Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][CH2:7][C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[C:4]([CH3:26])[CH:3]=1.C(N(CC)CC)C.[Cl:34][C:35]([Cl:40])([Cl:39])[C:36](Cl)=[O:37]>ClCCl>[Cl:34][C:35]([Cl:40])([Cl:39])[C:36]([C:21]1[N:13]2[C:12]([CH2:11][N:10]([C:8](=[O:9])[CH2:7][O:6][C:5]3[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=3[CH3:26])[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14]2)=[CH:23][CH:22]=1)=[O:37]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Cc1cc(Cl)ccc1OCC(=O)N1Cc2cccn2Cc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(Cl)ccc1OCC(=O)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Temperature: 25 °C

Procedure:
To a cold (0° C.) solution of 10-[(4-chloro-2-methylphenoxy)acetyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (2.70 mmol) and triethylamine (0.76 mL) in dichloromethane (15 mL) was added trichloroacetyl chloride (0.90 mL). This was stirred and allowed to warm to room temperature overnight. The reaction mixture was washed with water (2×), 0.1N hydrochloric acid (2×), dilute aqueous sodium bicarbonate (2×) and finally with water (1×). The organic phase was dried over anhydrous sodium sulfate and evaporated. The product was purified by crystallization from warm ethyl acetate/hexane (3/1), m.p. 156-158° C.
Reaction SMILES: C(OC([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12](Br)=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.[Cu][C:22]#[N:23].N.O>CN1CCCC1=O>[C:22]([C:12]1[CH:11]=[C:10]2[C:15]([C:16]([CH3:18])([CH3:19])[CH2:17][NH:8][CH2:9]2)=[CH:14][CH:13]=1)#[N:23]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Br)ccc2C(C)(C)C1
Reactant: N#C[Cu]
Agent: N
Solvent: CN1CCCC1=O
Solvent: O
Product: CC1(C)CNCc2cc(C#N)ccc21
Yield: 86.4 %

Procedure:
A mixture of N-tert-butyloxycarbonyl-7-bromo-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline (4.2 g, 0.01236 mol) and copper (I) cyanide (2.2 g, 0.0247 mol) in N-methylpyrrolidinone (120 ml) was heated at vigorous reflux for 2 hours. On cooling the mix was poured into 0.880 ammonia (300 ml) and water (300 ml) and extracted into ethyl acetate (4×200 ml). Combined organic extracts were washed with 1:10.880 ammonia:water (3×150 ml), water (3×200 ml) and brine (150 ml) and dried (Na2SO4). Solvent was removed in vacuo to afford the title compound as a pale brown solid (1.99 g, 86%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:14])[CH2:10][CH2:11][CH2:12][CH3:13])=[CH:5][CH:4]=1.[N:15]([O-])=[O:16].[Na+]>C1COCC1.C(OCC)C>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:14])/[C:10](=[N:15]\[OH:16])/[CH2:11][CH2:12][CH3:13])=[CH:7][CH:8]=1
Reactant: CCCCC(=O)c1ccc(Br)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC/C(=N/O)C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.1 %

