Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([O:11][CH3:12])=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](Cl)=[O:24].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCCl>[CH3:1][C:2]1[C:6]2[C:7]([O:11][CH3:12])=[CH:8][CH:9]=[C:10]([C:23]([C:19]3[S:18][CH:22]=[CH:21][CH:20]=3)=[O:24])[C:5]=2[O:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=C(Cl)c1cccs1
Reactant: CCOC(=O)c1oc2cccc(OC)c2c1C
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCOC(=O)c1oc2c(C(=O)c3cccs3)ccc(OC)c2c1C

Procedure:
To a solution of ethyl 3-methyl-4-methoxy-benzofuran-2-carboxylate (3.48 g, 14.86 mmol) in dry 1,2-dichloroethane (15 mL) was added a solution of thiophene-2-carbonyl chloride (6.54 g, 44.61 mmol) in 1,2-dichloroethane (10 mL) followed by the portionwise addition of aluminum chloride (7.92 g, 59.40 mmol). An exothermic reaction ensued and the mixture was allowed to stir until gas evolution had slowed, then warmed to reflux for 2 hours. Upon cooling the reaction mixture was poured into 2N HCl (100 mL) and extracted with methylene chloride (4×25 mL). The combined organic extracts were washed with 5% NaHCO3, dried (Na2SO4), and concentrated to a brown solid (5.40 g). Recrystallization from ethanol/benzene afforded pure ethyl 3-methyl-4-methoxy-7-(2-thienoyl)benzofuran-2-carboxylate, compound 1. mp 179°-182° C.; 1H NMR d 1.40 (3H, t, J=6 Hz), 2.77 (3H, s), 4.04 (3H, s), 4.42 (2H, q, J=6 Hz), 6.75 (1H, d, J=8 Hz), 7.17 (1H, dd, J=4 Hz), 7.72 (2H, m), 7.86 (1H, d, J=8 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH2:11](O)[CH2:12][OH:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:9])[O:13][CH2:12][CH2:11][O:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(Br)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC1(c2cccc(Br)c2)OCCO1

Procedure:
1-(3-bromophenyl)ethanone (60.6 g), ethylene glycol (83.7 mL), and p-toluenesulfonic acid (0.15 g) were dissolved in benzene (250 mL) and heated at reflux overnight in a Dean-Stark apparatus. The mixture was cooled and washed with water. The aqueous layer was further extracted twice with chlorobutane and the combined organic layers were dried (MgSO4), filtered and the solvent was removed under reduced pressure to yield 75.0 g of a yellow oil. The oil was purified by distillation under reduced pressure (19-24 Pa, 64-74° C.) to afford 70.1 g of the title compound of Step A as an oil. 1H NMR (CDCl3): δ 7.64 (s,1H), 7.40 (m,2H), 7.20 (m,1H), 4.0 (m,2H), 3.7 (m,2H), 1.63 (s,3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C@H:14]([C:16]([OH:18])=O)[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[NH2:20][C@@H:21]([CH2:26][CH3:27])[C:22]([O:24][CH3:25])=[O:23]>>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C@H:14]([C:16]([NH:20][C@@H:21]([CH2:26][CH3:27])[C:22]([O:24][CH3:25])=[O:23])=[O:18])[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC[C@H](N)C(=O)OC
Reactant: C[C@H](NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)O
Agent: Cl
Product: CC[C@H](NC(=O)[C@H](C)NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)OC

