Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8](I)[N:7]=3.N#N.C[Si](C)(C)N[Si](C)(C)C.C[N:29](C)[CH:30]=[O:31]>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>[Br:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:30]([NH2:29])=[O:31])[N:7]=3
Reactant: CN(C)C=O
Reactant: Brc1ccc2c(c1)OCCn1cc(I)nc1-2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: N#N
Product: NC(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Temperature: 70 °C
Yield: 76 %

Procedure:
Alternatively, a solution of 8-Bromo-2-iodo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (10.00 g, 0.02558 mol) in N,N-Dimethylformamide (250 mL) was thoroughly degassed with N2. Bis(triphenylphosphine)palladium(II) chloride (0.807 g, 0.00115 mol) was added followed by Hexamethyldisilazane (21.58 mL, 0.1023 mol). The solution was flushed with CO for 2 minutes and then sealed with a CO balloon attached. The reaction was heated to 70° C. for 2.5 hours. Methylene chloride and saturated NH4Cl were added and the mixture was extracted 4 times with methylene chloride. The organic phases were combined, dried with MgSO4 and concentrated. A small amount of isopropanol was added and the mixture was triturated overnight. The mixture was filtered to yield 5.97 g (76% yield) of 8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide as a fine brown powder. MS(ESI+) 308.0/310.0
Reaction SMILES: [NH2:1][C:2]1([CH2:8]O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.O=S(Cl)Cl.[CH3:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]=[C:25]=[S:26]>O1CCOCC1>[CH3:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]=[C:25]1[S:26][CH2:8][C:2]2([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[NH:1]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: NC1(CO)CCCCC1
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Product: Cc1cc([N+](=O)[O-])ccc1N=C1NC2(CCCCC2)CS1
Yield: 20 %

Procedure:
1-Amino-1-(hydroxymethyl)cyclohexane (Method B1a) was dissolved in p-dioxane (80 mL) then treated with SOCl2 followed by 2-methyl-4-nitrophenyl isothiocyanate in a manner analogous to Method C2a to give 2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.5]decane (20%), which was reacted with isobutyl bromide in a manner analogous to Method D2a to yield 1-isobutyl-2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.5]decane (0.026 g, 2%): TLC (20% EtOAc/hex) Rf0.69.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]([NH2:18])=[S:17])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:20][C:21](=O)[CH2:22][CH2:23][N:24]1[C:32](=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]1=[O:34].C(N(CC)CC)C.C(O)C>O>[CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]2[S:17][CH:20]=[C:21]([CH2:22][CH2:23][N:24]3[C:32](=[O:33])[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25]3=[O:34])[N:18]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CBr)CCN1C(=O)c2ccccc2C1=O
Reactant: NC(=S)Nc1ncccc1OCc1ccccc1
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCc1csc(Nc2ncccc2OCc2ccccc2)n1
Yield: 98.1 %