Procedure:
The conc. HCl (40 mL) was added dropwise to a solution of 1-(4-bromophenyl)pentan-1-one (4.68 g, 19.41 mmol) and sodium nitrite (4.02 g, 58.2 mmol) in THF (80 ml) at 0° C. and allowed to warm to room temperature and stirred 18 hours. The reaction mixture was diluted with diethyl ether and the organic phase washed with sat'd NaHCO3 and brine. Concentration gave (Z)-1-(4-bromophenyl)-2-(hydroxyimino)pentan-1-one 3.1 g (33%) as an oil which was used without further purification.). RT=2.1 min, (Condition 1) LCMS: Anal. Calcd. for C11H12BrN1O2 270.01; found: 270.15 (M+H)+.
Reaction SMILES: [Br:1][C:2]([Br:5])(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([C@H:29]1[CH2:34][CH2:33][C@H:32]([CH:35]=O)[CH2:31][CH2:30]1)[CH2:26][CH2:27][CH3:28].CCCCCC>C(Cl)Cl>[Br:1][C:2]([Br:5])=[CH:35][C@H:32]1[CH2:33][CH2:34][C@H:29]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:30][CH2:31]1
Reactant: BrC(Br)(Br)Br
Reactant: CCCC[C@H]1CC[C@H](C=O)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CCCC[C@H]1CC[C@H](C=C(Br)Br)CC1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
A solution, cooled to -20° C., of 398 g of tetrabromomethane in 1 l of methylene chloride was treated dropwise under nitrogen gasification within 30 minutes with a solution of 629.6 g of triphenylphosphine in 1 l of methylene chloride. The mixture was subsequently stirred at -10° C. for a further 30 minutes, then treated dropwise within 30 minutes with a solution of 101 g of trans-4-butylcyclohexanecarboxaldehyde in 500 ml of methylene chloride and stirred at -5° C. for a further 2 hours. The mixture was poured into 4 l of hexane, the resulting mixture was stirred at -20° C. for 1 hour and then the precipitate was filtered off under suction and rinsed well with 1 l of cold (-20° C.) hexane. The filtrate was concentrated to a volume of about 1 l on a rotary evaporator, diluted with 2 l of hexane, again concentrated to a volume of about 1 l and stirred at -20° C. for a further 30 minutes. The precipitate was filtered off under suction and rinsed well with 700 ml of cold (-20° C.) hexane. The filtrate was freed from solvent on a rotary evaporator and the resulting yellow oil (195 g) was filtered chromatographically on silica gel with about 3 l of hexane. The eluate was evaporated up to constant weight on a rotary evaporator, there being obtained 171.3 g (88.1%) of trans-1-(2,2-dibromovinyl)-4-butylcyclohexane as a colourless liquid; Rf-value (hexane) 0.55.
Reaction SMILES: CN1CCOCC1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10].[C:18]([C:20]1[CH:38]=[CH:37][C:23]([O:24][CH2:25][CH:26]([NH:28][C:29](=[O:36])[C@H:30]([CH2:32][CH:33]([CH3:35])[CH3:34])[NH2:31])[CH3:27])=[CH:22][CH:21]=1)#[N:19].O>C(Cl)Cl>[C:18]([C:20]1[CH:21]=[CH:22][C:23]([O:24][CH2:25][CH:26]([NH:28][C:29](=[O:36])[C@H:30]([CH2:32][CH:33]([CH3:34])[CH3:35])[NH:31][C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:10])[CH3:27])=[CH:37][CH:38]=1)#[N:19]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)C[C@H](N)C(=O)NC(C)COc1ccc(C#N)cc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: O
Product: CC(C)C[C@H](NC(=O)Oc1ccccc1)C(=O)NC(C)COc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 71.7 %

Procedure:
0.5 g of N-methylmorpholine, and subsequently 0.8 g of phenyl chloroformate were added to a suspension containing 1.5 g of N1 -[2-(4-cyanophenoxy)-1-methylethyl]-L-leucinamide suspended in 40 ml of methylene chloride at -15° C. The mixture was allowed to sit and warm naturally to room temperature and stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then the methylene chloride was removed tinder reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 1.5 g of the desired product in the form of colorless powder (yield: 73%)
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:22]=[CH:21][C:8](/[CH:9]=[N:10]/[C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][O:14][C:15]3=[O:20])=[CH:7][CH:6]=1)[CH3:3].[CH2:23]([C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1)[CH3:24].[O-:33][CH2:34][CH3:35].[Na+].C(O)C>C(OCC)(=O)CC>[CH3:1][N:2]([CH2:4][C:5]1[CH:22]=[CH:21][C:8]([CH:9]2[CH:29]([C:28]3[CH:31]=[CH:32][C:25]([CH2:23][CH3:24])=[CH:26][CH:27]=3)[C:34](=[O:33])[C:35]3[C:16]([C:15]([O:14][CH2:13][CH3:12])=[O:20])=[CH:17][CH:18]=[CH:19][C:11]=3[NH:10]2)=[CH:7][CH:6]=1)[CH3:3]
Reactant: CC[O-]
Reactant: CCc1ccc(C=O)cc1
Reactant: CN(C)Cc1ccc(/C=N/c2cccc3c2COC3=O)cc1
Agent: [Na+]
Solvent: CCOC(=O)CC
Solvent: CCO
Product: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(CC)cc1)C(c1ccc(CN(C)C)cc1)N2
Temperature: 0 °C
Reaction time: 3 h
Yield: 32 %

