Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:26][C:9]2[N:10]([CH3:25])[C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:15][C:16]=3[C:8]=2[CH2:7]1)=O)C.[CH3:27][NH2:28]>C(O)C>[C:19]1([CH2:18][O:17][C:14]2[CH:13]=[CH:12][C:11]3[N:10]([CH3:25])[C:9]4[CH2:26][CH:6]([C:4]([NH:28][CH3:27])=[O:3])[CH2:7][C:8]=4[C:16]=3[CH:15]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CN
Reactant: CCOC(=O)C1Cc2c(n(C)c3ccc(OCc4ccccc4)cc23)C1
Solvent: CCO
Product: CNC(=O)C1Cc2c(n(C)c3ccc(OCc4ccccc4)cc23)C1
Temperature: 100 °C
Reaction time: 144 h
Yield: 69.8 %

Procedure:
In a 50 ml sealed tube, was added a solution of 1,2,3,4-tetrahydro-7-phenylmethoxy-4-methylcyclopent[b]indole-2-carboxylic acid ethyl ester (10 g, 0.03 mole) in 25 ml absolute ethanol, followed by methylamine (40% aqueous solution, 10 ml, 0.13 mole). After stirring at 100° C. for six days, the mixture was cooled. A tan solid precipitated, which was collected and dried to give 7.0 g of the product as a solid, m.p. 176°-177° C. A sample of this solid was recrystallized from ethanol/ether (1:1) to give white crystals, m.p. 181°-182° C.
Reaction SMILES: [CH:1]1[CH:15]=[C:14]2[C:4]([CH:5](O)[C:6]3[C:11]([CH:12]=[CH:13]2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:3][CH:2]=1.C(O)(=O)[CH2:18][C:19]([OH:21])=[O:20]>>[CH:15]1[C:14]2[CH:13]=[CH:12][C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[CH:5]([CH2:18][C:19]([OH:21])=[O:20])[C:4]=2[CH:3]=[CH:2][CH:1]=1
Reactant: OC1c2ccccc2C=Cc2ccccc21
Reactant: O=C(O)CC(=O)O
Product: O=C(O)CC1c2ccccc2C=Cc2ccccc21
Temperature: 160 °C
Reaction time: 1.5 h

Procedure:
A round-bottom flask, equipped with a distillation apparatus, is charged with dibenzosuberenol (10.0 g, 48.01 mmol) and malonic acid (25.0 g, 240.08 mmol). The mixture is heated in a 160° C. oil bath. The solids melt. Gas bubbles form and water and acetic acid are distilled through the condenser. After 1.5 hours, the mixture is cooled to room temperature and dissolved in ethyl acetate. The organic solution is washed with brine and dried over MgSO4. The solvent is removed in vacuo to give an off-white solid, which is recrystallized from hexane-ethyl acetate- (AcOEt)/1:1 to yield the title compound as white crystals, 10.2 g; mp 167°-168° C.
Reaction SMILES: C([O-])=O.[NH4+].C(O)C.C([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[N:25]=[C:24]([O:35][CH:36]([CH3:38])[CH3:37])[CH:23]=2)=[CH:18][CH:17]=1)C1C=CC=CC=1>O.O1CCCC1.[Pd]>[CH:36]([O:35][C:24]1[CH:23]=[C:22]([C:19]2[CH:18]=[CH:17][C:16]([OH:15])=[CH:21][CH:20]=2)[N:26]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[N:25]=1)([CH3:38])[CH3:37]
Reactant: COc1ccc(-n2nc(OC(C)C)cc2-c2ccc(OCc3ccccc3)cc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-n2nc(OC(C)C)cc2-c2ccc(O)cc2)cc1

Procedure:
To a solution of ammonium formate (954 mg) in water (2 ml) were added ethanol (10 ml), a solution of 5-[4-(benzyl-oxy)phenyl]-3-isopropoxy-1-(4-methoxyphenyl)-1H-pyrazole obtained by Example 36 (2.09 g) in tetrahydrofuran (10 ml), and 10% palladium on carbon 50% wet (200 mg) successively. The mixture was refluxed for 1 hr.
Reaction SMILES: [CH2:1]([C:6]1[S:13][C:12]2[CH:11]=[C:10]([C:14](Cl)=[O:15])[S:9][C:8]=2[CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:17]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[CH2:18][CH2:19][CH2:20][CH3:21].N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C:6]1[S:13][C:12]2[CH:11]=[C:10]([C:14]([O:28][C:25]3[CH:24]=[CH:23][C:22]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:27][CH:26]=3)=[O:15])[S:9][C:8]=2[CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1cc2sc(C(=O)Cl)cc2s1
Reactant: CCCCCc1ccc(O)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCc1ccc(OC(=O)c2cc3sc(CCCCC)cc3s2)cc1

