Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[F:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][CH2:14][C@H:15]2[CH2:24][N:19]3[CH2:20][CH2:21][NH:22][CH2:23][C@@H:18]3[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.Cl>>[F:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][C@H:15]2[CH2:24][N:19]3[CH2:20][CH2:21][N:22]([C:2]4[N:7]=[CH:6][CH:5]=[CH:4][N:3]=4)[CH2:23][C@@H:18]3[CH2:17][CH2:16]2)=[CH:25][CH:26]=1
Reactant: Fc1ccc(OC[C@@H]2CC[C@H]3CNCCN3C2)cc1
Reactant: Clc1ncccn1
Agent: Cl
Product: Fc1ccc(OC[C@@H]2CC[C@H]3CN(c4ncccn4)CCN3C2)cc1

Procedure:
The title compound was prepared according to Preparation 3 with 2-chloropyrimidine and (7R,9aS)-7-(4-fluorophenoxy)methyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (Preparation 8). mp (—HCl) 283-285° C. HRMS calcd for C19H23FN4O: 342.1856; found: 342.1867.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:7]2[CH:8]=[CH:9][CH:4]([C:5]([CH2:10][CH2:11][OH:12])=[CH:6]2)[C:3]1=[O:13].[H][H]>[Pd].C(O)(C)C>[CH3:1][C:2]1([CH3:14])[CH:7]2[CH2:8][CH2:9][CH:4]([CH:5]([CH2:10][CH2:11][OH:12])[CH2:6]2)[C:3]1=[O:13]
Reactant: CC1(C)C(=O)C2C=CC1C=C2CCO
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)O
Product: CC1(C)C(=O)C2CCC1CC2CCO
Temperature: 100 °C
Yield: 89.8 %

Procedure:
A mixture of 60 g of 3,3-dimethyl-6-(2-hydroxyethyl)-bicyclo(2.2.2)-octa-5,7-diene-2-one produced according to Example I, 300 ml of isopropyl alcohol and 5 g of 5% palladium on charcoal catalyst is placed in an autoclave. The autoclave is pressurized with hydrogen and heated to 100° C. for six hours. The resulting reaction mixture is filtered and the solvent is removed by vacuum stripping. Distillation of the residue through a 3" microvigreaux column yields 55 g of 3,3-dimethyl-6-(2-hydroxyethyl)-bicyclo(2.2.2)-octanone having the structure: ##STR32##
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[O:8])=[C:5]([CH3:16])[CH:4]=[C:3]1[CH2:17][C:18]([O:20]CC)=[O:19].[OH-].[Na+].Cl>O>[CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[O:8])=[C:5]([CH3:16])[CH:4]=[C:3]1[CH2:17][C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(C)cc2)n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(C(=O)c2c(C)cc(CC(=O)O)n2C)cc1

Procedure:
A suspension of 8.5 g. (0.0284 mole) of ethyl 1,4-dimethyl-5-(p-toluoyl)-pyrrole-2-acetate in 29 ml. of 1N sodium hydroxide solution is heated under reflux for 20 min. The yellow solution is diluted with water and added to dilute hydrochloric acid. The precipitated solid is collected, dried in vacuo, and recrystallized from 2-propanol to give 1,4-dimethyl-5-(p-toluoyl)-pyrrole-2-acetic acid as a white solid, m.p. 160°-161° C.