Procedure:
Following General Procedure C and using N-(3-nitrophenylacetyl)-L-alanine (from Example DI 1 above) and methyl (S)-2-aminobutanoate hydrochloride (prepared from (S)-(+)-2-aminobutyric acid (Aldrich) using General Procedure H), the title compound was prepared as a solid (mp=154-157° C.).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[O:25][C:23](=[O:24])[CH2:22][CH2:21]2)=[CH:16][CH:15]=1.[CH:26]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]([CH3:37])[CH3:36])[C:30]=1[N:38]=[C:39]=[O:40])([CH3:28])[CH3:27]>CCOCC>[CH3:28][CH:26]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]([CH3:36])[CH3:37])[C:30]=1[NH:38][C:39]([CH:22]1[CH2:21][CH:20]([C:17]2[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=2)[O:25][C:23]1=[O:24])=[O:40])[CH3:27]
Reactant: O=C1CCC(c2ccc(F)cc2)O1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Product: CC(C)c1cccc(C(C)C)c1NC(=O)C1CC(c2ccc(F)cc2)OC1=O
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 71.2 %

Procedure:
To a cooled (-78° C.) solution of diisopropylamine (1.40 g, 0.013 mol) in 90 mL ether, n-BuLi (0.013 mol) was added dropwise followed by 45 mL ether. After stirring for 5 minutes at -78° C. under a nitrogen atmosphere, a solution of γ-(4-fluorophenyl)-γ-butyrolactone (2.50 g, 0.013 mol) in 23 mL ether was added dropwise and the resulting solution was stirred for 20 minutes at -78° C. A solution of 2,6-diisopropylphenyl isocyanate in 23 mL ether was then added dropwise and the reaction mixture was allowed to gradually warm to room temperature and stir for 16 hours under a nitrogen atmosphere (J. F. Wolfe, et al, Synthetic Communications 17, 13 (1987)). The reaction mixture was then quenched with a saturated solution of ammonium chloride and extracted with methylene chloride. The layers were separated and the organic layer was washed two times with water, dried (Na2SO4) and concentrated in vacuo (30° C.) to afford a white residue. The residue was washed with hexane, filtered, and oven-dried (30° C.) to yield a white solid, 3.77 g (0.009 mol, 71.2%) of the title compound, mp 203°-205° C.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[CH2:17]([N:24]=[C:25]=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([NH:24][C:25]([NH:16][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([C:3]2[N:4]([CH3:7])[N:5]=[CH:6][C:2]=2[Cl:1])[CH:9]=1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C
Reactant: O=C=NCc1ccccc1
Product: COc1ccc(NC(=O)NCc2ccccc2)cc1-c1c(Cl)cnn1C
Yield: 46.1 %

Procedure:
3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (59 mg, 0.25 mmol) was treated with benzyl isocyanate (34 μL, 0.28 mmol) in a similar manner to Example 1.53, providing 42.7 mg (46.1%) of Compound 105: LCMS m/z (%)=371 (M+H35Cl, 100), 373 (M+H37Cl, 40). 1H NMR (400 MHz, DMSO-d6) δ: 8.55 (s, 1H), 7.58 (s, 1H), 7.50 (dd, J1=8 Hz, J2=4 Hz, 1H), 7.33 (m, 5H), 7.30 (d, J=4 Hz, 1H), 7.10 (d, J=12 Hz, 1H), 6.58 (s, 1H), 4.28 (s, 2H), 3.73 (s, 3H), 3.58 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[F:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1>N1C=CC=CC=1>[F:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[O:18][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: Oc1cccc(F)c1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(Oc2cccc(F)c2)nc1
Temperature: 25 °C
Yield: 77.6 %