Procedure:
A mixture of (E)-4-(4-((dimethylamino)methyl)benzylideneamino)isobenzofuran-1(3H)-one (588 mg, 2 mmol) and 4-ethylbenzaldehyde (268 mg, 2 mmol) in ethyl propionate (15 mL) was cooled to 0° C. Then a solution of sodium ethoxide in ethanol (sodium (138 mg, 6 mmol) in ethanol (5 mL)) was added dropwise. After the addition, the mixture was stirred at room temperature for 3 hr. The mixture was quenched with water (10 mL) and solvent was removed in vacuum. The residue was dissolved in water, and then extracted with ethyl acetate (100 mL×4). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude product, which was purified by chromatography (silica gel, petroleum ether/ethyl acetate=1:1) to give the crude title compound (290 mg, yield 32%). LC-MS (ESI) m/z: 457 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:11]=[C:10]([CH3:12])[N:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:13]([C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18])#[CH:14]>>[ClH:1].[C:13]([C:15]1[CH:16]=[C:17]([NH:18][C:2]2[C:3]3[CH:11]=[C:10]([CH3:12])[N:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:19]=[CH:20][CH:21]=1)#[CH:14]
Reactant: Cc1cc2c(Cl)ncnc2cn1
Reactant: C#Cc1cccc(N)c1
Product: C#Cc1cccc(Nc2ncnc3cnc(C)cc23)c1
Product: Cl

Procedure:
This material was prepared from 4-chloro-6-methyl-pyrido[3,4-d]pyrimidine (1.0 eq.) and 3-ethynylaniline (1.1 eq.) as described for Example 74. After extraction chromatography of the residue on silica in 20% to 80% acetone/hexanes afforded 166 mg of the title product as its free-base which was converted to the title product (M.P. 250-252° C.; LC-MS: 261 (MH+); anal.RP-HPLC: 3.69 min.).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)([CH3:12])[CH2:8][O:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:23][O:24][CH2:25]Cl.O>CN(C)C=O>[OH:19][C:16]1[CH:17]=[CH:18][C:13]([C:7]2([CH3:12])[C:6](=[O:20])[C:5]3[C:10](=[CH:11][C:2]([O:1][CH2:23][O:24][CH3:25])=[CH:3][CH:4]=3)[O:9][CH2:8]2)=[CH:14][CH:15]=1
Reactant: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1=O
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccc2c(c1)OCC(C)(c1ccc(O)cc1)C2=O
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
To a solution of 7-hydroxyl-3-(4-hydroxyphenyl)-3-methylchroman-4-one (4.65 g, 17.20 mmol) in dry dimethylformamide (120 ml) was added sodium hydride (454 mg, 18.92 mmol) at room tempetarure and stirred for 30 minutes. To the reaction mixture was then added methoxymethyl chloride (1.523 g, 18.92 mmol) at the same temperature and stirred for 2 h. When the reaction was completed, water was added to the reaction solution which was then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (n-hexane:ethyl acetate=8:2 to 7:3) to give 3.55 g (yield: 66%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:20])[CH:7]([O:16][C:17](=O)[CH3:18])[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:2][CH2:3][CH3:4].[C:21]1([O-])[CH:26]=CC=[CH:23][CH:22]=1.[Na+].C1(O)C=CC=CC=1.C[O-].[Na+]>O1CCOCC1>[CH2:1]([O:5][C:6](=[O:20])[CH:7]([O:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:26][CH:18]=1)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)C(NC(=O)OC(C)(C)C)OC(C)=O
Reactant: [O-]c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: Oc1ccccc1
Product: CCCCOC(=O)C(NC(=O)OC(C)(C)C)Oc1ccccc1