Reaction SMILES: [CH3:1][CH:2]([NH2:12])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.ON1C2C=CC=CC=2N=N1.[C:23](O)(=[O:32])[C@@H:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[OH:25].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[OH:25][CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([NH:12][CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:32]
Reactant: CC(N)CCCc1cccnc1
Reactant: O=C(O)[C@H](O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(CCCc1cccnc1)NC(=O)C(O)c1ccccc1
Temperature: -5 °C
Reaction time: 18 h
Yield: 94.6 %

Procedure:
To a cooled (-5° C.) solution of 32 g of the above enriched amine, 33 g of 1-hydroxybenzotriazole and 31.22 g of (R)-mandelic acid in 350 mL of dimethylformamide, was added a solution of 44.26 g of 1,3-dicyclohexylcarbodiimide in 150 mL of dimethylformamide and the mixture was stirred at -5° C. for 18 hours. After the precipitated dicyclohexylurea was removed by filtration, the filtrate was evaporated and the residue dispersed in 300 mL of cold 2N sodium hydroxide. The resulting solids were removed by filtration, washed with dilute sodium hydroxide solution and with water and then dissolved in 500 mL of 2N hydrochloric acid. The acidic solution was extracted with dichloromethane (3×150 mL) to remove neutral impurities, then was basified with 10N sodium hydroxide and extracted with dichloromethane (6×300 mL). The dried extracts were evaporated to give 55 g of residual solid. Crystallization of the product from ethanol gave 25.6 g of [R-(R*,R)]-alpha-hydroxy-N-[1-methyl-4-(3-pyridinyl)butyl]benzeneacetamide, mp 141°-143° C. An additional 1.3 g of product, mp 141°-143° C., was obtained from the mother liquors.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](F)=[N:6][CH:7]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1F
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(Cl)cnc1N1CCOCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 5-chloro-2-fluoro-3-nitropyridine (5 g, 28 mmol) in THF (40 mL) was added morpholine (4 mL, 42 mmol). The reaction was stirred at 0° C. for ten min, at rt for 1 h, and refluxed for four h. The reaction was then cooled to rt, taken up in EtOAc, and washed with satd aq. sodium bicarbonate and brine. The organic layer was dried (magnesium sulfate) and concentrated, affording 4-(5-chloro-3-nitropyridin-2-yl)morpholine as a yellow oil. Mass Spectrum (ESI) m/e=244.0 (M+1).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CSC.[CH3:12][C:13]([CH2:17][CH2:18][CH:19]=[C:20]([CH3:28])[CH2:21][CH2:22][CH:23]=[C:24]([CH3:27])[CH2:25][CH3:26])=[CH:14]CO>ClCCl>[Cl:1][CH2:26]/[CH:25]=[C:24](\[CH3:27])/[CH2:23][CH2:22]/[CH:21]=[C:20](\[CH3:28])/[CH2:19][CH2:18][CH:17]=[C:13]([CH3:14])[CH3:12]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCC(C)=CCCC(C)=CCCC(C)=CCO
Solvent: CSC
Solvent: ClCCl
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84.8 %

Procedure:
(Note: all temperatures indicated are for the contents of the reaction flask). To a stirred solution of 299 mg (2.24 mmol) of N-chlorosuccinimide in 15 mL of dichloromethane at -30° C. under argon was added 0.18 mL (2.45 mmol) of distilled dimethyl sulfide over 5 minutes. After 10 minutes at -30° C., the reaction was allowed to warm to 0° C. for 10 minutes, followed by cooling to -40° C. A solution of 441.4 mg (1.99 mmol) of 3,7,11-trimethyl-2,6,10-tridecatrien-1-ol in 5 mL of dichloromethane was added dropwise over 10 minutes. The reaction was allowed to warm gradually to 0° C. over 1 hour, and then maintained for 1 hour. After quenching with cold water, the mixture was extracted with hexane and the hexane extract was washed with cold water and cold brine, dried (MgSO4) and evaporated to afford 483 mg of a crude product. Rapid flash chromatography on 20 g of silica gel eluted with 3:97 ethyl acetate:petroleum ether provided 406.5 mg (85%) of a colorless liquid. 13C NMR indicated that this material contained a trace (3%) impurity.