Procedure:
A solution of 2-chloro-5-nitropyridine (LXV) (1.98 g, 12.5 mmol) and 3-fluorophenol (LXVI) (1.4 g, 12.5 mmol) in pyridine (20 mL) was heated at 120° C. overnight under argon. The solution was cooled to room temperature and concentrated under vacuum. The residue was dissolved in EtOAc, washed with water, brine, dried over MgSO4 and evaporated. The residue was purified by silica gel column chromatography (100% hexane→2:98 EtOAc:hexane) to give 2-(3-fluorophenoxy)-5-nitropyridine (LXVII) as a yellow viscous oil (2.27 g, 9.7 mmol, 77% yield). 1H NMR (DMSO-d6) δ ppm 7.11 (dd, J=8 Hz, J=2 Hz, 1H), 7.17 (dt, J=8 Hz, J=6 Hz, 1H), 7.23 (td, J=10 Hz, J=2 Hz, 1H), 7.31 (d, J=9 Hz, 1H), 7.52 (q, J=9 Hz, 1H), 8.64 (dd, J=9 Hz, J=3 Hz, 1H), 9.05 (d, J=3 Hz, 1H); ESIMS found for C11H7FN2O3 m/z 234.9 (M+H).
Reaction SMILES: [Na].[C:2]([O:6][CH3:7])(=[O:5])[CH2:3][SH:4].C1(S(O[CH:18]=[C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])[C:20]#[N:21])(=O)=O)C=CC=CC=1.O>CO>[NH2:21][C:20]1[C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])=[CH:18][S:4][C:3]=1[C:2]([O:6][CH3:7])=[O:5]
Reactant: COc1ccccc1C(C#N)=COS(=O)(=O)c1ccccc1
Reactant: COC(=O)CS
Agent: [Na]
Solvent: CO
Solvent: O
Product: COC(=O)c1scc(-c2ccccc2OC)c1N

Procedure:
11 mmol of sodium are dissolved in 100 ml of methanol. After cooling the reaction mixture using an ice bath, 4.5 mmol of methyl thioglycolate and then 3.7 mmol of the compound obtained in Step B are added. After 2 hours' reaction, 100 ml of water are added, bringing about the formation of a precipitate, which is filtered off and then dried, allowing the to expected product to be isolated.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[Cl:5][C:6]1[C:7]([N:21]([CH2:26][CH2:27][NH2:28])[S:22]([CH3:25])(=[O:24])=[O:23])=[C:8]2[C:13](=[CH:14][C:15]=1[Cl:16])[N:12]=[C:11]([O:17][CH3:18])[C:10]([O:19][CH3:20])=[N:9]2>ClCCl>[Cl:5][C:6]1[C:7]([N:21]([CH2:26][CH2:27][NH:28][C:3]([NH:2][CH3:1])=[O:4])[S:22]([CH3:25])(=[O:24])=[O:23])=[C:8]2[C:13](=[CH:14][C:15]=1[Cl:16])[N:12]=[C:11]([O:17][CH3:18])[C:10]([O:19][CH3:20])=[N:9]2
Reactant: COc1nc2cc(Cl)c(Cl)c(N(CCN)S(C)(=O)=O)c2nc1OC
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)NCCN(c1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12)S(C)(=O)=O
Yield: 90.5 %

Procedure:
Methylisocyanate (8.2 μl, 8.0 mg, 0.14 mmol) was added to a solution of N-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(2-aminoethyl)-methanesulphonamide (from Preparation 27, 50 mg, 0.127 mmol) in dichloromethane (2 ml) at room temperature under nitrogen. After 30 minutes the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and concentrated under reduced pressure to give N-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)-N-(2-[methylaminocarbonyl]aminoethyl) methanesulphonamide as a pale yellow foam (52 mg, 91%).
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[CH:27]=[CH:28][C:29]([CH3:36])=[C:30]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:31]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[CH:27]=[CH:28][C:29]([CH3:36])=[C:30]([S:32]([NH2:35])(=[O:33])=[O:34])[CH:31]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Cc1ccc(Br)cc1S(N)(=O)=O
Product: Cc1ccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1S(N)(=O)=O

