Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:2]=1.N1C=CC=C(CCCO)C=1>CO.C(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[O:12])[CH:2]=1
Reactant: OCCCCCc1cccnc1
Agent: OCCCc1cccnc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=CCCCCc1cccnc1
Yield: 96 %

Procedure:
Utilising the procedure described in example 10(a) employing 5-(3-pyridyl)-1-pentanol in lieu of 3-(3-pyridyl)-1-propanol gave after purification by column chromatography (flash silica gel, 5% methanol in chloroform) 5-(3-pyridyl)-1-pentanal (96% yield).
Reaction SMILES: [CH2:1]([NH+:3]1[CH2:8][CH2:7][C:6](O)(O)[C:5]([F:12])([F:11])[CH2:4]1)[CH3:2].[NH2:13][OH:14]>C(O)C>[CH2:1]([N:3]1[CH2:8][CH2:7][C:6](=[N:13][OH:14])[C:5]([F:12])([F:11])[CH2:4]1)[CH3:2]
Reactant: NO
Reactant: CC[NH+]1CCC(O)(O)C(F)(F)C1
Solvent: CCO
Product: CCN1CCC(=NO)C(F)(F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
A suspension of 1-ethyl-3,3-difluoro-4,4-dihydroxy-piperidinium (10.213 g, 46.93 mmol) in ethanol (80 ml) was charged with aqueous hydroxylamine solution (50% by weight, 3.58 ml, 58.4 mmol) and left to stand overnight. The thick precipitate was dissolved with the addition of ethanol (20 ml) and heating. The solution was then cooled to room temperature before being place over ice. The precipitated solid was then collected by filtration and dried over vacuum to yield 8.27 g 1-ethyl-3,3-difluoro-piperidin-4-one oxime (99%) LCMS (Method F): RT=0.14 min, m+H=179.0 1H NMR (400 MHz, D2O) δ 4.07-3.82 (m, 2H), 3.53 (s, 2H), 3.38 (q, J=7.3 Hz, 2H), 3.13 (s, 2H), 1.38 (t, J=7.3 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:19])=[C:7]([Cl:18])[CH:8]=2)[N:3]=1.[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][NH2:24]>C1(C)C=CC=CC=1>[Cl:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[Cl:19])[N:3]=[C:2]([NH:24][CH2:23][CH2:22][N:21]([CH3:25])[CH3:20])[C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)=[N:10]2
Reactant: Clc1cc2nc(Cl)c(-c3ccccn3)nc2cc1Cl
Reactant: CN(C)CCN
Solvent: Cc1ccccc1
Product: CN(C)CCNc1nc2cc(Cl)c(Cl)cc2nc1-c1ccccn1
Yield: 44.6 %

Procedure:
A solution of 2,6,7-trichloro-3-pyridin-2-yl-quinoxaline (0.50 g) and N,N-dimethyl-ethane-1,2-diamine (0.28 g) in toluene (20 mL) was refluxed under nitrogen atmosphere for 16 hours. After refluxing, the reaction mixture was cooled, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, 1:9 methanol/dichloromethane) to give the product as a yellow solid (0.26 g); mp 95-97° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]3[O:15][C:14]([C:16]([O:18]CC)=[O:17])=[CH:13][C:12](=[O:21])[C:10]3=2)[N:5]=[C:4]([C:22]([O:24]C)=[O:23])[CH:3]=1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]3[O:15][C:14]([C:16]([OH:18])=[O:17])=[CH:13][C:12](=[O:21])[C:10]3=2)[N:5]=[C:4]([C:22]([OH:24])=[O:23])[CH:3]=1
Reactant: CCOC(=O)c1cc(=O)c2c(ccc3nc(C(=O)OC)cc(Cl)c32)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(Cl)c2c(ccc3oc(C(=O)O)cc(=O)c32)n1
Reaction time: 1.5 h
Yield: 79.2 %