Reaction SMILES: Cl.CC(C)([S@]([NH:7][CH:8]([C:10]1[CH:11]=[C:12]([C:27]([N:29]([CH3:31])[CH3:30])=[O:28])[CH:13]=[C:14]2[C:19]=1[O:18][C:17]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[CH:16][C:15]2=[O:26])[CH3:9])=O)C>O1CCOCC1>[NH2:7][CH:8]([C:10]1[CH:11]=[C:12]([C:27]([N:29]([CH3:30])[CH3:31])=[O:28])[CH:13]=[C:14]2[C:19]=1[O:18][C:17]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[CH:16][C:15]2=[O:26])[CH3:9]
Reactant: CC(N[S@](=O)C(C)(C)C)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Agent: Cl
Solvent: C1COCCO1
Product: CC(N)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
Hydrogen chloride in dioxane 4M (15 mL, 60.1 mmol) was added to 8-(1-((R)-1,1-dimethylethylsulfinamido)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (2.7 g, 6.0 mmol) dissolved in dioxane (40 mL). The resulting white suspension was stirred at RT for 1 hour, collected by filtration, washed with diethyl ether and dried. It was dissolved into a 5% methanolic ammonia (7 N) sol. in DCM (200 mL) and stirred for 5 minutes. The precipitate (NH4Cl) was removed by filtration and the filtrate was concentrated to dryness to afford 8-(1-aminoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (single enantiomer, 1.85 g, 89%) as an off-white solid. Mass Spectrum: M+H° 346. [α]D20°: +35° in acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9].C([Li])CCC.[S:19](Cl)([Cl:22])(=[O:21])=[O:20]>CCOCC>[Cl:1][C:2]1[C:3]([S:8](=[O:9])(=[O:10])[N:11]([CH3:13])[CH3:12])=[C:4]([S:19]([Cl:22])(=[O:21])=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)S(=O)(=O)c1ccccc1Cl
Reactant: O=S(=O)(Cl)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: CN(C)S(=O)(=O)c1c(Cl)cccc1S(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 29 g of 2-chloro-N,N-dimethylbenzenesulfonamide and 150 mL ether at -5° C. to 0° C. was added dropwise under nitrogen 94 mL of a 1.55M solution of n-butyllithium in hexanes. When the addition was complete, the reaction mixture was allowed to warm to room temperature and was stirred for 2 hours. The reaction mixture was then recooled to -30° C. to -20° C., and treated with a solution of 22 mL of sulfuryl chloride in 60 mL hexanes, added at a rate that maintained the temperature below -10° C. The reaction mixture was then stirred at room temperature for one hour. The precipitated solids were collected, washed with ether and water, and dried to afford 26 g of 3-chloro-2-(N,N-dimethylsulfamoyl)benzenesulfonyl chloride as a yellow solid, which was used without further purification; IR (KBr): 1375, 1350, 1180 and 1160 cm-1.
Reaction SMILES: [Br-:1].[C:2]([CH2:5][CH2:6][N+:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:10]=2[S:9][C:8]=1[CH3:17])([OH:4])=[O:3].[Br-].N([CH:26]=[CH:27][CH:28]=[CH:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N+:33]([CH2:40][CH3:41])=[CH:32][CH:31]=1)C1C=CC=CC=1.C(O)C>C(N(CC)CC)C>[Br-:1].[CH2:40]([N+:33]1[C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:30]([CH:29]=[CH:28][CH:27]=[CH:26][CH:17]=[C:8]2[N:7]([CH2:6][CH2:5][C:2]([OH:4])=[O:3])[C:11]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:10]=3[S:9]2)=[CH:31][CH:32]=1)[CH3:41]
Reactant: CC[n+]1ccc(C=CC=CNc2ccccc2)c2ccccc21
Reactant: Cc1ccc2c(c1)sc(C)[n+]2CCC(=O)O
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC[n+]1ccc(C=CC=CC=C2Sc3cc(C)ccc3N2CCC(=O)O)c2ccccc21
Yield: 15.2 %

Procedure:
To reaction were subjected 3.7 g of 3-(2-carboxyethyl)-2,6-dimethylbenzothiazolium bromide, 4.3 g of 4-(4-anilino-1,3-butadien-1-yl)-1-ethylquinolinium bromide, 150 ml of ethanol and 5 ml of triethylamine under reflux for one hour. After completion of the reaction, the reaction product was cooled, and the crude crystals thus obtained were purified by means of methanol to obtain 0.9 g of the objective compound (melting point 190° C.) which was glittering green. Its maximum absorption wavelength as measured in triethylamine-containing methanol was 740 nm.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C@H:12]3[CH2:16][C@:5]([C:17]([N:19]4[CH2:24][CH2:23][CH:22]([CH2:25][C:26]5[C:27](F)=[N:28][CH:29]=[CH:30][CH:31]=5)[CH2:21][CH2:20]4)=[O:18])([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1.[F-].[K+].[CH3:35][O-:36].[Na+]>CO>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C@H:12]3[CH2:16][C@:5]([C:17]([N:19]4[CH2:24][CH2:23][CH:22]([CH2:25][C:26]5[C:27]([O:36][CH3:35])=[N:28][CH:29]=[CH:30][CH:31]=5)[CH2:21][CH2:20]4)=[O:18])([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1
Reactant: C[O-]
Reactant: O=C(N1CCC(Cc2cccnc2F)CC1)[C@@]12C[C@@H](c3ccccc31)c1ccc(Cl)cc12
Agent: [F-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: COc1ncccc1CC1CCN(C(=O)[C@@]23C[C@@H](c4ccccc42)c2ccc(Cl)cc23)CC1
Temperature: 25 °C
Yield: 68 %

Procedure:
To a solution of 1-((9S,10S)-2-chloro-9,10-dihydro-9,10-methanoanthracen-9-ylcarbonyl)-4-(2-fluoro-3-pyridylmethyl)piperidine, (2.60 g, 5.8 mmol), prepared as described in Example 55a, in methanol (25 mL) was added potassium fluoride (4.15 g, 71.4 mmol) which caused a slight exotherm (-35° C.). Sodium methoxide solution in methanol (4.4 mL of a 25 wt % solution) was added which caused another exotherm (-50° C.) and thinned the suspension. This suspension was heated to reflux for 6 h. Additional potassium fluoride (4.15 g, 71.4 mmol) was added and the suspension was refluxed for 18 h. Additional sodium methoxide solution (1.0 mL) was added and the suspension was refluxed for 5 h. The mixture was cooled to room temperature, partitioned between basic brine and dichloromethane. The organic extract was separated and the aqueous was extracted with dichloromethane (2X). The dichloromethane extracts were combined, dried oversodium sulfate, filtered and concentrated on a rotary evaporator. The crude foam was purified by flash chromatography on silica (eluant: 15% acetone/hexanes) to give the title compound as a white solid (1.82 g, 3.95 mmol, 68%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=2)[N+:13]([O-])=[CH:12][CH:11]=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:12]1[CH:11]=[C:10]([C:3]2[C:2]([F:1])=[CH:7][C:6]([F:8])=[CH:5][C:4]=2[F:9])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=2)[N:13]=1
Reactant: COC(=O)c1ccc2c(c1)c(-c1c(F)cc(F)cc1F)cc[n+]2[O-]
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc2nc(Cl)cc(-c3c(F)cc(F)cc3F)c2c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 4-(2,4,6-trifluorophenyl)quinoline-6-carboxylate 1-oxide (1.3 g) and phosphoryl chloride (10 mL) was heated under stirring in an oil bath at 100° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with water, and then extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified under silica gel column chromatography (hexane/ethyl acetate) to obtain methyl 2-chloro-4-(2,4,6-trifluorophenyl)quinoline-6-carboxylate (370 mg).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:11][C:12]1[CH:13]=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:15]=[CH:16][C:17]=1[CH3:18]>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:11][C:12]1[CH:13]=[C:14]([C:19]([F:20])([F:21])[F:22])[CH:15]=[CH:16][C:17]=1[CH3:18]
Reactant: Cc1ccc(C(F)(F)F)cc1N
Reactant: Clc1nc2ccccc2[nH]1
Product: Cc1ccc(C(F)(F)F)cc1Nc1nc2ccccc2[nH]1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 3-amino-4-methylbenzotrifluoride by Procedure A. The product was isolated upon basic work-up and purified by preparative LCMS to give the title compound as the free base. 1NMR (DMSO-d6) δ 2.40 (s, 3H), 6.95-7.03 (m, 2H), 7.20-7.25 (m, 1H), 7.31-7.42 (m, 3H), 8.63 (s, 1H), 8.88 (s, 1H), 10.9 (s, 1H). MS(ES+) m/z 292 ([M+1]+, 100).