Procedure:
The title compound was prepared from 7-Difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (340 mg, 1.0 mmol) and 5-bromo-2-fluorobenzenesulfonamide (example B.18) (227 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (220 mg, 43%). MS (ISP) 507.3 [(M+H)+]; mp 265–267° C.
Reaction SMILES: [CH3:1][S:2]([CH2:5][O:6][CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]([OH:20])=O)=[CH:17][C:12]=2[N:11]=[CH:10]1)(=[O:4])=[O:3].[NH:21]1[CH:30]2[CH:25]([CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:24][CH2:23][CH2:22]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.Cl>CN(C=O)C>[CH3:1][S:2]([CH2:5][O:6][CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]([N:21]3[CH:30]4[CH:25]([CH2:26][CH2:27][CH2:28][CH2:29]4)[CH2:24][CH2:23][CH2:22]3)=[O:20])=[CH:17][C:12]=2[N:11]=[CH:10]1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)COCCn1cnc2cc(C(=O)O)ccc21
Reactant: C1CCC2NCCCC2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)COCCn1cnc2cc(C(=O)N3CCCC4CCCCC43)ccc21
Temperature: 0 °C
Reaction time: 12 h
Yield: 42.6 %

Procedure:
To a solution of 1-(2-methanesulfonylmethoxyethyl)-1H-benzimidazole-5-carboxylic acid (0.5 g, 1.677 mmol) in DMF (5 mL) was added decahydroquinoline (0.257 g, 1.845 mmol) followed by HOBt (0.25 g, 1.845 mmol) and DIPEA (0.65 g, 5 mmol). The reaction mixture was cooled to 0° C. and EDCl.HCl (0.354 g, 1.845 mmol) was added. It was gradually raised to ambient temperature and stirring continued for 12 h. The solvent was then evaporated, the residue diluted with water (5 mL) and extracted with CH2Cl2 (3×25 mL). The combined organic phases were washed with brine solution, dried (Na2SO4) and the solvent evaporated affording the crude amide which was purified by preparative HPLC to give 0.3 g (43%) of [1-(2-methanesulfonylmethoxy-ethyl)-1H-benzimidazol-5-yl]-(octahydroquinolin-1-yl)methanone. MS-ESI m/z 420 (M+1): 1H NMR (300 MHz, DMSO-d6) δ 1.1-1.9 (br, 13H), 2.8 (s, 3H), 3.0-3.3 (m, 2H), 4.15 (t, 2H), 4.5 (t, 2H), 4.65 (s, 2H), 7.3 (m, 1H), 7.6 (m, 1H), 7.7 (d, 1H), 8.3 (s, 1H)
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:3]=12.[C:17](Cl)(=[O:21])[CH2:18][CH2:19][CH3:20]>N1C=CC=CC=1>[C:17]([N:14]1[CH2:15][CH2:16][C:3]2[C:4](=[N:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[CH3:1])[CH2:12][CH2:13]1)(=[O:21])[CH2:18][CH2:19][CH3:20]
Reactant: CCCC(=O)Cl
Reactant: Cc1c2c(nc3ccccc13)CCNCC2
Solvent: c1ccncc1
Product: CCCC(=O)N1CCc2nc3ccccc3c(C)c2CC1
Yield: 67 %

Procedure:
3-Butyryl-1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline was prepared by acylation of 1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline with butyric acid chloride in pyridine.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[F:13][C:14]1[C:22]([O:23][C:24]2[C:33]3[C:28](=[CH:29][C:30]([OH:36])=[C:31]([O:34][CH3:35])[CH:32]=3)[N:27]=[N:26][CH:25]=2)=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[C:17]([CH3:37])[NH:18]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:57][S:58]([N:61]1[CH2:66][CH2:65][N:64]([CH2:67][CH2:68][CH2:69]O)[CH2:63][CH2:62]1)(=[O:60])=[O:59]>CN(C=O)C.C(Cl)Cl>[F:13][C:14]1[C:22]([O:23][C:24]2[C:33]3[C:28](=[CH:29][C:30]([O:36][CH2:69][CH2:68][CH2:67][N:64]4[CH2:65][CH2:66][N:61]([S:58]([CH3:57])(=[O:60])=[O:59])[CH2:62][CH2:63]4)=[C:31]([O:34][CH3:35])[CH:32]=3)[N:27]=[N:26][CH:25]=2)=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[C:17]([CH3:37])[NH:18]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1O
Reactant: CS(=O)(=O)N1CCN(CCCO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1OCCCN1CCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.6 %

