4° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[O:16][C:15]([NH:18][C:19]4[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=4)=[N:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>N1C=CC=CC=1>[CH3:26][O:25][C:23]1[CH:24]=[C:19]([NH:18][C:15]2[O:16][C:17]3[C:9]([C:6]4[CH:7]=[CH:8][C:3]([CH2:2][NH:1][S:32]([CH3:31])(=[O:34])=[O:33])=[CH:4][CH:5]=4)=[CH:10][CH:11]=[CH:12][C:13]=3[N:14]=2)[CH:20]=[C:21]([O:29][CH3:30])[C:22]=1[O:27][CH3:28]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(Nc2nc3cccc(-c4ccc(CN)cc4)c3o2)cc(OC)c1OC
Solvent: c1ccncc1
Product: COc1cc(Nc2nc3cccc(-c4ccc(CNS(C)(=O)=O)cc4)c3o2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 0.10 g (0.247 mmol) [7-(4-aminomethyl-phenyl)-benzooxazol-2-yl]-(3,4,5-trimethoxy-phenyl)-amine (example 29) and 0.037 g (0.32 mmol) methanesulfonyl chloride in 4 ml pyridine is stirred for 1.5 h at room temperature. Then the reaction mixture is poured on water and extracted 3× with EtOAc. The combined organic layers are washed with 0.1N NaOH solution and water, dried over MgSO4, filtered and the filtrate is concentrated in vacuo and co-evaporated twice with toluene. The residue is purified by crystallisation from dichloromethane to afford the title compound as off-white crystals. Rt=2.20 min (Waters Symmetry C8, 2.1×50 mm, detection 210-250 nM, 5% to 100% CH3CN in H2O in 2 min+0.05% TFA, flow rate 1.0 ml/min); MS: 474 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1>C(O)C>[OH:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1)c1ccc(O)cc1
Solvent: CCO
Product: Nc1ccc(NC(=O)c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 23.3 h

Procedure:
A portion (44.1 grams, 0.1708 mole) of 4-hydroxy-4'-nitrobenzanilide from A. above and ethanol (300 milliliters) are added to a 400 milliliter heavy walled glass bottle then sparged with nitrogen. After removal of air by nitrogen sparging, Raney nickel catalyst (5.5 grams of a 75% wt. slurry in water at pH 10) is added to the slurry in the glass bottle which is then stoppered and multiply purged with hydrogen to replace the nitrogen atmosphere. The bottle is then placed on a shaking type agitator, and pressurized to 48 psig hydrogen. Shaking of the pressurized slurry at room temperature (25° C.) commences until 23.3 hours later, the hydrogen pressure reading indicates that 47 psig of hydrogen has been consumed. By the completion of the hydrogenation, the light yellow colored reactant slurry became a light pink tan colored product slurry. The product slurry is recovered, diluted into dimethylsulfoxide (300 milliliters) to provide a solution of product containing precipitated Raney nickel, then filtered through a medium porosity fritted glass funnel. The recovered dimethylsulfoxide product solution is rotary evaporated at 130° C. under vacuum to provide a powder product. The powder product is further dried at 120° C. under vacuum to a constant weight of 38.94 grams (99.88% isolated yield). Fourier transform infrared spectrophotometric analysis of a nujol mull of a portion of the product on a sodium chloride plate revealed the presence of absorbances at 3376 (shoulder), 351 (shoulder), 3316 (sharp) and 3282 (shoulder) cm-1 due to secondary amide group N--H stretching (solid state), primary amine N--H group stretching and hydroxyl group O--H stretching: the secondary amide carbonyl stretching (solid state) at 1645 cm-1 (sharp): and complete disappearance of the conjugated nitro group absorbances at 1537 and 1339 cm-1 (sharp). Proton magnetic resonance spectroscopy (250 MHz) further confirmed the product structure as 4-hydroxy-4'-aminobenzanilide.
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[Na+].CN(C)C(=O)C.[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]2[NH:30][C:29](=[O:31])[C:28]([CH3:33])([CH3:32])[C:27](=[O:34])[N:26]([CH3:35])[C:25]=2[CH:36]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(I)C>O>[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]2[N:30]([CH2:1][CH3:2])[C:29](=[O:31])[C:28]([CH3:33])([CH3:32])[C:27](=[O:34])[N:26]([CH3:35])[C:25]=2[CH:36]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CN1C(=O)C(C)(C)C(=O)Nc2ccc(OCc3ccccc3)cc21
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCI
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCc3ccccc3)ccc21
Reaction time: 0.5 h
Yield: 91 %