Procedure:
3.5 g of 5-n-pentyl-thieno[3,2-b]thiophene-2-carboxylic acid chloride [obtainable by reacting 5-n-pentylthieno[3,2-b]thiophene-5-carboxylic acid (m.p. 156°, c.p. 196°) with thionyl chloride] in 20 ml of toluene are added dropwise to a mixture of 2.25 g of 4-n-pentylphenol, 1.08 g of pyridine and 30 ml of toluene, the mixture is heated to the boil for 2 hours and allowed to cool, the pyridine hydrochloride is filtered off, and the mixture is worked up in the usual manner. 4-n-Pentylphenyl 5-n-pentyl-thieno[3,2-b]thiophene-2-carboxylate of melting point 58° and clear point 93° is obtained.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][CH2:13][N:14]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)=[CH:33][CH:32]=2)[C:15](=[O:29])[CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][N:18]2C(OC(C)(C)C)=O)=[N:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][CH2:13][N:14]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)=[CH:35][CH:36]=2)[C:15](=[O:29])[CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][NH:18]2)=[N:2]1
Reactant: COc1ccc(-c2ccc(CN(CCCNc3nsc4ccccc34)C(=O)CC3CCCN3C(=O)OC(C)(C)C)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(-c2ccc(CN(CCCNc3nsc4ccccc34)C(=O)CC3CCCN3)cc2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 129.5 %

Procedure:
tert-Butyl 2-(2-((3-(benzo[d]isothiazol-3-ylamino)propyl)((4′-methoxybiphenyl-4-yl)methyl)amino)-2-oxoethyl)pyrrolidine-1-carboxylate (20 mg, 0.033 mmol) was dissolved in methylene chloride (0.5 mL) and cooled in an ice-bath. A cooled solution of trifluoroacetic acid (1.0 mL) in methylene chloride (1.0 mL) was added to the mixture, dropwise. The reaction was allowed to stir for 3 h at 0° C. The solution was concentrated under reduced pressure to yield N-(3-(benzo[d]isothiazol-3-ylamino)propyl)-N-((4′-methoxybiphenyl-4-yl)methyl)-2-(pyrrolidin-2-yl) acetamide (22 mg) as a solid. 1H NMR (300 MHz, CDCl3): 8.15-8.20 (m, 1H), 7.45-7.70 (m, 6H), 7.15-7.20 (m, 2H), 6.90-6.95 (m, 2H), 4.60-4.75 (m, 1H), 4.45-4.55 (m, 1H), 3.95-4.10 (m, 2H), 3.85 (s, 3H), 3.60-3.75 (m, 2H), 3.35-3.45 (m,2H), 3.15-3.25 (m, 2H), 2.75-2.85 (m,1H), 1.90-2.00 ppm (m, 1H). MW=515 confirmed by LC-MS, tr=4.50 min (Method B) MH+=514-516.
Reaction SMILES: O1CCCC1.Cl.[NH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[C:10]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[N:9]=1.[CH3:28][C:29](=[CH2:33])[C:30](Cl)=[O:31]>C(N(CC)CC)C>[NH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[C:10]([N:22]2[CH2:27][CH2:26][N:25]([C:30](=[O:31])[C:29]([CH3:33])=[CH2:28])[CH2:24][CH2:23]2)[N:9]=1
Reactant: C=C(C)C(=O)Cl
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)N1CCN(c2nc(N)c3cc(OC)c(OC)cc3n2)CC1
Reaction time: 0.5 h
Yield: 39 %