Procedure:
To 2.9 g. (0.01 mol.) of N-t-butoxycarbonyl-2-acetoxyglycine n-butyl ester in 10 ml. of dioxane was added a solution of sodium phenolate prepared from 0.94 g. of phenol and 0.54 g. of sodium methoxide in 15 ml. of dioxane. After refluxing for 2 hours, the solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with cold 10% aqueous sodium hydroxide, dried (MgSO4) and concentrated to yield the title compound as an oil.
Reaction SMILES: C([Li])C[CH2:3][CH3:4].[C:6]1([NH:12][C:13](=[O:23])[C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][C:15]=2OC)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[B:24](OC(C)C)([O:29]C(C)C)[O:25]C(C)C.Cl>O1CCCC1>[CH2:6]([NH:12][C:13]([C:14]1[CH:15]=[CH:16][C:17]([B:24]([OH:29])[OH:25])=[CH:18][CH:19]=1)=[O:23])[CH2:11][C:10]1[CH:9]=[CH:8][CH:7]=[CH:4][CH:3]=1
Reactant: [Li]CCCC
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1cc(Br)ccc1C(=O)Nc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(NCCc1ccccc1)c1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.6 %

Procedure:
n-Butyl lithium(1.6 M in hexane solution, 10 ml, 15.78 mmol) was added slowly to a solution of N1-phenyl-4-bromo-2-methoxybenzamide (1.92 g, 6.31 mmol) in tetrahydrofuran (47 mL) at −78° C. After 30 minutes, triisopropyl borate (2.2 mL, 9.47 mmol) was added rapidly. The reaction mixture was allowed to warm up to room temperature after 13 minutes and stirred for 16 hours. Hydrochloric acid (2.5N, 47 mL) was added and the mixture was stirred for 5 h hours. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The residue was recrystallized from ethyl acetate/heptane to give 4-[(phenethylamino)carbonyl]phenylboronic acid (0.486 g, 28%). 1H NMR (DMSO-d6) δ 2.85 (m, 2H), 3.49 (m, 2H), 7.22 (m, 5H), 7.73 (m, 4H), 8.17 (s, 2H), 8.54 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][C:5]1[N:6]=[C:7]([NH2:10])[S:8][CH:9]=1.[C:12]1([CH:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19](O)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:11])[CH2:4][C:5]1[N:6]=[C:7]([NH:10][C:19](=[O:20])[CH:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[S:8][CH:9]=1
Reactant: COC(=O)Cc1csc(N)n1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)Cc1csc(NC(=O)C(c2ccccc2)c2ccccc2)n1
Reaction time: 16 h

Procedure:
(2-Amino-thiazol-4-yl)-acetic acid methyl ester (45 mg, 0.20 mmol) and diphenyl-acetic acid (37 mg, 0.20 mmol) were dissolved in N,N-dimethylformamide (2 mL) containing triethylamine (84.1 μL, 0.600 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography (29.4 mg, 0.0802 mmol, 40. %). ESI-MS m/z calc. 380.1. found 381.3 (M+1)+ Retention time 3.28 minutes.
Reaction SMILES: C[C@H](C1C=CC=CC=1)N=[C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[CH2:10][CH3:11].[C:18]([O:22][CH3:23])(=[O:21])[CH:19]=[CH2:20].[O:24]1CCCC1>>[CH3:23][O:22][C:18](=[O:21])[CH2:19][CH2:20][C@:5]1([CH2:10][CH3:11])[CH2:6][CH2:7][CH2:8][CH2:9][C:4]1=[O:24]
Reactant: C1CCOC1
Reactant: C=CC(=O)OC
Reactant: CCC1CCCCC1=N[C@H](C)c1ccccc1
Product: CC[C@@]1(CCC(=O)OC)CCCCC1=O
Reaction time: 504 h
Yield: 57 %

Procedure:
A solution of (R)-α-methyl-N-(2-ethylcyclohexylidene)-benzenemethanamine (1.303 kg, 5.68 mol), and methyl acrylate (5.68 mol, 489 g, 511 mL) in 2.5 L of dry tetrahydrofuran was sealed under nitrogen and placed in the dark for 21 days. The tetrahydrofuran was then removed on a rotary evaporator and the residue was divided in half. Each half was stirred for 1.5 hours in 3.5 L of 1M hydrochloric acid and extracted with ether (4×700 mL). The extracts were combined, washed with 1M hydrochloric acid (2×500 mL), 1M sodium hydroxide (500 mL) and brine (500 mL). The two halves were combined and concentrated affording 689 g (3.25 mol, 57%) of yellow oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[N:5][CH:4]=1.[F:23][C:24]1[CH:30]=[C:29]([CH3:31])[C:28]([OH:32])=[CH:27][C:25]=1[NH2:26]>CC(O)CCC>[ClH:2].[F:23][C:24]1[CH:30]=[C:29]([CH3:31])[C:28]([OH:32])=[CH:27][C:25]=1[NH:26][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[N:5][CH:4]=1
Reactant: Cc1cc(F)c(N)cc1O
Reactant: COc1cc2c(Cl)cnnc2cc1OCc1ccncc1
Agent: Cl
Solvent: CCCC(C)O
Product: COc1cc2c(Nc3cc(O)c(C)cc3F)cnnc2cc1OCc1ccncc1
Yield: 29.3 %