Procedure:
Under ice cooling, sodium t-butoxide (1.96 g, 20.4 mmol) was added to a N,N-dimethylacetamide (30 mL) solution of 8-benzyloxy-1,3,3-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (6.0 g, 18.5 mmol), and the mixture was stirred for 30 minutes. 1.63 mL (20.4 mmol) of ethyl iodide was added dropwise. The reaction solution was stirred at 10-20° C. for 4 hours. Water (42 mL) was added to the reaction solution, and the mixture was stirred at 10° C. or less for 30 minutes. Thereafter, precipitated crystals were collected by filtration, and the crystals were added to methanol (60 mL). The resultant was heated under reflux, and stirred at 10° C. or less for 30 minutes. Crystals were collected by filtration, then washed with methanol, and dried at 60° C., thereby obtaining 5.90 g of a white, powdery target compound (yield: 91%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][C:9]([C:11](=[O:14])[CH2:12][CH3:13])=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br-:15].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>>[Br:15][CH:12]([CH3:13])[C:11]([C:9]1[S:8][C:7]2[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=2[CH:10]=1)=[O:14]
Reactant: [Br-]
Reactant: CCC(=O)c1cc2cccc(Cl)c2s1
Agent: C[N+](C)(C)c1ccccc1
Product: CC(Br)C(=O)c1cc2cccc(Cl)c2s1
Yield: 230.4 %

Procedure:
In a similar manner to Example 18, methylthioglycolate (13 g) was reacted with 3-chloro-2-fluorobenzaldehyde (19.57 g) in dimethylformamide to give methyl 7-chlorobenzo[b]thiophene-2-carboxylate, which was hydrolysed, chlorinated and reacted with N,O-dimethylhydroxylamine hydrochloride to give 7-chloro-N-methoxy-N-methylbenzo[b]thiophene-2-carboxamide, which was reacted with ethylmagnesium bromide to give 1-(7-chlorobenzo[b]thiophen-2-yl)propan-1-one. This ketone (1.17 g) was reacted with phenyltrimethylammonium tribromide (2.15 g) to give 2-bromo-1-(7-chlorobenzo[b]thiophen-2-yl)propan-1-one (2.32 g) which was used without further purification.
Reaction SMILES: [O:1]1[CH2:6][CH:5]([O:7][C:8](=[O:30])[NH:9][C@@H:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@H:11]([OH:22])[CH2:12][NH:13][CH2:14][C:15]([CH3:21])([CH3:20])[CH2:16][CH2:17][C:18]#[N:19])[CH2:4][O:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[O:40]1[C:44]2[CH:45]=[CH:46][C:47]([S:49](Cl)(=[O:51])=[O:50])=[CH:48][C:43]=2[O:42][CH2:41]1>C(Cl)Cl>[O:1]1[CH2:6][CH:5]([O:7][C:8](=[O:30])[NH:9][C@@H:10]([CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C@H:11]([OH:22])[CH2:12][N:13]([S:49]([C:47]2[CH:46]=[CH:45][C:44]3[O:40][CH2:41][O:42][C:43]=3[CH:48]=2)(=[O:50])=[O:51])[CH2:14][C:15]([CH3:21])([CH3:20])[CH2:16][CH2:17][C:18]#[N:19])[CH2:4][O:3][CH2:2]1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OCO2
Reactant: CC(C)(CCC#N)CNC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC1COCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(CCC#N)CN(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC1COCOC1)S(=O)(=O)c1ccc2c(c1)OCO2
Yield: 73.4 %