Procedure:
A mixture of 1-(3-(benzyloxy)pyridin-2-yl)thiourea (prepared according to Example 2, Steps A and B) (8.00 g, 30.8 mmol), 2-(4-bromo-3-oxobutyl)isoindoline-1,3-dione (12.8 g, 43.2 mmol; prepared according to J. Med. Chem. (1992) 35, 3239-3246), triethylamine (7.31 mL, 52.4 mmol), and ethanol (200 mL) was heated at reflux for 2 hours. The reaction mixture was cooled, diluted with water (200 mL), filtered, washed several times with water and hexanes, and dried. The product was recrystallized the solid from hexanes:methylene chloride (1:1, 250 mL) to afford 2-(2-(2-(3-(benzyloxy)pyridin-2-ylamino)thiazol-4-yl)ethyl)isoindoline-1,3-dione (13.8 g, 98.0% yield) as a white powder. 1H NMR (d6-DMSO) δ 9.93 (bs, 1H), 7.80-7.87 (m, 6H), 7.57 (d, 2H), 7.35-7.43 (m, 4H), 6.89 (m, 1H), 6.70 (s, 1H), 5.25 (s, 2H), 3.88 (t, 2H), 2.91 (t, 2H). Mass spectrum (apci) m/z=457 (M+H).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:18][C:19](=[O:33])[NH:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@:22]1([CH2:31][OH:32])[CH2:27][CH2:28][CH2:29][OH:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:11]([O:18][C:19](=[O:33])[NH:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@:22]1([CH:31]=[O:32])[CH2:27][CH2:28][CH:29]=[O:30])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(N[C@@H]1CCCC[C@]1(CO)CCCO)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=CCC[C@@]1(C=O)CCCC[C@H]1NC(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
A solution of dimethyl sulfoxide (1.6 g, 19 mmol) in dichloromethane (50 mL) was cooled to −78° C. and treated dropwise with oxalyl chloride (1.42 g, 11.2 mmol). After the addition was complete, the solution was stirred for 30 minutes and was then treated dropwise with a solution of [(1R,2S)-2-hydroxymethyl-2-(3-hydroxypropyl)-cyclohexyl]-carbamic acid benzyl ester (0.65 g, 1.9 mmol) in dichloromethane (10 mL). After the addition was complete, the solution was stirred for 40 minutes and then treated with triethylamine (1.8 g, 18 mmol). The mixture was stirred for 30 minutes before removing the cooling bath and stirring at room temperature for 1 hour. The mixture was quenched with saturated aqueous sodium bicarbonate (100 mL) and the organic phase was separated and washed successively with water and saturated aqueous sodium chloride, and then dried over sodium sulfate. The solvent was removed under vacuum to give an oil (0.6 g). 1H NMR (300 MHz, CDCl3) δ9.74 (bs, 1H), 9.43 (bs, 1H), 7.39-7.27 (m, 5H), 5.06 (m, 2H), 4.91 (bd, J=9 Hz, 1H), 4.14 (bm, 1H), 2.60-1.30 (m, 12H). Mass spec (ES+) m/z 318.2 (M+H+, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([OH:23])[CH2:21]Br)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C)C=O>[N:24]([CH2:21][C@@H:20]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16](=[O:19])[NH:17]2)[OH:23])=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=[N-]
Reactant: O=c1ccc2c([C@@H](O)CBr)ccc(OCc3ccccc3)c2[nH]1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@H](O)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 65 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
8-Benzyloxy-5-((R)-2-bromo-1-hyroxyethyl)-1H-quinolin-2-one (20.8 g, 55.6 mmol) and sodium azide (3.61 g, 55.5 mmol) were suspended in N,N-dimethylformamide (100 mL) and the mixture was stirred at 65° C. for 3 hours. Sodium azide (1.81 g, 27.8 mmol) was added thereto and the mixture was stirred at the same temperature overnight. To the reaction solution was added purified water and stirred at room temperature for 1 hour. The precipitate was collected by filtration and washed with purified water. By drying under reduced pressure, 5-((R)-2-azido-1-hyroxyethyl)-8-benzyloxy-1H-quinolin-2-one (16.8 g) was obtained.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([NH:9][C:10](=O)C(C)(C)C)[C:6]([CH3:16])=[CH:5][CH:4]=1)[CH3:2].C([Li])(C)(C)C.CN(C)C=O.Cl>C(OCC)C>[CH2:1]([C:3]1[N:8]=[C:7]2[NH:9][CH:10]=[CH:16][C:6]2=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C)c(NC(=O)C(C)(C)C)n1
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCc1ccc2cc[nH]c2n1
Temperature: -30 °C
Reaction time: 1 h
Yield: 57.8 %

