Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:24][CH2:23][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][NH:13][C:12]2=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][N:13]([CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:12]2=[O:22])[CH2:23][CH2:24]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCCCBr
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCN1CN(c2ccccc2)C2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
To a stirred solution of 2.3 g (6.95 mmol) of 8-(t-butoxycarbonyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one in 40 ml of dry dimethylformamide at 0° C. was added 0.4 g (13 mmol) of sodium hydride (80% in mineral oil). The mixture was stirred at 0° C. under argon for 30 minutes and then ethyl 5-bromopentanoate (2.09 g, 10 mmol) was added dropwise. After being allowed to come to ambient temperature, the mixture was stirred for an additional 20 hours. The mixture was quenched with aqueous ammonium chloride, diluted with water and extracted with ethyl acetate. The extracts were washed with water, dried over magnesium surf ate and concentrated. The residue was purified by column chromatography (silica gel, 0-25% gradient of ethyl acetate in hexane) to provide 2.4 g (75.2%) of the indicated ester as a colorless liquid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.[CH3:11][N:12]([CH3:26])[C:13]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10][CH:2]1[NH:1][CH:16]1[CH2:15][CH2:14][C:13]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([N:12]([CH3:26])[CH3:11])[CH2:18][CH2:17]1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: NC1Cc2ccccc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN(C)C1(c2ccccc2)CCC(NC2Cc3ccccc3C2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.2 %

Procedure:
2-Aminoindane (266 mg, 2 mmol) and 4-dimethylamino-4-phenylcyclohexanone (434 mg, 2 mmol) were dissolved in dry 1,2-dichloroethane (10 ml) under argon. Glacial acetic acid (2 mmol) and sodium triacetoxyborohydride (600 mg) were added to this mixture and the mixture was stirred for 24 hours at RT. For working up, the mixture was concentrated and the residue was adjusted to pH 11 with five molar sodium hydroxide solution. The alkaline phase was diluted with water (10 ml) and extracted with ethyl acetate (4×20 ml). The combined extracts were dried over sodium sulfate and filtered and the filtrate was concentrated. The crude product was chromatographed over silica gel with ethyl acetate/ethanol (1:1). 490 mg N′-Indan-2-yl-N,N-dimethyl-1-phenyl-cyclohexane-1,4-diamine were obtained as a white solid which, for preparation of the hydrochloride, was dissolved in 2-butanone (10 ml), and 1.85 M ethanolic HCl (2 ml) was added. The mixture of cis- and trans-N′-indan-2-yl-N,N-dimethyl-1-phenyl-cyclohexane-1,4-diamine dihydrochloride obtained was filtered off with suction and dried (540 mg, m.p. 224-226° C.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[H-].[Na+:13].[C:14](=O)([O:17][CH3:18])[O:15]C.[OH-].[Na+]>C1COCC1.C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[C:6]([Na:13])([C:14]([O:17][CH3:18])=[O:15])[CH2:5]2
Reactant: [Na+]
Reactant: COC(=O)OC
Reactant: O=C1CCc2cc(Br)ccc21
Agent: [H-]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)C1([Na])Cc2cc(Br)ccc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
5-Bromo indanone (8 g, 37.9 mmol) was added to an ice cold solution of sodium hydride (2.72 g, 113.3 mmol) in THF (100 mL) and stirred at room temperature for 30 min. Dimethyl carbonate (17.25 g, 189.56 mmol) was then added and mixture was refluxed for 16 h. Reaction mixture was cooled to room temperature and poured into ice water. pH of solution was made basic using saturated aqueous solution of NaOH solution and extracted with twice with ethyl acetate and concentrated under vacuum. Residue obtained was dissolved in diethyl ether and cooled to 0° C. A solution of saturated aqueous solution of NaOH was added (10 mL) while stirring. Resulting sodium salt was collected by filtration and dried under vacuum to afford crude title compound (7 g) as solid. 1H NMR (400 MHz, DMSO-d6): δ 7.52 (s, 1H), 7.40 (m, 1H), 7.34 (m, 1H), 3.52 (s, 3H), 3.3 (s, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[C@H:14]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:13][C@@H:12]1[CH3:33])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:41]([O:43][CH2:44][CH3:45])=[O:42].[OH-].[K+]>ClCCl.O>[CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[C@H:14]([N:25]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:13][C@@H:12]1[CH3:33])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2c(cc1OC)N(C(=O)OCc1ccccc1)[C@@H](C)C[C@H]2NCc1ccccc1
Reactant: CCOC(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)N(Cc1ccccc1)[C@@H]1C[C@H](C)N(C(=O)OCc2ccccc2)c2cc(OC)c(OC)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
To a solution of cis-4-benzylamino-6,7-dimethyoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid benzyl ester (Example 2B) (150 mg, 0.34 mmol) in anhydrous dichloromethane (5 mL) were added pyridine (0.20 mL, 2.3 mmol) and ethyl chloroformate (0.16 mL, 1.7 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was then poured into water (20 mL), and aqueous 2N KOH (10 mL) was added. The solution was stirred for 30 min, then the mixture was extracted with ether (3×25 mL). The organic phases were combined and washed with 1N HCl (3×10 mL) and then a saturated sodium bicarbonate solution (10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give 190 mg of crude product. Purification by silica gel chromatography using 0-40% ethyl acetate/hexanes as eluent afforded the desired final product (146 mg, 83%): MS m/z 519 (M+ +1), 537 (M+ +19), 340 (M+ -178); 1H NMR (CDCl3) δ 6.99 (C8, s, 1H), 6.42 (C5, s, 1H).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][N:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:36][C:37]1[S:38][C:39]([CH:42]=[O:43])=[CH:40][N:41]=1>>[Br:36][C:37]1[S:38][C:39]([CH:42]([C:22]2[C:23]([F:35])=[C:24]([Cl:34])[C:25]([N:26]3[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]3)=[C:20]([CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[N:21]=2)[OH:43])=[CH:40][N:41]=1
Reactant: O=Cc1cnc(Br)s1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ncc(F)c2Cl)C[C@H](C)O1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc(C(O)c3cnc(Br)s3)c(F)c2Cl)C[C@H](C)O1