Procedure:
Under nitrogen, diethyl azodicarboxylate (0.19 ml, 1.2 mmol) was added dropwise to a suspension of 4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxycinnoline (0.2 g, 0.6 mmol), (prepared as described in Example 4), triphenylphosphine (0.31 g, 1.2 mmol) and 3-(4-methylsulfonylpiperazin-1-yl)propan-1-ol (0.2 g, 0.9 mmol) in DMF (4 ml). The mixture was stirred for 2 hours at ambient temperature. Methylene chloride was added and the mixture was poured onto silica and eluted with ethyl acetate/methylene chloride (1/1) followed by methanol/ethyl acetate/methylene chloride (1/4/4) followed by methanol/methylene chloride (1/9). The fractions containing the expected product were combined and evaporated. The residue was triturated with diethyl ether and filtered. The solid was washed with ether and dried under vacuum to give 4-(4-fluoro-2-methylindol-5-yl)oxy-6-methoxy-7-(3-(4-methylsulfonylpiperazin-1-yl)propoxy)cinnoline (90 mg, 28%).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[CH:9]=O)(=[O:4])=[O:3].[I-].[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([CH2:33][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:25]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26](/[CH:33]=[CH:9]/[C:8]2[CH:11]=[CH:12][C:13]([O:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:7]=2)=[N:25]1
Reactant: c1ccc([P+](Cc2n[nH]c3ccccc23)(c2ccccc2)c2ccccc2)cc1
Reactant: CS(=O)(=O)Nc1cc(C=O)ccc1OCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cc(/C=C/c2n[nH]c3ccccc23)ccc1OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.7 %

Procedure:
A solution of 3-methanesulfonylamino-4-(2-morpholinoethoxy)benzaldehyde obtained in Step 4 (0.27 g, 0.83 mmol) in DMF (5.0 mL) was added with (1H-indazol-3-ylmethyl)triphenylphosphonium iodide obtained in Step 4 of Example 1 (0.40 g, 0.77 mmol) and potassium carbonate (0.23 g, 1.66 mmol), followed by stirring at room temperature for 2 hours, and further stirring at 60° C. for 11 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure, the crude product was purified by silica gel chromatography [amino-modified chemically bound silica gel Chromatorex (registered trademark) NH, Fuji Silysia Chemical Ltd.; ethyl acetate, then methanol/ethyl acetate=1/19], was crystallized from ethyl acetate to obtain Compound 7 (0.05 g, 14%).
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:26])[NH:6][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][OH:25])[CH:17]=2)[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[CH3:29][C@H:30]1[CH2:35][CH2:34][CH2:33][C@@H:32](C)[N:31]1[C:37]1[N:41]2[CH:42]=[C:43]([O:46][CH:47]3[CH2:52][CH2:51][CH:50]([NH2:53])[CH2:49][CH2:48]3)[CH:44]=[CH:45][C:40]2=[N:39][N:38]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:53][CH:50]2[CH2:51][CH2:52][CH:47]([O:46][C:43]3[CH:44]=[CH:45][C:40]4[N:41]([C:37]([N:31]5[CH2:32][CH2:33][CH2:34][CH2:35][C@@H:30]5[CH3:29])=[N:38][N:39]=4)[CH:42]=3)[CH2:48][CH2:49]2)=[O:26])[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][OH:25])[CH:17]=2)[N:9]=1)([CH3:14])([CH3:13])[CH3:15]
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(OC3CCC(N)CC3)cn12
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(OCCO)c2)n1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CCCCN1c1nnc2ccc(OC3CCC(NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCO)c4)CC3)cn12
Temperature: 60 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
A mixture of {5-tert-butyl-2-[3-(2-hydroxy-ethoxy)-phenyl]-2H-pyrazol-3-yl}-carbamic acid 2,2,2-trichloro-ethyl ester (WO 2007/063868, which is incorporated herein by reference in its entirety, 287.6 mg, 0.638 mmol), Intermediate 18a (140 mg, 0.425 mmol) and DIPEA (223 μL, 1.28 mmol) in dioxane (10 mL) was stirred at 60° C. for 18 h. The volatiles were concentrated in vacuo and the resultant residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to afford the title compound (222 mg, 82%). LCMS (Method 3): Rt 3.35 min, m/z 631 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](C=O)[CH:5]=[N:6][C:7]=1[I:8].[CH:11](OC)([O:14][CH3:15])[O:12][CH3:13].Cl.C(Cl)Cl>CO>[CH3:13][O:12][CH:11]([O:14][CH3:15])[C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([I:8])=[N:6][CH:5]=1
Reactant: O=Cc1cnc(I)c(Cl)c1
Reactant: COC(OC)OC
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(OC)c1cnc(I)c(Cl)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 78.7 %