Procedure:
A solution of N-(6-ethyl-3-methyl-pyridin-2-yl)-2,2-dimethyl-propionamide (17.6 g, 0.080 mol) in diethyl ether (400 mL) is cooled to −78° C. and treated with tert-butyllithium (99 mL 1.7 M in pentane). After stirring for 1 h, the solution is warmed to −30° C. for 4 h and treated with N,N-dimethylformamide (19.8 mL, 0.26 mol). After stirring an additional 10 min, the suppension is carefully added to 6 N HCl, pre-cooled to −20° C., at a rate such that the temperature warms to about 0° C. After the addition is complete, the aqueous layer is subsequently washed with ethyl acetate and heated to a gentle reflux for 36 h. The resulting solution is cooled to 0° C. and basified with aq 6 N NaOH to pH 10-12. The solution is then extracted with dichloromethane, dried over MgSO4 and concentrated. The resulting pale orange solid is passed through a plug of silica gel with 30% ethyl acetate in hexanes and recrystaliztion from heptane to give 6-ethyl-1H-pyrrolo[2,3-b]pyridine (6.76 g, 58%) as an off-white solid. mp 117-120° C.; Rf 0.57 (50% ethyl acetate in hexanes); 1H NMR (DMSO-d6, 300 MHz) δ 11.46 (s, 1 H), 7.80 (d, J=8.1 Hz, 1 H), 7.33 (d, J=2.7 Hz, 1 H), 6.90 (d, J=8.1 Hz, 1 H), 6.34 (d, J=3.0 Hz, 1 H), 2.76 (q, J=7.5 Hz, 2 H), 1.23 (t, J=7.5 Hz, 3 H); LRMS calcd for C9H10N: 146.0; found 146.0 (M)+. Anal. Calcd for C9H10N: C, 73.94; H, 6.89; N, 19.16. Found C, 73.93; H, 6.91; N, 19.23.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][C:22]#[C:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([NH2:14])[C:5]=2[N:15]=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:3]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([NH2:14])[C:5]=2[N:15]=1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCCCOCC#Cc1ccccc1
Solvent: Cc1ccccc1
Product: Cc1nc2c(N)nc3ccccc3c2n1CCCCOCCCc1ccccc1
Reaction time: 3 h
Yield: 28.4 %

Procedure:
2-Methyl-1-{4-[(3-phenylprop-2-ynyl)oxy]butyl}-1H-imidazo[4,5-c]quinolin-4-amine (2.00 g, 5.202 mmol) from Example 149 was combined with toluene (15 mL) in a Parr flask and heated to reflux. The resulting solution was purged with nitrogen. Palladium (1 g 10% palladium on carbon) was added to the solution under nitrogen, and the flask was pressurized with hydrogen at 310 kPa for 3 hours. Monitoring by HNMR indicated complete reaction. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The concentrate was dissolved in dichloromethane and basified with 1 N potassium hydroxide to a pH of about 14. The layers were separated and the aqueous layer was extracted with dichloromethane (3×). The organic layers were combined, washed with 0.5 N potassium hydroxide (2×), water (3×), and brine (3×), dried with sodium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was recrystallized from acetonitrile, and the resulting shinny tan crystals were dried for 2 days, triturated with ether, collected by vacuum filtration, and dried to provide 0.5744 g of 2-methyl-1[4-(3-phenylpropoxy)butyl]-1H-imidazo[4,5-c]quinolin-4-amine, m.p. 105.1-106.0° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O.O1CCOCC1.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>[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[C:18]([C:2]2[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1ccc(Br)s1
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1ccc(-c2cccc(C(F)(F)F)c2)s1
Temperature: 80 °C
Reaction time: 12 h
Yield: 83.3 %

Procedure:
Under a nitrogen atmosphere, to a mixed solvent of ethyl 5-bromothiophene-2-carboxylate (2.4 g, 10 mmol), 3-(trifluoromethyl)phenylboronic acid (2.9 g, 15 mmol) and sodium carbonate (2.1 g, 20 mmol) in water/1,4-dioxane (v/v=1/1, 10 mL) was added tetrakistriphenylphosphinepalladium (1.1 g, 1.0 mmol), and the mixture was stirred at 80° C. for 12 hr. The reaction mixture was cooled to room temperature, water was added and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (petroleum ether/ethyl acetate=60/1) to give the title compound (2.5 g, 83%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1)=[O:3].[BH4-].[Na+].Br.[NH3:16]>>[NH2:16][CH2:1][CH:2]([OH:3])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1
Reactant: N
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1
Agent: Br
Agent: [BH4-]
Agent: [Na+]
Product: NCC(O)c1cccc([N+](=O)[O-])c1

Procedure:
3-Nitroacetophenone is brominated in the α-position, the bromination product is reduced by means of sodium borohydride to the corresponding bromohydride and this is treated with ammonia. There is obtained rac.-α-(aminomethyl)-3-nitrobenzyl alcohol which melts at 107°-108° (softening from 105°) after crystallization from ethyl acetate-ether.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1([CH2:13][CH2:14][CH2:15][C:16]#[N:17])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.O>CCOCC>[N:7]1([CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: N#CCCCN1CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: NCCCCN1CCOCC1
Temperature: -55 °C
Reaction time: 5 h