Procedure:
Ethyl methyl 10-chloro-1-oxo-1H-pyrano[3,2-f]quinoline-3,8-dicarboxylate (300 mg; 0.83 mmole) in methanol (30 ml) was heated under reflux during the dropwise addition of M/10 aqueous sodium hydroxide (16.6 ml; 1.66 mmole) with stirring over 1.5 hrs. After the addition the mixture was heated under reflux for a further 2 hrs when it was cooled and poured into dilute aqueous hydrochloric acid. The brown solid was filtered off and dried in a vacuum oven over sodium hydroxide pellets. This gave analytically pure title compound 210 mg (79%) (decomp. 253°). NNMR (d6DMSO) δ, 8.48, 8.13 (AB quartet, J=9H); δ, 8.33 (s,1H), 7.2 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[C:3]=1[CH:12]=[CH2:13].[CH2:14]([NH2:17])[CH:15]=[CH2:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:14]([NH:17][C:4]1[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[CH:12]=[CH2:13])[CH:15]=[CH2:16]
Reactant: C=CCN
Reactant: C=Cc1c(F)ccc([N+](=O)[O-])c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCNc1c([N+](=O)[O-])ccc(F)c1C=C
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
To a solution of 1,3-difluoro-4-nitro-2-vinylbenzene (115 mg, 0.621 mmol) in DMF (3 mL) was added allylamine (0.0513 mL, 0.683 mmol) and potassium carbonate (0.173 g, 1.24 mmol). The reaction mixture was stirred at RT for 2 h, and then partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc and the combined organic layers were washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, eluant 1-5% EtOAc in cyclohexane) affording the title compound as a yellow oil (109.6 mg, 79%). 1H NMR (CDCl3, 300 MHz): 8.08 (1H, dd J=9.4, 5.8 Hz), 7.64 (1H, bs), 6.57 (1H, t, J=9.3 Hz), 6.51 (1H, dd, J=18.0, 11.6 Hz), 5.81 (1H, tdd, J=17.1, 10.2, 5.5 Hz), 5.72 (1H, ddd, J=18.0, 2.5, 1.6 Hz), 5.65 (1H, ddd, J=11.6, 1.5, 0.9 Hz), 5.26 (1H, dq, J=17.1, 1.5 Hz), 5.17 (1H, dq, J=10.2, 1.4 Hz), 3.98 (2H, ddt, J=6.3, 5.5, 1.6 Hz)
Reaction SMILES: Cl.[C:2]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:14][S:13][C:12]3=[N:15][CH:16]=[C:17]([C:18]([OH:20])=O)[N:11]23)=[CH:6][C:5]=1F)#[N:3].[Br:22][C:23]1[CH:36]=[CH:35][C:34]([O:37][Si:38]([C:51]([CH3:54])([CH3:53])[CH3:52])([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:33][C:24]=1[CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][C:27]1=[O:32].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>>[Br:22][C:23]1[CH:36]=[CH:35][C:34]([O:37][Si:38]([C:51]([CH3:54])([CH3:53])[CH3:52])([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:33][C:24]=1[CH2:25][N:26]1[CH2:31][CH2:30][N:29]([C:18]([C:17]2[N:11]3[C:12]([S:13][CH2:14][CH:10]3[C:7]3[CH:6]=[CH:5][C:4]([C:2]#[N:3])=[CH:9][CH:8]=3)=[N:15][CH:16]=2)=[O:20])[CH2:28][C:27]1=[O:32]
Reactant: N#Cc1ccc(C2CSc3ncc(C(=O)O)n32)cc1F
Reactant: CC(C)(C)[Si](Oc1ccc(Br)c(CN2CCNCC2=O)c1)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](Oc1ccc(Br)c(CN2CCN(C(=O)c3cnc4n3C(c3ccc(C#N)cc3)CS4)CC2=O)c1)(c1ccccc1)c1ccccc1