Procedure:
A mixture of 5-chloro-6-iodo-3-pyridinecarbaldehyde (260 mg, 0.972 mmol), trimethyl orthoformate (1.064 ml, 9.72 mmol), HCl (3M in MeOH) (0.778 ml, 2.333 mmol), DCM (1.5 ml) and MeOH (1.5 ml) was stirred at 50° C. for 3 h. TLC showed full conversion. The solution was cooled to room temperature and concentrated under vacuum. The residue was diluted with sat. NaHCO3 and EtOAc. Extraction, drying (MgSO4), filtration, and concentration afforded 271.5 mg of crude material. Purification by flash chromatography using Flashmaster II, a 5 g silica gel cartridge, and mixtures of hexane and EtOAc as eluent afforded 5-[bis(methyloxy)methyl]-3-chloro-2-iodopyridine (239.9 mg, 79%) as a yellow oil. It will be used in the next step without further purification.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]2[NH:16][C:15](=[O:17])[CH2:14][N:9]2[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>C(O)C.CN(C)C=O>[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:4]([C:6]2[N:7]=[C:8]3[NH:16][C:15](=[O:17])[CH2:14][N:9]3[C:10](=[O:13])[C:11]=2[OH:12])=[O:5])=[CH:21][CH:20]=1
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CC(=O)N2
Solvent: CCO
Solvent: CN(C)C=O
Product: O=C1Cn2c(nc(C(=O)NCc3ccc(F)cc3)c(O)c2=O)N1
Yield: 34.4 %

Procedure:
A mixture of intermediate 5, 6-hydroxy-2,5-dioxo-1,2,3,5-tetrahydro-imidazo[1,2-a]pyrimidine-7-carboxylic acid ethyl ester, (0.035 g, 0.146 mmol) and 4-fluorobenzylamine (0.11 g, 0.88 mmol) in anhydrous ethyl alcohol (5 ml) and N,N-dimethylformamide (2 ml) was heated under reflux for 18 h. The solvent was then evaporated in vacuo and the residue was partitioned between ethyl acetate and 0.1 N hydrochloric acid. The organic phase was washed with water and brine then dried over anhydrous sodium sulfate. Evaporation of the solvent and recrystallization of the resulting solid from ethanol gave 0.016 g (34% yield) of the title amide as white crystals. 1HNMR 400 MHz (DMSO-d6) δ (ppm): 4.46 (4H, broad s, 2×CH2), 7.17 (2H, m, aromatics), 7.36 (2H, m, aromatics), 9.07 (1H, broad t, NH), 11.8–12.4 (2H, broad, OH and NH). MS (ESI+) m/z 319 [M+H+].
Reaction SMILES: [O:1]=[S:2]1(=[O:39])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([C:16]3[CH:17]=[CH:18][CH:19]=[C:20]4[C:25]=3[N:24]=[C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N:32]5[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]5)[CH:27]=3)[CH:22]=[N:21]4)=[CH:11][C:10]=2[F:38])[CH2:4][CH2:3]1.C=O.[BH3-][C:43]#N.[Na+]>CO.C(Cl)Cl>[O:39]=[S:2]1(=[O:1])[CH2:3][CH2:4][N:5]([CH2:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([C:16]3[CH:17]=[CH:18][CH:19]=[C:20]4[C:25]=3[N:24]=[C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N:32]5[CH2:37][CH2:36][N:35]([CH3:43])[CH2:34][CH2:33]5)[CH:27]=3)[CH:22]=[N:21]4)=[CH:11][C:10]=2[F:38])[CH2:6][CH2:7]1
Reactant: [BH3-]C#N
Reactant: O=S1(=O)CCN(Cc2c(F)cc(-c3cccc4ncc(-c5cccc(N6CCNCC6)c5)nc34)cc2F)CC1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(c2cccc(-c3cnc4cccc(-c5cc(F)c(CN6CCS(=O)(=O)CC6)c(F)c5)c4n3)c2)CC1