Procedure:
[(1S,2R)-1-Benzyl-3-(4-cyano-2,2-dimethyl-butylamino)-2-hydroxy-propyl]-carbamic acid [1,3]dioxan-5-yl ester (0.059 g, 0.14 mmol) was dissolved in CH2Cl2 and treated with diisopropylethylamine (0.075 ml, 0.42 mmol) and Benzo[1,3]dioxole-5-sulfonyl chloride (0.037 g, 0.17 mmol) at ambient temperature under argon with stirring. After 15 h the reaction mixture was concentrated in vacuo, taken up in EtOAc, washed with sat. aq. NaHCO3, and brine. The organic phase was dried over MgSO4, filtered and solvent removed in vacuo. Purification by column chromatography (1% to 3% MeOH in CH2Cl2) gave 0.062 g of a white solid. MS (ES): 604 (M+1).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.[CH3:25][C:26]1[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:27]=1[C:28]([NH:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][C:32]=1[Cl:40])=[O:29]>C(Cl)Cl>[CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][N:6]([C:35]([C:34]3[CH:38]=[CH:39][C:31]([NH:30][C:28](=[O:29])[C:27]4[CH:41]=[CH:42][CH:43]=[C:44]([F:45])[C:26]=4[CH3:25])=[C:32]([Cl:40])[CH:33]=3)=[O:36])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)CNc1ccccc1C2
Reactant: Cc1c(F)cccc1C(=O)Nc1ccc(C(=O)Cl)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(F)cccc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.1 %

Procedure:
A mixture of 1.0 g of 6,11-dihydro-5H-dibenz-[b,e]azepine, 0.80 g of N,N-diisopropylethylamine and 2.01 g of 4-[(2-methyl-3-fluorobenzoyl)amino]-3-chlorobenzoyl chloride in 100 ml of methylene chloride is stirred at room temperature for 18 hours. The reaction mixture is washed with water, saturated NaHCO3, dried (Na2SO4) and passed through a pad of hydrous magnesium silicate. Hexane is added to the filtrate at the boil to give 1.79 g of the desired product as a crystalline solid, m.p. 254°-256° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C@@H:20]([OH:24])[CH:21]([CH3:23])[CH3:22])[C:13]([O:15]C(C)(C)C)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C@@H:20]([OH:24])[CH:21]([CH3:22])[CH3:23])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@H](O)[C@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](O)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 109.9 %

Procedure:
A solution of tert-butyl (2S,3S)-2-{[(benzyloxy)carbonyl]amino}-3-hydroxy-4-methylpentanoate (400 mg, 1.19 mmol) in methylene chloride (7 ml) was cooled to 0° C. under nitrogen atmosphere. To this solution was added trifluoroacetic acid (10 ml), and the resulting mixture was warmed up to room temperature and stirred for 2.5 hours. The volatiles were removed in vacuo to provide (2S,3S)-2-{[(benzyloxy)carbonyl]amino}-3-hydroxy-4-methylpentanoic acid (368 mg, 100%) as an orange oil.
Reaction SMILES: O=[C:2]([C:8]1[S:12][CH:11]=[N:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(O)C.C([O-])(=O)C.[Na+].Cl.[NH2:22][OH:23]>CCCCCC.C(OCC)(=O)C>[OH:23][N:22]=[C:2]([C:8]1[S:12][CH:11]=[N:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: NO
Reactant: CCOC(=O)C(=O)c1cncs1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=NO)c1cncs1
Temperature: 85 °C
Yield: 93.5 %