Procedure:
The carboxylic acid from Step K (221 mg, 0.679 mmol), the piperazinone from Step E (390 mg, 0.679 mmol), EDC hydrochloride (156 mg, 0.814 mmol), HOBT (110 mg, 0.814 mmol), and N,N-diisopropylethylamine (0.591 mL, 3.39 mmol) were stirred together in dry, degassed DMF (5 mL) at 25° C. for 16 hours. The reaction was poured onto saturated aqueous sodium bicarbonate and extracted with methylene chloride (3×25 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to provide a yellow oil. The crude product was purified by column chromatography (3% methanol/methylene chloride) to provide the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([F:21])[C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[C:22]([C:24]1[CH:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=1)#[N:23].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>C1COCC1.CO>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:17])([F:16])[F:15])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30](=[O:31])[C:27]3[CH:26]=[CH:25][C:24]([C:22]#[N:23])=[CH:29][N:28]=3)[CH:3]=[C:4]([F:21])[C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: C[C@@]1(c2cc(N)cc(F)c2F)C[C@@H](C(F)(F)F)OC(N)=N1
Reactant: N#Cc1ccc(C(=O)O)nc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@]1(c2cc(NC(=O)c3ccc(C#N)cn3)cc(F)c2F)C[C@@H](C(F)(F)F)OC(N)=N1
Reaction time: 0.5 h
Yield: 39.4 %

Procedure:
To a cooled (ice bath) solution of (4S,6S)-4-(5-amino-2,3-difluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (0.095 g, 0.307 mmol) and 5-cyano-2-pyridinecarboxylic acid (0.055 g, 0.369 mmol) in THF (2.5 mL) and MeOH (1.5 mL) was added 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (0.118 g, 0.399 mmol). After stirring for 30 min, the ice bath was removed. The reaction was stirred at ambient temperature for 15 h. The reaction was quenched with saturated sodium bicarbonate solution. MeOH was removed by rotary evaporation. The aqueous residue was extracted with EtOAc (2×). The organic extracts were combined, concentrated and purified by Shimadzu HPLC to afford N-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4,5-difluorophenyl)-5-cyanopicolinamide (0.053 g, 0.121 mmol, 39.3% yield) as white solid. MS m/z=440.1 [M+H]+. Calculated for C19H14F5N5O2: 439.3
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][CH:13]=[C:14]([CH2:16][OH:17])[N:15]=3)[S:10][C:3]=12.[CH3:18][NH:19][C:20]([C:22]1[C:30]2[C:25](=[CH:26][C:27]([OH:31])=[CH:28][CH:29]=2)[N:24]([CH3:32])[C:23]=1[CH3:33])=[O:21].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:18][NH:19][C:20]([C:22]1[C:30]2[C:25](=[CH:26][C:27]([O:31][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]5[S:12][CH:13]=[C:14]([CH2:16][OH:17])[N:15]=5)[S:10][C:3]=34)=[CH:28][CH:29]=2)[N:24]([CH3:32])[C:23]=1[CH3:33])=[O:21]
Reactant: OCc1csc(-c2cc3nccc(Cl)c3s2)n1
Reactant: CNC(=O)c1c(C)n(C)c2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNC(=O)c1c(C)n(C)c2cc(Oc3ccnc4cc(-c5nc(CO)cs5)sc34)ccc12

Procedure:
This material was prepared by the reaction of [2-(7-chloro-thieno[3,2-b]pyridin-2-yl)-thiazol-4-yl]-methanol with 6-hydroxy-1,2-dimethyl-1H-indole-3-carboxylic acid methyl amide 16e and Cs2CO3 in a manner as previously described for example 1. 1H NMR (300 MHz, DMSO-d6) δ 8.52 (1H, d, J=5.5 Hz), 8.14 (1H, s), 7.83 (1H, d, J=8.6 Hz), 7.63 (1H, s), 7.58 (1H, d, J=4.7 Hz), 7.54 (1H, d, J=2.0 Hz), 7.04 (1H, dd, J=2.0, 8.6 Hz), 6.64 (1H, d, J=5.5 Hz), 4.60 (2H, s), 3.67 (3H, s), 2.80 (3H, d, J=4.3 Hz), 2.61 (3H, s). LCMS (ESI+) [M+H]/z Calc'd 465. found 465. Anal. (C23H20N4O3S2.0.6CH3OH) C, H, N.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1>O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:11]#[N:12])=[CH:6][CH:5]=1
Reactant: N#CCc1ccc(F)cc1
Reactant: Brc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: N#CC(c1ccc(F)cc1)c1ccccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.6 %