Procedure:
14.8 g lithium aluminium hydride were weighed under N2 atmosphere into a round-bottomed flask. The substance was cooled down to −55° C. and 150 ml ether was added dropwise. The suspension was allowed to stir; then 30 g 4-Morpholin-4-yl-butyronitrile were dissolved in 200 ml ether and the solution was added dropwise to the reaction mixture. Again 200 ml ether were added to the mixture and the reaction was stirred at room temperature overnight. At the next day the mixture was cooled down to less than 10° C. and 35 ml H2O were added carefully. After five hours the mixture was fritted and the residue was washed with 300 ml ether. The filtrate was dried, concentrated and finally distilled under vacuum. The product fractions were collected at 74-78° C. and 2.1-1.6 Torr. The purity of the colourless oil was judged by gas chromatography, GC-MS and 1H-NMR.
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:41])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:40])[CH2:12][CH2:13][C@@:14]3([C:30](=[O:39])[NH:31][CH:32]4[CH2:36][CH:35]([CH2:37][OH:38])[CH:34]=[CH:33]4)[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:43])[CH3:42])(=O)C.C1COCC1.[OH-].[Na+]>CO>[OH:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:41])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:40])[CH2:12][CH2:13][C@@:14]3([C:30]([NH:31][CH:32]4[CH2:36][CH:35]([CH2:37][OH:38])[CH:34]=[CH:33]4)=[O:39])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:43])[CH3:42]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NC3C=CC(CO)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NC3C=CC(CO)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 6 h
Yield: 68.5 %

Procedure:
(1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-(4-(hydroxymethyl)cyclopent-2-enylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl acetate (Example 27, 0.22 g) in MeOH:THF (8:8 ml) and cooled the contents to 0° C. then sodium hydroxide (0.05 g in 4 ml water) was added and the contents were stirred for about 6 hours at room temperature then completion of the reaction was monitored by TLC. The reaction mixture was evaporated under reduced pressure, the residue was taken in water and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in DCM as eluent to furnish the title compound (0.14 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.76-0.99 (m, 16H); 1.25-1.85 (m, 35H); 2.03-2.28 (m, 6H); 2.47 (s, 3H); 2.86-3.10 (m, 3H); 3.18 (s, 1H); 4.60 (s, 1H); 4.74 (s, 1H); ES Mass: 551 (100%), [M+1] 551; HPLC: 96.94%.
Reaction SMILES: [ClH:1].CN(C)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:17]=[C:18]([C:23]([NH2:25])=[NH:24])[S:19][C:20]=3[S:21][CH3:22])[N:15]=2)=[CH:6][CH:5]=1.Br.CN(C)C1C=CC(NC2SC=C(C3C=C([C:48]([O:50]C)=S)SC=3C)N=2)=CC=1>>[ClH:1].[CH3:48][O:50][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:17]=[C:18]([C:23]([NH2:25])=[NH:24])[S:19][C:20]=3[S:21][CH3:22])[N:15]=2)=[CH:6][CH:5]=1
Reactant: COC(=S)c1cc(-c2csc(Nc3ccc(N(C)C)cc3)n2)c(C)s1
Reactant: CSc1sc(C(=N)N)cc1-c1csc(Nc2ccc(N(C)C)cc2)n1
Agent: Br
Agent: Cl
Product: COc1ccc(Nc2nc(-c3cc(C(=N)N)sc3SC)cs2)cc1
Yield: 22 %

Procedure:
4-(2-{[4-(Dimethylamino)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxamidine hydrochloride: Methyl 4-(2-{[4-(dimethylamino)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboxylate hydrobromide (50 mg, 0.10 mmol) was treated as described in Example 154, step (b) to give 9.4 mg (22% yield) of 4-{2-[(4-methoxyphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidine hydrochloride. 1H NMR (DMSO-d6, 300 MHz) 2.70 (s, 3H), 2.84 (s, 6H), 6.75 (d, 2H, J=9.2 Hz), 7.00 (s, 1H), 7.56 (d, 2H, J=9.1 Hz), 8.31 (s, 1H), 8.68 (bs, 3H), 9.92 (bs, 1H).
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:21]=[CH:20][CH:19]=[CH:18][C:6]=2[C:7]=1[S:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH3:2].[CH2:22]([N:24]([CH2:28][CH3:29])[CH2:25][CH2:26]Cl)[CH3:23]>>[CH2:1]([C:3]1[O:4][C:5]2[CH:21]=[CH:20][CH:19]=[CH:18][C:6]=2[C:7]=1[S:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:23][CH2:22][N:24]([CH2:28][CH3:29])[CH2:25][CH3:26])=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH3:2]
Reactant: CCc1oc2ccccc2c1S(=O)(=O)c1ccc(O)cc1
Reactant: CCN(CC)CCCl
Product: CCc1oc2ccccc2c1S(=O)(=O)c1ccc(OCCN(CC)CC)cc1