Procedure:
Starting materials: 2R,6S)-4-(2-((tert-butyldiphenylsilyloxy)methyl)-4-chloro-5-fluoropyridin-3-yl)-2,6-dimethylmorpholine (Intermediate 45) and 2-bromothiazole-5-carbaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([CH2:25][NH:26][CH3:27])[CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C:19]3=[O:24])[CH2:14][CH2:13]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[F:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][CH:15]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C:19]3=[O:24])[CH2:16][CH2:17]2)[CH2:25][N:26]([CH3:27])[C:31](=[O:32])[C:30]2[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=2[F:28])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNC[C@@H](CCN1CCC(N2CCCCC2=O)CC1)c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)c1ccccc1F
Solvent: ClCCl
Product: CN(C[C@@H](CCN1CCC(N2CCCCC2=O)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1F
Reaction time: 0.75 h

Procedure:
To solution of (S)-1′-[3-(3,4-dichloro-phenyl)-4-methylamino-butyl]-[1,4′]bipiperidinyl-2-one (0.3 g) in dichloromethane (7 mL) at 0° C. was added 2-fluorobenzoyl chloride neat. After 45 minutes at ambient temperature, the solution was washed with aqueous sodium bicarbonate, dried and evacuated to an oil which was purified with chromatography, eluting with methanol:dichloromethane (gradient 3:97, 6:94). Concentration to a viscous oil under high vacuum provided the title compound (0.3 g). MS: m/z=534(M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:19])[C:9]=1[O:10][C:11]1[N:15]([CH3:16])[N:14]=[C:13]([CH3:17])[C:12]=1I)[C:5]#[N:6].[Cl:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C:12]1[C:13]([CH3:17])=[N:14][N:15]([CH3:16])[C:11]=1[O:10][C:9]1[C:2]([F:1])=[CH:3][C:4]([C:5]#[N:6])=[CH:7][C:8]=1[F:19]
Reactant: OB(O)c1ccc(F)cc1Cl
Reactant: Cc1nn(C)c(Oc2c(F)cc(C#N)cc2F)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nn(C)c(Oc2c(F)cc(C#N)cc2F)c1-c1ccc(F)cc1Cl