Procedure:
To 20 ml of tetrahydrofuran were added 2.4 g of 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline hydrochloride and 2.6 g of triethylamine, after which the mixture was stirred for 30 minutes. There was then added 0.6 g of 2-methylacryloyl chloride, after which the mixture was stirred at room temperature for 8 hours. The crystals which were produced were collected by filtration, washed with water and recrystallized from ethanol to give 0.8 g of the desired Compound No. 2 in the form of colourless needles melting at 262°-263° C. (with decomposition).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl.[Br-].[O:13]1[C:21]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[CH:15]=[C:14]1[CH2:22][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:42]([O:46][C:47]([N:49]1[CH2:54][CH2:53][CH:52]([CH:55]=O)[CH2:51][CH2:50]1)=[O:48])([CH3:45])([CH3:44])[CH3:43]>C1COCC1.CCOC(C)=O>[C:42]([O:46][C:47]([N:49]1[CH2:54][CH2:53][CH:52]([CH:55]=[CH:22][C:14]2[O:13][C:21]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[CH:15]=2)[CH2:51][CH2:50]1)=[O:48])([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: c1ccc([P+](Cc2cc3cnccc3o2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C=Cc2cc3cnccc3o2)CC1
Temperature: 20 °C
Reaction time: 0.75 h

Procedure:
LiHMDS (5.9 mL of a 1.0 M solution in THF, 5.90 mmol) was added dropwise to a stirred suspension of furo[3,2-c]pyridin-2-ylmethyltriphenylphosphonium bromide hydrochloride (Preparation 6, 1.50 g, 2.94 mmol) in anhydrous THF (25 mL) at 0° C. After 45 min, the mixture was treated with 4-formylpiperidine-1-carboxylic acid tert-butyl ester (0.63 g, 2.94 mmol), before being stirred at 20° C. for 16 h. The reaction mixture was diluted with EtOAc (300 mL), before being washed with H2O (2×100 mL) and dried (MgSO4). Filtration, solvent evaporation, and flash chromatography (IH-EtOAc, 1:1) furnished 4-(2-furo[3,2-c]pyridin-2-ylvinyl)piperidine-1-carboxylic acid tert-butyl ester: m/z (ES+)=329.1 [M+H]+. This alkene (830 mg, 2.53 mmol) was dissolved in EtOH (15 mL), then Pd (10% on C, 83 mg, 0.08 mmol) was added. The reaction was stirred under a H2 atmosphere for 16 h, before being filtered through celite. The celite was washed with MeOH, then the combined solutions were concentrated to provide the title compound: RT=2.86 min; m/z (ES+)=331.2 [M+H]+.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[S:6]1[CH2:11][CH2:10][CH2:9][S:8]C1.ICCC>O1CCCC1>[CH2:2]([CH:1]1[S:8][CH2:9][CH2:10][CH2:11][S:6]1)[CH2:3][CH3:4]
Reactant: [Li]CCCC
Reactant: C1CSCSC1
Solvent: C1CCOC1
Solvent: CCCI
Product: CCCC1SCCCS1
Reaction time: 2.5 h

Procedure:
n-Butyl lithium (2.5M, 56.32 ml, 141 mmol) was added dropwise to a 500 ml tetrahydrofuran solution of 1,3-dithiane (15.42 g, 128 mmol) at -20°. After stirring for 2.5 hours at -20°, the solution was cooled to -78° and 1-iodopropane (12.5 ml, 128 mmol) was added to it in one portion. The reaction mixture was left for gradual warming (-78° to 0° C.) and overnight stirring (19 hours). Tetrahydrofuran was removed on the rotary evaporator, residue taken in ether (250 ml) and washed with water (200 ml). The aqueous layer was reextracted with ether (250 ml). Combined ethereal extracts were washed sequentially once with water, once with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated to give a yellow oil which on distillation under vacuum yielded 19.310 g of the title A compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:14]2[CH:13]=[C:12](B(O)O)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[Br:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25](Br)[CH:26]=2)[CH:21]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.O.C(COC)OC>[Br:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[C:25]([C:12]1[CH:11]=[CH:10][C:9]3[C:8]4[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:2]([CH3:1])([CH3:18])[C:14]=3[CH:13]=1)[CH:24]=[CH:23]2
Reactant: Brc1ccc2cc(Br)ccc2c1
Reactant: CC1(C)c2ccccc2-c2ccc(B(O)O)cc21
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: Cc1ccccc1
Solvent: COCCOC
Solvent: O
Product: CC1(C)c2ccccc2-c2ccc(-c3ccc4cc(Br)ccc4c3)cc21
Temperature: 85 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
In argon atmosphere, a mixture of 16.65 g (69.9 mmol) of 9,9-dimethyl-9H-fluorene-2-ylboronic acid, 20.0 g (69.9 mmol) of 2,6-dibromonaphthalene, 4.04 g (3.50 mmol) of tetrakis(triphenylphosphine)palladium (0), 200 ml of toluene, 200 ml of dimethoxyethane, and 106 g of a 2 M sodium carbonate aqueous solution was stirred at 85° C. for 8 h and left standing overnight. After adding water, the mixture was stirred at room temperature for one hour. After filtration and extraction with toluene, the organic phase was washed with water and then with a saturated saline solution. After drying over sodium sulfate, the toluene was distilled off under reduced pressure. The obtained brown oily substance was purified by silica gel chromatography to obtain 11.84 g (yield: 42.4%) of 2-(6-bromonaphthalene-2-yl)-9,9-dimethyl-9H-fluorene.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[C:14](O)=[O:15])([CH3:10])([CH3:9])[CH3:8].[CH2:25]([N:27]([CH2:29][CH3:30])O)[CH3:26]>C(N(CC)CC)C>[C:21]([C:18]1[CH:17]=[C:13]([CH:12]=[C:11]([C:7]([CH3:9])([CH3:8])[CH3:10])[C:19]=1[OH:20])[CH2:14][O:15][N:27]([CH2:29][CH3:30])[CH2:25][CH3:26])([CH3:22])([CH3:23])[CH3:24]
Reactant: CCN(O)CC
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Product: CCN(CC)OCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 45.2 %