Procedure:
Reaction of 2-ethyl-3-(4-hydroxyphenylsulfonyl)benzofuran with 2-diethylaminoethyl chloride by the procedure described in Example 1 gives the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:19][C:20]1[C:21]([C:26](O)=[O:27])=[N:22][N:23]([CH3:25])[CH:24]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26]([C:21]3[C:20]([Cl:19])=[CH:24][N:23]([CH3:25])[N:22]=3)=[O:27])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: Cn1cc(Cl)c(C(=O)O)n1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Product: Cn1cc(Cl)c(C(=O)Nc2ccc(F)c([C@@]3(C)N=C(N)OCC3(F)F)c2)n1

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 4-chloro-1-methyl-1H-pyrazole-3-carboxylic acid following procedure I yielded the title compound as a colorless amorphous material. MS (ISP): m/z=402.3 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:19]Cl)=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[N:11]=2)[CH:8]=1.[F:21][C:22]1[CH:27]=[C:26]([F:28])[N:25]=[C:24]([NH2:29])[N:23]=1>>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:19][NH:29][C:24]3[N:25]=[C:26]([F:28])[CH:27]=[C:22]([F:21])[N:23]=3)=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[N:11]=2)[CH:8]=1
Reactant: Nc1nc(F)cc(F)n1
Reactant: Fc1ccc(-c2nc3ccc(Cl)cn3c2CCl)cc1
Agent: Cl
Product: Fc1ccc(-c2nc3ccc(Cl)cn3c2CNc2nc(F)cc(F)n2)cc1
Yield: 45 %

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 139 from 6-chloro-3-(chloromethyl)-2-(4-fluorophenyl)imidazo[1,2-a]pyridine hydrochloride and 4,6-difluoropyrimidin-2-amine. (0.42 g, 45% yield). M/e+ 390.2 for C18H11ClF3N5 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.O1CCOCC1>[F:21][C:18]1[CH:19]=[CH:20][C:15]([N:10]2[CH2:11][CH2:12][N:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:9]2=[O:13])=[CH:16][CH:17]=1
Reactant: Cc1ccncc1N1CCNC1=O
Reactant: Fc1ccc(Br)cc1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2ccc(F)cc2)C1=O
Yield: 43.5 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8465 mmol) was reacted with 1-bromo-4-fluoro-benzene (148.1 mg, 0.8465 mmol), 1,4-dioxane (25 mL), copper iodide (16 mg, 0.08465 mmol), trans-1,2-diamino cyclohexane (29 mg, 0.2539 mmol) and potassium carbonate (468 mg, 3.3860 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in chloroform) afforded 100 mg of the product (43% yield).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH:19]1(Br)[CH2:21][CH2:20]1>CN(C=O)C.O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH:19]2[CH2:21][CH2:20]2)=[CH:4][N:3]=1
Reactant: Oc1cnc(Cl)c2ccccc12
Reactant: BrC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ncc(OC2CC2)c2ccccc12
Temperature: 145 °C
Yield: 3.3 %

Procedure:
To a solution of 1-chloroisoquinolin-4-ol (1.0 g, 55.7 mmol) in DMF (20 m) was added Cs2CO3 (2.72 g, 8.35 mmol) followed by cyclopropylbromide (6.74 g, 55.7 mmol) at room temperature. The reaction vessel (Pressure tube) was sealed and heated at 145° C. for 18 h. The reaction mass was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get desired compound (0.4 g, 32.7%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ ppm 8.22-8.24 (m, 2H), 8.14 (s, 1H), 8.14-8.12 (m, 1H), 7.74-7.67 (m, 2H), 4.00-3.95 (m, 1H), 0.92-0.90 (m, 4H); MS: MS m/z 220.0 (M++1).