Procedure:
A sample of sodium hydride (60%, 1.60 g, 0.04 mole) was washed with dry hexanes. After removal of hexanes a 100 ml portion of dimethyl sulfoxide was added. To this mixture was added a solution of 4-fluorophenylacetonitrile (5.41 g, 0.04 mole). The mixture was stirred 3 hrs at room temperature under nitrogen. 2-Bromopyridine (6.32 g, 0.04 mole) was added to the mixture, the reaction mixture was then stirred overnight at 65° C. The reaction mixture was poured into 1200 ml of water and the aqueous phase was extracted several times with chloroform (the chloroform layer was filtered using Celite®). The combined chloroform layer was extracted with water and 5% sodium hydroxide. The chloroform layer was dried over sodium sulfate, filtered, and solvent removed to give a red oil. The oil was subjected to flash chromatography on silica gel using 10% ethyl acetate-90% hexanes and 20% ethyl acetate-80% hexanes for elution. Fractions of similar purity was combined and solvent removed in vacuo. The oil obtained was dried in vacuo overnight at 80° C. to give 2.43 g (28.6%) of clear oil.
Reaction SMILES: [C:1]1([C:7](Cl)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:21]=[C:22]1[N:27]2[CH2:28][CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[CH:26]2[CH2:25][NH:24][CH2:23]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:24]2[CH2:23][C:22](=[O:21])[N:27]3[CH2:28][CH2:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[CH:26]3[CH2:25]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CNCC2c3ccccc3CCCN12
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC2c3ccccc3CCCN12
Reaction time: 1.5 h
Yield: 100.4 %

Procedure:
Triphenylmethyl chloride (0.47 g) was added to a mixture of 4-oxo-1,2,3,4,6,7,8,12b-octahydropyrazino[2,1-a][2]benzazepine (0.31 g) and triethylamine (0.25 ml) in chloroform (25 ml, ethanol-free) at 0°. The mixture was maintained at 0° for 30 min then at room temperature for 90 min. The solution was washed with saturated sodium bicarbonate solution, dried (MgSO4) and evaporated. The residue was purified by column chromatography (SiO2, Et2O) to give the title compound (0.66 g, 100%) as a white powder.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[F:20])[CH2:8][CH2:7]1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:19][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([F:20])[C:13]=1[O:12][CH:9]1[CH2:10][CH2:11][CH:6]([CH2:4][OH:3])[CH2:7][CH2:8]1
Reactant: CCOC(=O)C1CCC(Oc2c(F)cccc2F)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1CCC(Oc2c(F)cccc2F)CC1
Yield: 81.8 %

Procedure:
4-(2,6-Difluorophenoxy)cyclohexanecarboxylic acid ethyl ester (155 mg, 0.55 mmol) was carried out using Method H with lithium aluminum hydride (150 mg; 3.95 mmol) in tetrahydrofuran at 0° C. under nitrogen flow. Material was purified by flash chromatography using 2% methanol in dichloromethane to give 109 mgs of title compound. (82% yield).
Reaction SMILES: [C:1]([CH:5]1[CH2:25][CH2:24][C:8]2([O:12][CH2:11][CH:10](OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C-:26]#[N:27].[Na+]>CN(C=O)C>[C:1]([CH:5]1[CH2:6][CH2:7][C:8]2([O:12][CH2:11][CH:10]([C:26]#[N:27])[CH2:9]2)[CH2:24][CH2:25]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)OC2COC3(CCC(C(C)(C)C)CC3)C2)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)C1CCC2(CC1)CC(C#N)CO2
Temperature: 100 °C
Yield: 99.4 %