Procedure:
Following the procedure of Example II, the compound is prepared from 3.17 g of oxalyl chloride, 6.25 g of 3,5-di-tert-butyl-4-hydroxybenzoic acid, 2.53 g of N,N-diethylhydroxylamine, and 2.53 g of triethylamine. The residue is recrystallized from petroleum ether to give 3.47 g of a white solid: mp 129°-137° C.
Reaction SMILES: [N:1]([CH2:4][C:5]([S:8]([C:11]1[CH:28]=[CH:27][C:14]2[N:15]([CH2:23][CH:24]3[CH2:26][CH2:25]3)[C:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[N:17][C:13]=2[CH:12]=1)(=[O:10])=[O:9])([CH3:7])[CH3:6])=[N+]=[N-]>[C].[Pd].CO>[CH:24]1([CH2:23][N:15]2[C:14]3[CH:27]=[CH:28][C:11]([S:8]([C:5]([CH3:6])([CH3:7])[CH2:4][NH2:1])(=[O:10])=[O:9])=[CH:12][C:13]=3[N:17]=[C:16]2[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:25][CH2:26]1
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)C(C)(C)CN=[N+]=[N-])ccc2n1CC1CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)C(C)(C)CN)ccc2n1CC1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.9 %

Procedure:
A mixture of 5-[(2-azido-1,1-dimethylethyl)sulfonyl]-1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-1H-benzimidazole (Step J, 265 mg, 0.66 mmol), 10% palladium carbon (30 mg) and methanol (8 mL) was stirred at room temperature for 18 h under hydrogen atmosphere. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=15:1 as eluent) to afford the title compound (199 mg, 80%) as a white brown solid.
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[N:13][C:14]=1[CH3:15])[N:11]=[CH:10][C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:8]2[NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[CH3:3].[C:30]([OH:34])(=[O:33])[CH:31]=O.C(=O)(O)[O-].[Na+].Cl>O.C(O)(=O)C>[ClH:1].[CH2:2]([O:4][C:5]1[C:14]([CH:15]=[CH:31][C:30]([OH:34])=[O:33])=[N:13][C:12]2[C:7]([CH:6]=1)=[C:8]([NH:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][N:11]=2)[CH3:3].[CH2:2]([O:4][C:5]1[C:14]([CH:15]=[CH:31][C:30]([OH:34])=[O:33])=[N:13][C:12]2[C:7]([CH:6]=1)=[C:8]([NH:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][N:11]=2)[CH3:3]
Reactant: CCOC(=O)c1cnc2nc(C)c(OCC)cc2c1Nc1ccc(OC)cc1
Reactant: O=CC(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cnc2nc(C=CC(=O)O)c(OCC)cc2c1Nc1ccc(OC)cc1