Reaction SMILES: [C:1]([C:3]1[N:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].I[C:13]1[CH:14]=[C:15]([C:20]2[NH:24][C:23]3[CH:25]=[C:26]([N:29]4[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30]4)[CH:27]=[CH:28][C:22]=3[N:21]=2)[CH:16]=[CH:17][C:18]=1[CH3:19]>>[CH3:19][C:18]1[CH:17]=[CH:16][C:15]([C:20]2[NH:21][C:22]3[CH:28]=[CH:27][C:26]([N:29]4[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30]4)=[CH:25][C:23]=3[N:24]=2)=[CH:14][C:13]=1[C:2]#[C:1][C:3]1[N:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1
Reactant: Cc1cn(-c2ccc3nc(-c4ccc(C)c(I)c4)[nH]c3c2)cn1
Reactant: C#Cc1cnc2cccnn12
Product: Cc1cn(-c2ccc3[nH]c(-c4ccc(C)c(C#Cc5cnc6cccnn56)c4)nc3c2)cn1

Procedure:
The title compound was synthesized from 3-ethynylimidazo[1,2-b]pyridazine and 2-(3-iodo-4-methylphenyl)-6-(4-methyl-1H-imidazol-1-yl)-1H-benzo[d]imidazole (as prepared above) in a manner similar to that described for in Example 1. The title compound was obtained a pale yellow solid. Mp: 182-184° C.; 1H NMR (400 MHz, CD3OD) δ: 8.57 (2 H, brs), 8.26 (1 H, s), 7.98-8.05 (3 H, m), 7.74 (1 H, s), 7.68-7.70 (1 H, d, J=8.4 Hz), 7.46-7.48 (2 H, m), 7.42-7.44 (1 H, d, J=8.4 Hz), 7.29-7.33 (1 H, dd, J=4.4 and 9.2 Hz), 2.61 (3 H, s), 2.31 (3 H, s). HRMS (ESI-TOF+): m/z [M+H]+ calcd for C26H20N7: 430.1775. found: 430.1778.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[C:9]([N+:14]([O-])=O)[CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[Cl-].[NH4+].[O:20]([C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](O)=[O:35])=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>[Fe].C(O)C.O>[CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[C:9]([NH:14][C:34](=[O:35])[CH2:33][C:30]3[CH:31]=[CH:32][C:27]([O:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:28][CH:29]=3)[CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: CN(C)CCn1ncc2c([N+](=O)[O-])cccc21
Reactant: O=C(O)Cc1ccc(Oc2ccccc2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CN(C)CCn1ncc2c(NC(=O)Cc3ccc(Oc4ccccc4)cc3)cccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of dimethyl-[2-(4-nitro-indazol-1-yl)-ethyl]-amine (1.6 g, 6.8 mmol), iron powder (3.8 g, 68 mmol), and ammonium chloride (0.18 g, 3.4 mmol) in a 4:1 ethanol/H2O solution (20 mL) was heated to reflux for 3 hours, cooled to room temperature and concentrated under reduced pressure. The residue was taken up and stirred in triethylamine/ethyl acetate (1/4, 10 mL) for 15 minutes and then filtered through a plug of silica gel which was rinsed with triethylamine/ethyl acetate (1/4). The combined filtrate was concentrated under reduced pressure to provide a play yellow oil. This material was then processed with (4-phenoxy-phenyl)-acetic acid according to the procedure described in Example 5 to provide the title compound. 