Procedure:
To a r.b. flask (500 cm3) was added the ethyl oxo-thiazol-5-ylacetate (6.30 g, 34.02 mmol) to ethanol (ca. 180 cm3) with stirring. Sodium acetate (3.06 g, 37.30 mmol) and hydroxylamine hydrochloride (3.78 g, 54.43 mmol) were then added to give an off-white suspension. This was brought to reflux at 85° C. for 1 hour. Reaction monitored by TLC (60% hexane/ethyl acetate; s.m. r.f 0.5, prod. r.f. 0.3.). Reaction cooled and concentrated in vacuo. Product taken up in ethyl acetate (c.a. 200 cm3) and washed with 5% hydrochloric acid solution. Ethyl acetate layer was dried over magnesium sulphate and evaporated to dryness to give a cream solid (6.372 g, 31.825 mmol) [94% Yield].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C@@H:9]([NH:13]C(=O)OC(C)(C)C)[CH2:8][O:7][C:6]=2[CH:21]=1.[C:22]([OH:28])([C:24]([F:27])([F:26])[F:25])=[O:23]>ClCCl>[F:25][C:24]([F:27])([F:26])[C:22]([OH:28])=[O:23].[NH2:13][C@H:9]1[CH2:8][O:7][C:6]2[CH:21]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[NH:11][C:10]1=[O:12]
Reactant: Cc1ccc2c(c1)OC[C@H](NC(=O)OC(C)(C)C)C(=O)N2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2c(c1)OC[C@H](N)C(=O)N2
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 103 %

Procedure:
(S)-tert-butyl 8-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (2.50 g, 8.55 mmol, Eq: 1.00) was dissolved in dichloromethane (DCM, 10 mL) at 0° C. and TFA (10 mL) was added. The mixture was stirred at 0° C. for 1.5 h and concentrated to give the title compound (2.69 g, 103%) which was used without purification.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[OH-].[CH2:7]([N+:14](C)(C)C)[C:8]1C=CC=C[CH:9]=1.C(#N)C=C>C(O)(=O)C>[CH2:1]([O:5][CH:8]([CH3:9])[C:7]#[N:14])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCO
Reactant: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C=CC#N
Product: CCCCOC(C)C#N
Yield: 74 %