Procedure:
A mixture of ethyl 6-ethoxy-4-(4-methoxyanilino)-7-methyl-1,8-naphthyridine-3-carboxylate hydrochloride (4.76 g), glyoxylic acid (1.73 g) and glacial acetic acid (50 ml) was boiled under reflux for 24 hours. The mixture was cooled and a solid was collected by filtration. The filtrate was acidified with concentrated hydrochloric acid and filtered to give a second crop of solid. The two crops of solid were combined, stirred in water and the mixture basified with sodium bicarbonate. The pH of the mixture was adjusted to pH 6 with concentrated hydrochloric acid and the mixture was extracted with ethyl acetate and then with dichloromethane. The combined organic extracts were washed with water, dried and evaporated. The residue was triturated with ethyl acetate and then filtered to give 3-[3-ethoxy-6-ethoxycarbonyl-5-(4-methoxyanilino)-1,8-naphthyridin-2-yl]acrylic acid hemihydrochloride, m.p. 259°-261° C.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH3:50])[CH2:30][CH2:31][N:32]([S:40]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)(=[O:42])=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1>>[CH3:28][N:29]([CH3:50])[CH2:30][CH2:31][N:32]([C:33]1[CH:34]=[CH:35][C:36]([NH:39]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:37][CH:38]=1)[S:40]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)(=[O:41])=[O:42]
Reactant: CN(C)CCN(c1ccc(N)cc1)S(=O)(=O)Cc1ccccc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(CCN(C)C)S(=O)(=O)Cc2ccccc2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-(2-dimethylamino-ethyl)-N-benzylsulphonyl-p-phenylenediamine Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C34H34N4O5S
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([CH2:37][CH:38]=O)[CH:34]=2)[CH2:29]1)=[O:27])C1C=CC=CC=1.[C:40]([O:44][C:45](=[O:52])[C@H:46]([CH2:48][CH:49]([CH3:51])[CH3:50])[NH2:47])([CH3:43])([CH3:42])[CH3:41]>>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[C:12]([CH:23]([CH3:24])[CH3:25])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([CH2:37][CH2:38][NH:47][C@H:46]([C:45]([O:44][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:52])[CH2:48][CH:49]([CH3:50])[CH3:51])[CH:34]=2)[CH2:29]1)=[O:27]
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Reactant: C=C(C)c1cc(C(=O)N2Cc3ccc(CC=O)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Product: CC(C)C[C@H](NCCc1ccc2c(c1)CN(C(=O)c1cc(C(C)C)c(O)cc1O)C2)C(=O)OC(C)(C)C

Procedure:
Prepared from Intermediate F and L-leucine tert-butyl ester. 1H NMR (300 MHz, d3-MeOD) 7.31-7.12 (4H, m), 6.38 (1H, s), 3.24-3.04 (2H, m), 2.90-2.69 (4H, m), 1.76-1.56 (1H, m), 1.45 (9H, s), 1.23 (6H, d, J=7.0 Hz), 0.93 (6H, dd, J=10.9, 6.6 Hz). LC/MS: purity >98%, m/z 511 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[C:5]([Cl:11])=[CH:4][C:3]=1[OH:12].[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH:14]=O.C([BH3-])#N.[Na+]>CO.CC(O)=O>[Cl:11][C:5]1[C:6]([CH:8]2[CH2:10][CH2:9]2)=[CH:7][C:2]([NH:1][CH2:14][C:13]([O:17][CH2:18][CH3:19])=[O:16])=[C:3]([OH:12])[CH:4]=1
Reactant: CCOC(=O)C=O
Reactant: Nc1cc(C2CC2)c(Cl)cc1O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)CNc1cc(C2CC2)c(Cl)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.5 %