Procedure:
To a solution of 3,5-difluoro-4-[(4-iodo-1,3-dimethyl-1H-pyrazol-5-yl)oxy]-benzonitrile (i.e. the product of Step B) (1.0 g, 2.67 mmol) in 1,4-dioxane (6 mL) was added 2-chloro-4-fluorobenzeneboronic acid (alternatively named B-(2-chloro-4-fluorophenyl)-boronic acid) (0.93 g, 5.33 mmol), dichloro(bis)triphenylphosphine palladium(II) (alternatively named bis(triphenylphosphine)palladium(II) dichloride) (93 mg, 0.13 mmol), potassium carbonate (0.74 g, 5.33 mmol), and water (4 mL). The resulting mixture was heated at reflux for 5 h, allowed to cool, and partitioned between water (20 mL) and ethyl acetate (20 mL). The organic layer was dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel with a gradient of hexanes/ethyl acetate to obtain the title compound as an off-white solid (110 mg).
Reaction SMILES: C([O-])=O.[NH4+].[C:5]1([CH:11]2[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C([BH3-])#[N:19].[Na+]>CO.C(Cl)Cl>[C:5]1([C@H:11]2[CH2:16][CH2:15][C@H:14]([NH2:19])[CH2:13][CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C1CCC(c2ccccc2)CC1
Reactant: [BH3-]C#N
Agent: O=C[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: N[C@H]1CC[C@H](c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Ammonium formate (18 g, 285 mmol) was added to a solution of 4-phenylcyclohexanone (5 g, 28.7 mmol) in methanol (150 ml) under nitrogen at room temperature followed by the portionwise addition of sodium cyanoborohydride (1.85 g, 29.4 mmol). After stirring the reaction mixture at room temperature for 24 hours, the methanol was removed under vacuum to leave an oily residue. The residue was dissolved in methylene chloride (100 ml) which was then washed with 1N sodium hydroxide (2×100 ml). The organic layer was separated, dried over sodium sulfate, filtered and concentrated to leave an off-white solid. Purification by flash chromatography (silica gel, 0-20% methanol/methylene chloride) provided 3.46 g of trans-4-phenyl-cyclohexylamine as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27]([OH:29])=O)[CH:5]=[CH:6][CH:7]=1.[NH2:30][C:31]1[CH:35]=[CH:34][N:33]([CH2:36][C:37]([CH3:40])([OH:39])[CH3:38])[N:32]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:39][C:37]([CH3:40])([CH3:38])[CH2:36][N:33]1[CH:34]=[CH:35][C:31]([NH:30][C:27]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:12]([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:25])([CH3:24])[CH3:26])[NH:10]2)=[O:29])=[N:32]1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(C)(C)O)n2)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.6 %

Procedure:
A mixture of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol), 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (93.12 mg, 0.3 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide (54.1 mg, 47.6%) as an off-white powder. HRMS (ES+) m/z Calcd for C30H35Cl2N5O2+H [(M+H)+]: 568.2241. found: 568.2246.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([CH:16]=[CH:17][CH:18]=1)[C:9]([C:11]1[NH:12][CH:13]=[CH:14][CH:15]=1)=[O:10])([O-:5])=[O:4].Br[CH2:20][CH2:21][CH2:22][CH3:23].C(OCC)(=O)C>CN(C)C=O>[CH2:20]([N:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:9](=[O:10])[C:8]1[CH:16]=[CH:17][CH:18]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=1)[CH2:21][CH2:22][CH3:23]
Reactant: O=C(c1cccc([N+](=O)[O-])c1)c1ccc[nH]1
Reactant: CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCn1cccc1C(=O)c1cccc([N+](=O)[O-])c1
Yield: 95.8 %

Procedure:
4 G (160 mmol) of 50% sodium hydride were suspended, under nitrogen atmosphere, in 250 ml of anhydrous dimethylformamide. A solution of 15 g (69 mmol) of 2-(3-nitrobenzoyl)pyrrole, prepared, for example, as described in Preparation 3A, in 50 ml of anhydrous dimethylformamide was added thereto, in a dropwise fashion and under stirring, maintaining the temperature at 20°-25° C. The resulting mixture was stirred for 2 additional hours and then a solution of 18 ml (170 mmol) of 1-bromobutane in 50 ml of dry dimethylformamide was added. The reaction mixture was stirred at room temperature for 18 hours further and then poured into 2000 ml of ethyl acetate. The organic extract was washed with water (5×500 ml), dried and evaporated in vacuo. The residue was purified by column chromatography on 1 Kg of silica gel, using hexane-acetone (90:10) as eluant, thus obtaining 18 g (95%) of 1-butyl-2 -(3'-nitrobenzoyl)pyrrole, the title compound, as an oil.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([C:16]3[N:24]4[C:19]([CH:20]=[N:21][C:22](O)=[N:23]4)=[CH:18][CH:17]=3)[CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:26][C:27]1[CH:28]=[CH:29][C:30]2[N:34]=[C:33]([CH2:35][OH:36])[NH:32][C:31]=2[CH:37]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[N:1]1([S:7]([C:10]2[CH:11]=[C:12]([C:16]3[N:24]4[C:19]([CH:20]=[N:21][C:22]([NH:26][C:27]5[CH:28]=[CH:29][C:30]6[N:34]=[C:33]([CH2:35][OH:36])[NH:32][C:31]=6[CH:37]=5)=[N:23]4)=[CH:18][CH:17]=3)[CH:13]=[CH:14][CH:15]=2)(=[O:8])=[O:9])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=S(=O)(c1cccc(-c2ccc3cnc(O)nn23)c1)N1CCOCC1
Reactant: Nc1ccc2nc(CO)[nH]c2c1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: O=S(=O)(c1cccc(-c2ccc3cnc(Nc4ccc5nc(CO)[nH]c5c4)nn23)c1)N1CCOCC1