Procedure:
A mixture of 148 grams (2.0 moles) of n-butanol and 2.0 grams of 40% benzyltrimethylammonium hydroxide (Triton B) is combined in a 1 liter 4-neck round bottom flask stirred at reflux while 106 grams (2.0 moles) of acrylonitrile is added at a rate such that the temperature does not exceed 45° C. The mixture is stirred an hour after all the acrylonitrile has been added, made acidic with acetic acid, and fractionated under vacuum through a Vigreux column. The product boils at 75° C./2 mm (literature value: 98° C./20 mm). The product totalled 188.0 grams of 99.0% pure material which constituted a 74.0% yield. The density of the product was determined to be 0.93 grams/ml. The nuclear magnetic resonance and infrared spectra were obtained and were determined to be consistent with the expected structure of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22](F)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.[N:31]1([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:35][CH2:34][CH2:33][CH2:32]1>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([N:39]4[CH2:40][CH2:41][CH:36]([N:31]5[CH2:35][CH2:34][CH2:33][CH2:32]5)[CH2:37][CH2:38]4)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1
Reactant: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1F
Reactant: C1CCN(C2CCNCC2)C1
Solvent: CN1CCCC1=O
Product: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1N1CCC(N2CCCC2)CC1
Temperature: 105 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
A mixture of 150 mg (0.34 mmol) of 4-[3-chloro-4-(1-methyl-1H-imidazole-2-ylsulfanyl)-phenylamino]-7-fluoro-6-methoxyquinoline-3-carbonitrile and 316 mg (2.05 mmol) of 4-pyrrolidin-1-yl-piperidine in 1 mL of 1-methyl-2-pyrrolidinone is heated at 105° C. for 16 hours. The solvents are removed in vacuo. A 10 mL portion of water is added to the residue, from which a tan solid is precipitated out. The solid is filtered off and washed with water. After drying in vacuo, the solid is suspended in ethyl acetate and stirred for 1 hour. The solid is filtered off, washed with ethyl acetate and dried in vacuo to provide 140 mg of 4-[3-chloro-4-(1-methyl-1H-imidazole-2-ylsulfanyl)-phenylamino]-6-methoxy-7-(4-pyrrolidin-1-yl-piperidin-1-yl)quinoline-3-carbonitrile as a yellow solid, mp 225-229° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([F:12])([F:11])[F:10])=[N:7][CH:8]=1.BrCC1CCCCO1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2([C:41]3[C:32](=[CH:33][C:34]4[O:39][CH2:38][CH2:37][O:36][C:35]=4[CH:40]=3)[O:31][CH2:30]2)[C:22]1=[O:42]>>[F:10][C:9]([F:12])([F:11])[C:6]1[N:7]=[CH:8][C:3]([CH2:2][N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]3([C:41]4[C:32](=[CH:33][C:34]5[O:39][CH2:38][CH2:37][O:36][C:35]=5[CH:40]=4)[O:31][CH2:30]3)[C:22]2=[O:42])=[CH:4][CH:5]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: FC(F)(F)c1ccc(CCl)cn1
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccc(C(F)(F)F)nc2)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 5-chloromethyl-2-(trifluoromethyl)pyridine to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (90%) as a colorless solid: mp 204-207° C. (dichloromethane); 1H NMR (300 MHz, CDCl3) δ 8.74 (d, J=1.6 Hz, 1H), 7.82 (dd, J=8.1, 1.6 Hz, 1H), 7.66 (d, J=8.1 Hz, 1H), 7.27-7.15 (m, 1H), 7.03-7.05 (m, 1H), 6.75 (d, J=7.8 Hz, 1H), 6.50 (s, 1H), 6.18 (s, 1H), 5.11 (d, J=16.0 Hz, 1H), 4.92 (d, J=16.1 Hz, 1H), 4.91 (d, J=9.0 Hz, 1H), 4.64 (d, J=9.0 Hz, 1H), 4.22-4.07 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 177.7, 155.3, 149.0, 147.9 (q, J=139.5 Hz), 144.8, 141.2, 138.4, 136.5, 134.9, 132.1, 129.1, 124.4, 124.1, 121.4, 120.8 (q, J=10.8 Hz), 120.5, 111.4, 108.6, 99.6, 80.1, 64.5, 63.9, 58.0, 41.3; MS (ES+) m/z 429.9 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([NH:14][NH2:15])=[N:12][N:11]([CH2:16][C:17]3[C:18]([CH3:27])=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[C:10](=[O:28])[C:9]=2[C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)=[CH:4][CH:3]=1.[CH2:37]1C[O:40][CH2:39][CH2:38]1.CCN(CC)CC.C(Cl)(=O)CC>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([NH:14][NH:15][C:39](=[O:40])[CH2:38][CH3:37])=[N:12][N:11]([CH2:16][C:17]3[C:18]([CH3:27])=[N:19][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:22]=3)[C:10](=[O:28])[C:9]=2[C:29]2[CH:30]=[CH:31][C:32]([C:33]#[N:34])=[CH:35][CH:36]=2)=[CH:4][CH:3]=1
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1nc(NN)c(-c2ccc(Cl)cc2)c(-c2ccc(C#N)cc2)c1=O
Reactant: C1CCOC1
Agent: CCC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCC(=O)NNc1nn(Cc2ccc(C(F)(F)F)nc2C)c(=O)c(-c2ccc(C#N)cc2)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47 %