Procedure:
To a solution of 2-amino-5-chloro-4-cyclopropylphenol (200 mg, 1.01 mmol) in MeOH (20 mL) at RT, AcOH (3 drops) and ethyl glyoxalate (416 mg, 2.02 mmol, 50% in toluene) were added. The mixture was stirred at RT for 2 h and then sodium cyanoborohydride (190 mg, 3.03 mmol) was added to the mixture. The resulting mixture was stirred at 40° C. for 15 h. The mixture was allowed to cool to RT and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel (10-20% methanol/dichloromethane) to afford the desired product (290 mg, 100% yield) as a solid. 1H NMR (400 MHz, DMSO-d6) δ: 9.63 (s, 1H), 6.66 (s, 1H), 5.93 (s, 1H), 5.07 (t, J=6.4 Hz, 1H), 4.12 (q, J=7.2 Hz, 2H), 3.91 (d, J=6.4 Hz, 2H), 1.92-1.97 (m, 1H), 1.20 (t, J=6.8 Hz, 2H), 0.84-0.87 (m, 2H), 0.51-0.55 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([S:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]#[N:17])=[N:14][CH:15]=2)[CH:6]=[CH:7][CH:8]=1.[CH2:18]([C:20]1[C:21]([OH:30])=[C:22]([C:27](=[O:29])[CH3:28])[CH:23]=[CH:24][C:25]=1O)[CH3:19]>>[C:27]([C:22]1[CH:23]=[CH:24][C:25]([O:1][CH2:2][C:3]2[CH:4]=[C:5]([S:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]#[N:17])=[N:14][CH:15]=3)[CH:6]=[CH:7][CH:8]=2)=[C:20]([CH2:18][CH3:19])[C:21]=1[OH:30])(=[O:29])[CH3:28]
Reactant: N#Cc1ccc(Sc2cccc(CO)c2)cn1
Reactant: CCc1c(O)ccc(C(C)=O)c1O
Product: CCc1c(OCc2cccc(Sc3ccc(C#N)nc3)c2)ccc(C(C)=O)c1O
Yield: 77.5 %

Procedure:
Using the method of Preparation 166 using 5-(3-(hydroxymethyl)phenylthio) picolinonitrile (1.70 g, 7.02 mmol) and 1-(3-ethyl-2,4-dihydroxyphenyl)ethanone (1.26 g, 7.02 mmol) affords the title compound (2.20 g, 78%). MS (APCI-neg) m/z (rel intensity): 403 (M−H, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7](B(O)O)[N:8]2C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.[CH2:21]([O:28]N1C=CC=C(Br)C1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.CN(C=O)C>[CH2:21]([O:28][C:2]1[CH:3]=[C:4]([C:7]2[NH:8][C:9]3[C:5]([CH:6]=2)=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=3)[CH:5]=[CH:9][CH:10]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccc(Cl)cc21
Reactant: BrC1=CC=CN(OCc2ccccc2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc2cc(-c3cccc(OCc4ccccc4)c3)[nH]c2c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A flask is charged with 6-chloro-1-Boc-indole-2-boronic acid (0.839 g, 2.83 mmol), 1-benzyloxy-3-bromo-pyridine (0.500 g, 1.89 mmol), potassium phosphate (1.2 g, 5.67 mmol) and DMF (5 mL). The flask is evacuated and filled with nitrogen thrice and Pd(PPh3)4 (0.164 g, 0.141 mmol) is added. The flask is evacuated and filled with nitrogen thrice again, and heated to 80° C. for 3.5 h. The mixture is then diluted with ethyl acetate and washed with water thrice. The organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is redissolved in DCM (1 mL) and trifluoroacetic acid (2 mL) is added. After 1 h, 4M aqueous NaOH is added and following extraction with DCM, the organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is purified by silica gel flash chromatography (heptane-ethyl acetate, 1:1) to afford 2-(3-benzyloxy-phenyl)-6-chloro-1H-indole as a yellow solid. MS (ESI) m/z 335.07 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][CH:7]=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].C[O-].[Na+].[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]Br>CO>[CH2:1]([C:5]1[N:6]([CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[Cl:13])[CH:7]=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Clc1ccccc1CBr
Reactant: CCCCc1ncc[nH]1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCc1nccn1Cc1ccccc1Cl
Temperature: 50 °C
Yield: 61.3 %

Procedure:
2-n-Butylimidazole (9.7 g, 0.078 mol) was dissolved in methanol (50 mL) and added dropwise to a solution of sodium methoxide (from sodium hydride (2.31 g, 0.0934 mol) in methanol (250 mL)). After one hour the solution was evaporated to dryness, and the sodium salt was taken up in dry dimethylformamide (150 mL) and 2-chlorobenzylbromide (16.3 g, 0.079 mol) was added. The mixture was heated at 50° C. for 17 hours under argon, poured onto ice water and the product was extracted into ethyl acetate. The extract was washed, dried, and concentrated to give 18.5 g of crude product which was chromatographed over silica gel with 2:1 ethyl acetate/hexanes to provide 11.9 g (61%) of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazole as an oil. Thin layer chromatography on silica gel with 4:1 ethyl acetate/hexanes gave an Rf value of 0.59.