Procedure:
(6-{7-[3-(Morpholine-4-sulfonyl)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino}-1H-benzoimidazol-2-yl)-methanol was prepared from 7-[3-(morpholine-4-sulfonyl)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ol and (6-amino-1H-benzoimidazol-2-yl)-methanol; dihydrochloride in an analogous manner to Example 1052a. Product isolated as a yellow solid (31 mg, 21%). m.p.=232-237° C.; LCMS (m/e) 506 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 12.05 (bs, 1H), 9.40 (s, 1H), 9.03 (s, 1H), 8.72 (d, 1H, J=7.8 Hz), 8.28 (s, 1H), 7.86-7.74 (m, 2H), 7.72 (d, 1H, J=7.8 Hz), 7.55 (d, 1H, J=8.7 Hz), 7.46 (d, 1H, J=8.7 Hz), 7.29 (d, 1H, J=4.8 Hz), 6.97 (d, 1H, J=4.8 Hz), 4.66 (s, 2H), 3.62-3.55 (m, 4H), 2.93-2.86 (m, 4H).
Reaction SMILES: O[C:2]([C:5]1[S:9][C:8](=[O:10])[S:7][C:6]=1[C:11]1[C:12](=[O:21])[NH:13][C:14]2[C:19]([N:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)([CH3:4])[CH3:3].C(OC(Cl)=O)C1C=CC=CC=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:4][C:2]1([CH3:3])[O:21][C:12]2[C:11](=[N:20][C:19]3[C:14]([N:13]=2)=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:6]2[S:7][C:8](=[O:10])[S:9][C:5]1=2
Reactant: CC(C)(O)c1sc(=O)sc1-c1nc2ccccc2[nH]c1=O
Agent: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)Oc2nc3ccccc3nc2-c2sc(=O)sc21
Reaction time: 8 h

Procedure:
3-(5-(2-Hydroxypropan-2-yl)-2-oxo-1,3-dithiol-4-yl)quinoxalin-2(1H)-one (6) (130 mg, 0.405 mmol) was partially dissolved in CH2Cl2 (10 mL). Benzylchloroformate (125 μL, 0.81 mmol) and triethylamine (120 μL) were added and the resulting yellow solution was stirred overnight. The volume of the solution was reduced to ca. 3 mL and it was purified by chromatography (silica gel, CH2Cl2) to give pure 4,4-dimethyl-4H-5-oxa-1,3-dithia-6,1,1-diaza-cyclopenta[a]anthracen-2-one (7). Yield: 82 mg (70%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:11][N:12]2[C:16]([C:17]([O:19]CC)=[O:18])=[C:15]([S:22][CH:23]3[CH2:28][CH2:27][C:26](=[CH:29][C:30]([O:32]CC)=[O:31])[CH2:25][CH2:24]3)[N:14]=[C:13]2[CH2:35][CH2:36][CH3:37])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.O1CCCC1>C(O)C>[C:30]([CH:29]=[C:26]1[CH2:25][CH2:24][CH:23]([S:22][C:15]2[N:14]=[C:13]([CH2:35][CH2:36][CH3:37])[N:12]([CH2:11][C:3]3[C:2]([Cl:1])=[CH:10][C:6]4[O:7][CH2:8][O:9][C:5]=4[CH:4]=3)[C:16]=2[C:17]([OH:19])=[O:18])[CH2:28][CH2:27]1)([OH:32])=[O:31]
Reactant: CCCc1nc(SC2CCC(=CC(=O)OCC)CC2)c(C(=O)OCC)n1Cc1cc2c(cc1Cl)OCO2
Solvent: CCO
Solvent: C1CCOC1
Product: CCCc1nc(SC2CCC(=CC(=O)O)CC2)c(C(=O)O)n1Cc1cc2c(cc1Cl)OCO2
Reaction time: 24 h
Yield: 62 %