Procedure:
To a round bottom flask was added 4-(5-(4-chlorophenyl)-6-hydrazinyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-oxo-2,3-dihydropyridazin-4-yl)benzonitrile (96 mg, 0.187 mmol), THF (31 ml), Et3N (37.8 mg, 0.374 mmol) and propionyl chloride (17.3 mg, 0.187 mmol). The resulting reaction mixture was stirred at rt for 20 min. After this time, the reaction mixture was diluted with EtOAc (30 ml). The resulting solution was poured into a separatory funnel and the layers were separated. The organic layer was washed with water (2×10 ml) and saturated aqueous NaCl (10 mL). The organic layer was then slurried with MgSO4 to remove excess water, filtered and concentrated to give the crude product. The crude product was purified using an automated column chromatography system (ISCO, 4 gm silica gel) eluting with a gradient of 20-80% EtOAc/Hex to give product N′-(4-(4-chlorophenyl)-5-(4-cyanophenyl)-1-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-1,6-dihydropyridazin-3-yl)propionohydrazide as light yellow solid 50 mg (47% yield, for 2 steps). HPLC retention time (method A) 2.941 min; LCMS (M+H)=567.3.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:30]=[N:31][CH:32]=[C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:36]=2[Cl:42])[CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:30]=[N:31][CH:32]=[C:33]([C:35]5[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:36]=5[Cl:42])[CH:34]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Fc1cccc(-c2cncc(Br)c2)c1Cl
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cncc(-c5cccc(F)c5Cl)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-bromo-5-(2-chloro-3-fluoro-phenyl)-pyridine.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][C@H:11]2[N:21]3[C:22]4[N:13]([C:14](=[O:24])[CH:15]=[N:16][C:17]=4[CH:18]=[CH:19][C:20]3=[O:23])[CH2:12]2)[CH2:6][CH2:5]1.C(N(CC)CC)C.[O:32]1[C:36]2=[CH:37][N:38]=[C:39]([CH:41]=O)[CH:40]=[C:35]2[CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.CO.C(Cl)Cl.CO>[ClH:1].[O:32]1[C:36]2=[CH:37][N:38]=[C:39]([CH2:41][NH:3][CH:4]3[CH2:9][CH2:8][N:7]([CH2:10][C@H:11]4[N:21]5[C:22]6[N:13]([C:14](=[O:24])[CH:15]=[N:16][C:17]=6[CH:18]=[CH:19][C:20]5=[O:23])[CH2:12]4)[CH2:6][CH2:5]3)[CH:40]=[C:35]2[CH2:34][CH2:33]1
Reactant: O=Cc1cc2c(cn1)OCC2
Reactant: NC1CCN(C[C@@H]2Cn3c(=O)cnc4ccc(=O)n2c43)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: O=c1cnc2ccc(=O)n3c2n1C[C@H]3CN1CCC(NCc2cc3c(cn2)OCC3)CC1
Reaction time: 0.25 h
Yield: 71.2 %

Procedure:
A suspension of (1R)-1-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione dihydrochloride (for a preparation see Example 13(k) or 15(d)) (50 mg, 0.100 mmol) in chloroform (20 ml) and methanol (0.800 ml) at room temperature under nitrogen was treated with triethylamine (0.042 ml, 0.301 mmol) and stirred for 0.25 h (the suspension turned into a solution). 2,3-Dihydrofuro[2,3-c]pyridine-5-carbaldehyde (for a synthesis see WO2007122258, Example 43(0(14.94 mg, 0.100 mmol) was then added and the reaction was stirred at room temperature for 0.5 h. Sodium triacetoxyborohydride (67.1 mg, 0.301 mmol) was then added and the reaction was stirred at room temperature. After 3 h there was still some starting material so 30 mg of sodium triacetoxyborohydride were added. After 1 h a saturated aqueous solution of sodium bicarbonate (25 mL) was added followed by 20% methanol/DCM (25 mL) and the aqueous layer was extracted and then separated from the organic layer. The aqueous layer was extracted again twice with 20% methanol/DCM (2×25 mL). The combined organic extracts were dried on sodium sulphate, filtered and evaporated to afford 50 mg of crude product. The crude product was purified by silica chromatography (0-20% methanol/DCM) to afford the free base of the title compound as a yellow solid (31 mg, 71.2%).