Procedure:
A solution of 4-chloro-6-methoxy-7-(4-pyridylmethoxy)cinnoline hydrochloride (268 mg, 0.71 mmol), (prepared as described for the starting material in Example 10), and 2-fluoro-5-hydroxy-4-methylaniline, (109 mg, 0.77 mmol), (prepared as described for the starting material in Example 11), in 2-pentanol (6 ml) was heated at reflux for 4 hours. After dilution with isopropanol, the solid was filtered off, washed with isopropanol followed by ether to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(4-pyridylmethoxy)cinnoline hydrochloride (92 mg, 29%).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[N:5]([CH2:13][CH3:14])[C:4]=1[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([CH:24]2[CH2:26][CH2:25]2)=[O:23])=[CH:17][CH:16]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:34][CH2:35][Cl:36].O>CCC(C)=O.C(OCC)(=O)C>[Cl:36][CH2:35][CH2:34][O:12][C:8]1[CH:7]=[C:6]2[C:11]([C:3]([C:1]#[N:2])=[C:4]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([CH:24]4[CH2:26][CH2:25]4)=[O:23])=[CH:17][CH:16]=3)[N:5]2[CH2:13][CH3:14])=[CH:10][CH:9]=1
Reactant: CCn1c(-c2ccc(NC(=O)C3CC3)cc2)c(C#N)c2ccc(O)cc21
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCC(C)=O
Product: CCn1c(-c2ccc(NC(=O)C3CC3)cc2)c(C#N)c2ccc(OCCCl)cc21
Temperature: 25 °C
Yield: 81 %

Procedure:
To a solution of cyclopropanecarboxylic acid [4-(3-cyano-1-ethyl-6-hydroxy-1H-indol-2-yl)-phenyl]-amide (4 g, 11.6 mmol) in 15 mL of MEK is added K2CO3 (8 g, 58 mmol) and 1-bromo-2-chloro-ethane (6.7 mL, 70 mmol). Then the mixture is heated at reflux overnight. After it is cooled to room temperature, water and ethyl acetate are added. The organic layer is separated, washed with brine (2×), dried over anhydrous Na2SO4, filtered and concentrated to yield 81% of the crude cyclopropanecarboxylic acid {4-[6-(2-chloroethoxy)-3-cyano-1-ethyl-1H-indol-2-yl]-phenyl}-amide.
Reaction SMILES: C(Cl)(Cl)(Cl)Cl.O.[CH2:7]([O:14][CH2:15][C@H:16]1[O:18][C@H:17]1[CH2:19][OH:20])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C[CH2:22][O:23]CC>>[CH2:7]([O:14][CH2:15][C@H:16]1[O:18][C@H:17]1[C:19]([O:23][CH3:22])=[O:20])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: OC[C@@H]1O[C@@H]1COCc1ccccc1
Reactant: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)[C@@H]1O[C@@H]1COCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 10 ml CCl4, 10 ml CH3CH, and 15 ml of H2O was added 50 mg of RuCl3 --H2O and 1.00 g (5.16 mmole) of (2S-cis)-3-(benzyloxymethyl)oxirane methanol. The solution was cooled to 0° C. and 3.50 g (15.5 mmole) of H5IO6 was added in portions over 15 min with vigorous stirring. The reaction was allowed to stir vigorously for 2 hours. The mixture was poured into 100 ml of Et2O, the organic layer separated and the aqueous layer washed with 20 ml of Et2O. The combined organic layers were washed four times with 50 ml 0.1N NaOH. The aqueous layers were combined, acidified to pH 2, and extracted three times with 50 ml Et2O. The ether layers were dried over MgSO4, filtered and evaporated to yield a pale yellow residue.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][C:7](Cl)=[O:8].[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][C:11]1=[O:19]>C(=S)=S>[Cl:5][CH2:6][C:7]([C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[NH:10][C:11](=[O:19])[CH2:12]2)=[O:8]
Reactant: O=C1Cc2ccccc2N1
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: O=C1Cc2cc(C(=O)CCl)ccc2N1
Reaction time: 0.17 h
Yield: 98.9 %