1H NMR (300 MHz, DMSO-d6) ppm 2.85 (s, 6H), 3.62 (t, J=6.24, 2H), 3.80 (s, 2H), 4.78 (t, J=6.24, 2H), 6.99–7.01 (m, 3H), 7.13 (m, 2H), 7.36–7.40 (m, 5H), 7.45 (m, 1H), 7.71 (m, 1H), 8.40 (s, 1H), 9.61 (s, 1H); MS (DCI/NH3) m/z 415 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:33])[C:10]([NH:12][NH:13][C:14](=[O:32])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:17]([CH3:29])[C:16]=2[CH2:30][CH3:31])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1>O1CCCC1.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C@@H:9]([OH:33])[C:10]([NH:12][NH:13][C:14](=[O:32])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[C:17]([CH3:29])[C:16]=2[CH2:30][CH3:31])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCc1c(C(=O)NNC(=O)C(=O)c2cc(F)cc(F)c2)ccc(OCc2ccccc2)c1C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCc1c(C(=O)NNC(=O)[C@H](O)c2cc(F)cc(F)c2)ccc(OCc2ccccc2)c1C
Reaction time: 6 h
Yield: 20.8 %

Procedure:
302 mg of N′-[2-(3,5-difluorophenyl)-2-oxoacetyl]-4-benzyloxy-2-ethyl-3-methylbenzohydrazide (B3) are dissolved in 25 ml of tetrahydrofuran. This solution is added dropwise over the course of 5 min to a solution of 49 μl of borane/dimethyl sulfide complex and 55 μl of (R)-methyloxazaborolidine [(R)-Me-CBS, 1-1.5 M in toluene) in 17 ml of tetrahydrofuran at a temperature of (−)78° C. The cooling bath is subsequently removed, and the solution is stirred for 6 h, during which the reaction solution warms to room temperature: 100 ml of water are then added, and the mixture is extracted three times with 150 ml of ethyl acetate each time. The combined organic phases are washed with 40 ml of each of water, 0.1 M HCl and sat. NaCl solution, dried over NaSO4, filtered off with suction and evaporated to dryness. The residue is purified by means of preparative HPLC (solvent gradient: water/1-50% by vol. of acetonitrile), giving 63 mg of the title compound as colourless, amorphous solid. MS: 932 (2M+Na+); TLC: Rf=0.56 (cyclohexane/methyl tert-butyl ether 1:4, parts by volume).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[C:11]2[CH2:12][CH:13]([CH2:15][O:16][CH3:17])[O:14][C:10]=2[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:31](OC(C1C=C(OC2C=CC(S(C)(=O)=O)=CC=2)C2CC(CO)(C)OC=2C=1)=O)(C)(C)C.CI>>[C:1]([O:5][C:6]([C:8]1[CH:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[C:11]2[CH2:12][C:13]([CH2:15][O:16][CH3:17])([CH3:31])[O:14][C:10]=2[CH:9]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COCC1Cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)OC(C)(C)C)cc2O1
Reactant: CC(C)(C)OC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2c(c1)OC(C)(CO)C2
Solvent: CI
Product: COCC1(C)Cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)OC(C)(C)C)cc2O1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 201a, from 2-hydroxymethyl-4-(4-methanesulfonyl-phenoxy)-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (227d) and methyl iodide. 1H NMR (400 MHz, CDCl3) δ 7.88-7.93 (m, J=9.47, 2.78, 2.40 Hz, 2 H) 7.28 (s, 1 H) 7.21 (d, J=1.26 Hz, 1 H) 7.04-7.10 (m, 2 H) 3.41-3.50 (m, 2 H) 3.40 (s, 3 H) 3.10 (d, J=16.67 Hz, 1 H) 3.07 (s, 3 H) 2.75 (d, J=16.67 Hz, 1 H) 1.56 (s, 9 H) 1.46 (s, 3 H); LCMS for C23H28O7S m/z 449.00 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH2:14][OH:15])[CH:6]=[CH:5]2.