Procedure:
A mixture of 8-t-butyl-3-(p-toluenesulfonyloxy)-1-oxaspiro-(4,5)decane (18.3 g, 50 mmol) and sodium cyanide (4.9 g, 100 mmol) in dry DMF (75 ml) was heated to 100° C. for 6 hours. Light petroleum/ethylacetate 4:1 (50 ml) was added and the mixture was filtrated from insoluble material. The filtrate was then evaporated in vacuo and the resulting residue was taken up in toluene (100 ml). It was washed with water, dried (MgSO4) and evaporated in vacuo to yield a brownish oil (11.0 g) which was Kugelrohr distilled (120°-125° C., 0.015 mbar) to furnish the product as colourless crystals (8.94 g, m.p. 35°-40° C.).
Reaction SMILES: [BH4-].[Na+].[NH2:3][C:4]1[S:5][C:6]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]>CC(C)C(O)=O>[CH3:6][CH:7]([CH3:14])[CH2:8][NH:3][C:4]1[S:5][C:6]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)c1c(N)sc(Cc2ccccc2)c1C(=O)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)C(=O)O
Product: CCOC(=O)c1c(Cc2ccccc2)sc(NCC(C)C)c1C(=O)OCC
Yield: 99.8 %

Procedure:
Prepared from sodium borohydride (2.2 g) and diethyl 2-amino-5-phenylmethylthiophene-3,4-dicarboxylate (4.10 g) in 2-methylpropanoic acid (20 ml) following the method of Example 3 step b to give the subtitle compound (2.39 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][C:9]([C:13]([O:15]CC)=[O:14])=[C:8]2[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25].[OH-].[Na+].C(O)C.Cl>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][C:9]([C:13]([OH:15])=[O:14])=[C:8]2[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25]
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Nc1ccccc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cccc2c(Nc3ccccc3C)c(C(=O)O)cnc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of Ethyl 8-methoxy-4-[(2-methylphenyl)amino]-3-quinolinecarboxylate, 15.00 g (0.0445 mole), 100 ml of 3 N sodium hydroxide solution and 100 ml of ethanol was stirred at room temperature for 16 hours. The mixture was diluted with 300 ml of water and acidified to pH 6.8 with 6 N hydrochloric acid solution. The precipitate was collected by filtration, washed in succession with water and acetone and air dried for about 1.5 hr. Weight of solid was 13.41 g (98%), m.p. 272° C. (d).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:18][N:19]([CH2:21][CH2:22]Cl)[CH3:20]>O1CCOCC1.O>[CH3:18][N:19]([CH3:20])[CH2:21][CH2:22][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CN(C)CCCl
Reactant: NC(=O)c1ccccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CN(C)CCOc1ccccc1C(N)=O
Temperature: 85 °C
Yield: 60.7 %

Procedure:
A solution of 2-hydroxy-benzamide (10 g) and potassium carbonate (35.4 g) in dioxane (50 ml) and water (4.5 ml) was added with N,N-dimethyl-2-chlorethylamine hydrochloride (6.5 g). The mixture was heated at 85° C. for 3 hours. The solvent was evaporated off, the resulting residue was poured into 5% HCI and extracted with diethyl ether. The aqueous phase was adjusted to pH with sodium bicarbonate, then extracted with ethyl acetate. The organic layer was dried and evaporated to dryness to give the title compound as a white solid (5.7 g).
Reaction SMILES: [CH:1]#[C:2][C@H:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].I[C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:9][C@H:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:2]#[C:1][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Reactant: C#C[C@H](O)CCCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCC[C@@H](O)C#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, (R)-(+)-1-octyn-3-ol (61 mg, 0.48 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (146 mg, 0.4 mmol) (Starting Material 2 supra) using (Ph3P)2PdCl2 (20 mg) and CuI (10 mg) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 15 h to yield (R)-(Z)-1,3-dihydro-4-(3-hydroxy-1-octynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 91 mg, 62%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12](=[O:14])[NH:11][C@H:10]([CH2:15][C:16]2[CH:21]=[C:20](Br)[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])[C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]1(C)C=CC=CC=1>O1CCOCC1.C[Zn]C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([N:8]1[CH2:13][C:12](=[O:14])[NH:11][C@H:10]([CH2:15][C:16]2[CH:21]=[C:20]([CH3:26])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])[C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1
Reactant: COc1ccc(Br)cc1C[C@H]1NC(=O)CN(Cc2ccccc2)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C[Zn]C
Solvent: C1COCCO1
Product: COc1ccc(C)cc1C[C@H]1NC(=O)CN(Cc2ccccc2)C1=O
Temperature: 25 °C