Procedure:
To a 250 ml round-bottomed flask equipped with condenser and nitrogen inlet were added 30.7 grams (230 mmol) aluminum chloride, 150 ml carbon disulfide, and 3.8 ml (48 mmol) chloroacetyl chloride. To the stirring mixture was added 5.0 grams (37 mmol) of oxindole portionwise over 15 minutes. The reaction was stirred a further 10 minutes, then refluxed 2 hours. The reaction was cooled, added to ice, stirred thoroughly, and the beige precipitate filtered, washed with water, and dried to afford 7.67 grams (97%) of 5-chloroacetyl-oxindole. NMR (d, DMSO-d6): 3.40 (s, 2H), 5.05 (s, 2H), 6.8-7.9 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:14]=1[NH2:15]>>[CH3:11][O:12][C:13]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:14]=1[NH:15][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: COc1ccc(N)c(OC)c1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: COc1ccc(NC(=O)c2ccc(F)cc2)c(OC)c1

Procedure:
The protocol is identical to that described for Example 1.1, with 4-fluorobenzoyl chloride replacing 2,6-difluorobenzoyl chloride and 2,4-dimethoxyaniline replacing 3,5-dimethoxyaniline.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH:6]([NH:13][C:14]([NH2:16])=[S:15])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:19][I:20]>CO>[IH:20].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([NH:13][C:14]([S:15][CH3:19])=[NH:16])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:17][CH:18]=1
Reactant: CI
Reactant: NC(=S)NC(c1ccccc1)c1ccc(Cl)cc1
Solvent: CO
Product: CSC(=N)NC(c1ccccc1)c1ccc(Cl)cc1
Product: I
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5.3 g (0.019 mole) of N-(4-chlorobenzhydryl)thiourea in 25 ml of methanol is treated with 2.64 g (0.019 mole) of methyl iodide and allowed to stir at room temperature overnight. The methanol is removed in vacuo to yield the crude pseudothiourea as an oil. The oily methyl N-(4-chlorobenzhydryl)carbamimidothioate hydroiodide is used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([Br:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH3:19])[CH:12]=3)[CH:7]=1.[C:24]1([N:30]=[C:31]=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[Br:22][C:5]1[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH3:19])[CH:12]=3)=[CH:7][C:2]([NH:1][C:31]([NH:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:32])=[C:3]([F:23])[CH:4]=1
Reactant: CNc1cc2c(cn1)cc(-c1cc(N)c(F)cc1Br)c(=O)n2C
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: CNc1cc2c(cn1)cc(-c1cc(NC(=O)Nc3ccccc3)c(F)cc1Br)c(=O)n2C
Temperature: 25 °C
Reaction time: 12 h
Yield: 42.6 %

Procedure:
A solution of 3-(5-amino-2-bromo-4-fluoro-phenyl)-1-methyl-7-methylamino-1H-[1,6]naphthyridin-2-one (420 mg, 1.16 mmol) in DCM (25 mL) was treated with phenyl isocyanate (0.19 g, 1.62 mmol) and TEA (0.326 g, 3.23 mmol) and stirred at RT for 12 h. The mixture was concentrated under reduced pressure and washed with MTBE (1×). The crude product was purified by prep-HPLC separation (MeCN/H2O with 0.1% TFA) to give 1-(4-bromo-2-fluoro-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)phenyl)-3-phenylurea (245 mg, 44% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.08 (s, 1H), 8.67 (s, 1H), 8.40 (s, 1H), 8.17 (d, J=8.8 Hz, 1H), 7.70 (s, 1H), 7.64 (d, J=10.8 Hz, 1H), 7.40 (d, J=7.6 Hz, 2H), 7.28-7.24 (t, J=7.6 Hz, 2H), 7.04-7.03 (m, 1H), 6.98-6.94 (t, J=8 Hz, 1H), 6.17 (s, 1H), 3.50 (s, 3H), 2.85 (d, J=4.8 Hz, 3H).