[C:19](OC(=O)C)(=[O:21])[CH3:20].N1C=CC=CC=1.C(Cl)Cl>>[C:19]([O:15][CH2:14][CH2:13][N:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[C:3]=2[N+:16]([O-:18])=[O:17])[C:8]1=[O:12])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1c2ccc(Cl)c([N+](=O)[O-])c2ccn1CCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCCn1ccc2c([N+](=O)[O-])c(Cl)ccc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A round bottom flask was charged with 6-chloro-2-(2-hydroxyethyl)-5-nitroisoquinolin-1(2H)-one (400.0 mg, 0.00149 mol), acetic anhydride (0.21 mL, 0.0022 mol), pyridine (0.18 mL, 0.0022 mol) and methylene chloride (20 mL, 0.2 mol) and the reaction was stirred at room temperature overnight. The solvent was removed under reduced pressure to afford the product as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(N(CC)CC)C.Br[CH2:18][C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1>C(O)C>[CH3:1][C:2]1[N:7]=[C:6]([S:8][CH2:18][C:19]2[N:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:5]=[C:4]([OH:9])[CH:3]=1
Reactant: BrCc1ncccn1
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(O)nc(SCc2ncccn2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.8 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (867 mg, 6.1 mmol) was dissolved in absolute ethanol (130 mL), and then triethylamine (3.75 mL, 27.3 mmol) and 2-(bromomethyl)pyrimidine (1.57 g, 9.1 mmol) were added. The mixture was stirred overnight at room temperature. The solid was removed by filtration, and the filtrate was evaporated. The residue was triturated in water, filtered, and washed with water followed with diethyl ether. The solid was then dissolved in DCM and purified on silica gel using 10% DCM/MeOH to afford 6-methyl-2-[(pyrimidin-2-ylmethyl)sulfanyl]pyrimidin-4-ol (326 mg, 23% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.13 (s, 3H), 4.67 (s, 2H), 6.02 (bs, 1H), 7.42 (t, J=4.9 Hz, 1H), 8.78 (d, J=4.9 Hz, 2H); LRMS (ES+) m/z 235 (100%, M+1).
Reaction SMILES: [CH2:1]([C:3]1[N:15]2[C:6]([C:7](=[O:25])[NH:8][C:9]3[C:10]([N:16](CC4C=CC=CC=4)[CH3:17])=[N:11][CH:12]=[N:13][C:14]=32)=[CH:5][N:4]=1)[CH3:2].C(O)C.[OH-].[Na+]>[Pd]>[CH2:1]([C:3]1[N:15]2[C:6]([C:7](=[O:25])[NH:8][C:9]3[C:10]([NH:16][CH3:17])=[N:11][CH:12]=[N:13][C:14]=32)=[CH:5][N:4]=1)[CH3:2]
Reactant: CCc1ncc2c(=O)[nH]c3c(N(C)Cc4ccccc4)ncnc3n12
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1ncc2c(=O)[nH]c3c(NC)ncnc3n12

Procedure:
Prepared by hydrogenation of the product of Example 19 with palladium on carbon in ethanol containing 2 eq. NaOH, at 50 psi and 50° C. for 24 hours. The catalyst was removed and the product was precipitated by addition of a saturated solution of ammonium chloride. The solids were filtered and washed with water and ethanol to provide 9-ethyl-4-(methylamino)imidazo[5,1-h]pteridin-6(5H)-one.