Procedure:
To a degassed mixture of (R)-1-benzyl-3-(5-bromo-2-methoxy-benzyl)-piperazine-2,5-dione (1.91 g, 4.74 mmol) and Pd(dppf)Cl2 (0.12 g, 0.14 mmol) in dioxane (18 mL), 2M dimethyl zinc in toluene (4.74 mL, 9.48 mmol) was slowly added at 0° C. and heated at reflux for 1 h to give dark brownish reaction mixture. The mixture was then cooled RT and quenched with methanol (10 mL) and filtered off the precipitate and rinsed with more methanol (20 mL). Filtrate was concentrated and purified (SiO2, 95:5, CH2Cl2:MeOH) to give (1.33 g, 83%) as a amber oil. MS (ESI) 339 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)[N:2]=1.N1(C2C=C[C:23]([CH:24]=[O:25])=CC=2)C=CC=N1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:14]=[CH:13][C:10](/[CH:11]=[CH:23]/[CH:24]=[O:25])=[CH:9][CH:8]=2)[N:2]=1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1ccc(-c2cccnn2)cc1
Product: O=C/C=C/c1ccc(-c2cccnn2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(3-pyridazinyl)benzaldehyde (prepared as described in Reference Example 16) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 211 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]1[N:8]=[C:9]([NH:12][C:13](=[O:30])[CH:14]([NH:22]C(OC(C)(C)C)=O)[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:10][CH:11]=1)=[O:5])[CH3:2].FC(F)(F)C(O)=O>>[CH2:1]([O:3][C:4]([CH2:6][C:7]1[N:8]=[C:9]([NH:12][C:13](=[O:30])[CH:14]([NH2:22])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1csc(NC(=O)C(Cc2ccccc2)NC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)Cc1csc(NC(=O)C(N)Cc2ccccc2)n1
Yield: 93.9 %

Procedure:
Alternatively, by deprotecting N-(4-ethoxycarbonylmethyl-2-thi-azolyl)-3-phenyl-2-(tert-butoxycarbonyl)amino-propanamide (5 g; 11.5 mmoles), prepared as described in example 1, in the presence of trifluoroacetic acid, N-(4-ethoxycarbonylmethyl-2-thiazolyl)-2-amino-3-phenyl-propanamide (3.6 g; 93.2% yield) having the same above reported spectroscopic characteristics, was obtained.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=2)[C:3]1=[O:17].[O:18]=[C:19]1[N:28]([CH:29]2[CH2:34][CH2:33][N:32]([C:35](Cl)=[O:36])[CH2:31][CH2:30]2)[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20]1>>[OH:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[CH2:9][N:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C@@H:2]([NH:1][C:35]([N:32]2[CH2:33][CH2:34][CH:29]([N:28]3[CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][C:19]3=[O:18])[CH2:30][CH2:31]2)=[O:36])[C:3]1=[O:17]
Reactant: O=C(Cl)N1CCC(N2Cc3ccccc3NC2=O)CC1
Reactant: N[C@@H]1CCCCN(Cc2cccc(O)c2)C1=O
Product: O=C(N[C@@H]1CCCCN(Cc2cccc(O)c2)C1=O)N1CCC(N2Cc3ccccc3NC2=O)CC1

Procedure:
The title compound was prepared with (3R)-3-amino-1-(3-hydroxybenzyl)azepan-2-one and 4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1-carbonyl chloride using a similar procedure to Example 16. MS 492.2599 (M+1).