Procedure:
880 mg of the product of Example 9 is introduced into 20 ml of tetrahydrofuran, 50 ml of ethanol and 25 ml of 2N soda are added and the reaction medium is left for 24 hours at ambient temperature. The tetrahydrofuran and the ethanol are evaporated off, then the reaction medium is acidified to pH 1. Extraction is carried out with ethyl acetate, followed by evaporation to dryness and the residue is recrystallized from ethyl acetate. In this way 490 mg of expected product is obtained. M.p.=168° C.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH:13]=[C:14]([C:16]([CH3:22])([CH3:21])[C:17](OC)=[O:18])[N:15]=2)[N:12]=1.[CH:23]([OH:26])([CH3:25])[CH3:24]>>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([CH:13]=[C:14]([C:16]([CH3:22])([CH3:21])[C:17]([O:26][CH:23]([CH3:25])[CH3:24])=[O:18])[N:15]=2)[N:12]=1
Reactant: COC(=O)C(C)(C)c1cn2nc(Cl)ccc2n1
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Product: CC(C)OC(=O)C(C)(C)c1cn2nc(Cl)ccc2n1

Procedure:
In 18 ml of isopropanol, 995 mg of concentrated sulfuric acid was dissolved; 1.0 g of methyl 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate was added, followed by thermal refluxing for 40 hours. After cooling, the mixture was concentrated under reduced pressure, neutralized by the addition of aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure; the crystal precipitated was collected, washed with hexane and dried to yield 794 mg of the title compound. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane:ethyl acetate (5:1). The desired fraction was collected and dried to yield 215 mg of the title compound.
Reaction SMILES: C(O)(C)C.[CH3:5][N:6]1[C:11]([N:12]([CH3:17])[CH2:13][CH2:14][NH:15][CH3:16])=[CH:10][C:9](=[O:18])C(C)[C:7]1=[O:20].[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32]Br)=[CH:26][CH:25]=1)([O-:23])=[O:22].[CH2:34]([N:36](CC)CC)C>>[CH3:5][N:6]1[C:11]([N:12]([CH2:13][CH2:14][N:15]([CH2:32][CH2:31][CH2:30][C:27]2[CH:28]=[CH:29][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=2)[CH3:16])[CH3:17])=[CH:10][C:9](=[O:18])[N:36]([CH3:34])[C:7]1=[O:20]
Reactant: O=[N+]([O-])c1ccc(CCCBr)cc1
Reactant: CNCCN(C)C1=CC(=O)C(C)C(=O)N1C
Reactant: CCN(CC)CC
Solvent: CC(C)O
Product: CN(CCCc1ccc([N+](=O)[O-])cc1)CCN(C)c1cc(=O)n(C)c(=O)n1C

Procedure:
To 60 ml of isopropanol were added 5.0 g of the above compound 18, 5.5 g of 3-(4-nitrophenyl)propyl bromide and 6 ml of triethylamine, and the resuting mixture was then treated by the same procedure as in Example 2 in order to obtain 8.1 g of 1,3-dimethyl-6-{N-methyl-2-[N-methyl-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: OC[C@@H](N)C(C)CC.COC(=O)[C@H]([C@H](CC)C)N.OCCN.[CH3:23][C:24]1[CH:31]=[C:30]([N+:32]([O-])=O)[C:29]([CH3:35])=[CH:28][C:25]=1[C:26]#[N:27].NC1C=CC=CC=1.C([C:45]1C(C)=[CH:49][C:48]([N:52]=[C:53]=[S:54])=[C:47]([CH3:55])[CH:46]=1)#N>>[C:26]([C:25]1[C:24]([CH3:23])=[CH:31][C:30]([N:32]=[C:53]2[NH:52][C@@H:48]([CH:47]([CH2:46][CH3:45])[CH3:55])[CH2:49][S:54]2)=[C:29]([CH3:35])[CH:28]=1)#[N:27]
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1C#N
Reactant: Cc1cc(N=C=S)c(C)cc1C#N
Agent: CCC(C)[C@H](N)CO
Agent: CC[C@H](C)[C@H](N)C(=O)OC
Solvent: NCCO
Solvent: Nc1ccccc1
Product: CCC(C)[C@H]1CSC(=Nc2cc(C)c(C#N)cc2C)N1

Procedure:
(1S)-1-(Hydroxymethyl)-2-methylbutylamine was made from (L)-isoleucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-2-methylbutanammonium chloride as described in Method B7a. 2,5-Dimethyl-4-nitrobenzonitrile was converted to 4-cyano-2,5-methylaniline according to Method A1a. The aniline was converted to 4-cyano-2,5-dimethylphenyl isothiocyanate as described in Method A2a, Step 3. 4-Cyano-2,5-dimethylphenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-2-methylbutanammonium chloride to Method C1a to give (4S)-2-(4-cyano-2,5-dimethylphenylimino)-4-(2-butyl)-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(4-cyano-2,5-dimethylphenylimino)-4-butyl-3-isobutyl-1,3-thiazolidine.