Procedure:
A solution of 8-[4-(1,1-Dioxido-thiomorpholin-4-ylmethyl)-3,5-difluoro-phenyl]-2-(3-piperazin-1-yl-phenyl)-quinoxaline (as obtained in example 169, 79 mg, 0.137 mmol) in MeOH (3 ml) and CH2Cl2 (1.5 ml) is treated with HCHO (41 μl, 0.550 mmol, 37% in H2O/MeOH 9:1) and NaBH3CN (35 mg, 0.546 mmol) at RT for 2 h. The reaction mixture is concentrated under reduced pressure. The residue is purified by reverse phase prep-HPLC (Waters) to afford the title compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:9]Br>OS(O)(=O)=O.O=S(=O)=O>[Br:9][C:5]1[CH:4]=[N:3][C:2]([CH3:1])=[C:7]([CH3:8])[CH:6]=1
Reactant: BrBr
Reactant: Cc1cccnc1C
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: Cc1cc(Br)cnc1C

Procedure:
2,3-Dimethylpyridine is treated with bromine in oleum to give 3-bromo-5,6-dimethylpyridine which is converted into a Grignard reagent, and this is treated with ethyl orthoformate and the product hydrolysed to give 5,6-dimethylpyridine-3-carboxaldehyde. This aldehyde is condensed with malonic acid and the product is hydrogenated and esterified to give ethyl β-(5,6-dimethyl-3-pyridyl)propionate. Substitution of this ester for ethyl β-(3-pyridyl)propionate in the procedure of Example 6 and fusion of the product with 2-(5-methyl-4-imidazolylmethylthio)ethylamine gives 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(5,6-dimethyl-3-pyridylmethyl)-4-pyrimidone.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=O)[CH:9]=[CH:10][CH:11]=1)=[O:4].[CH2:18]([NH2:21])[C:19]#[CH:20].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(#N)C>[F:16][C:2]([F:1])([F:17])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][C:13](=[O:15])[NH:21][CH2:18][C:19]#[CH:20])[CH:7]=1)=[O:4]
Reactant: O=C(O)Cc1cccc(NC(=O)C(F)(F)F)c1
Reactant: C#CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C#CCNC(=O)Cc1cccc(NC(=O)C(F)(F)F)c1
Reaction time: 2 h
Yield: 41.6 %

Procedure:
To the mixture of 2-(3-(2,2,2-trifluoroacetamido)phenyl)acetic acid (2.96 g, 12 mmol), propargylamine (0.97 ml, 15 mmol), HATU (4.5 g, 12 mmol) in acetonitrile (50 ml), added DIPEA (5.2 ml, 30 mmol) slowly. Stirring was kept 2 hours at room temperature. Removed solvent, extracted with EtOAc, washed with 1N HCl, water and brine, dried over sodium sulfate. Concentrated to get 1.42 g 2,2,2-trifluoro-N-(3-(2-oxo-2-(prop-2-ynylamino)ethyl)phenyl)acetamide as white solid.