Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[CH3:12].[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](OCC)=[O:24].[H-].[Na+].O>CS(C)=O>[CH3:12][N:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[CH2:5][CH2:4][C:3]1[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=1[NH:1][C:23](=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=1
Reactant: CCOC(=O)c1ccccn1
Reactant: CN1CCCCC1CCc1ccccc1N
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CN1CCCCC1CCc1ccccc1NC(=O)c1ccccn1
Reaction time: 2 h

Procedure:
A solution of 2-(o-aminophenethyl)-1-methylpiperidine (8.0 g., 0.037 mole) and ethyl picolinate (5.5 g., 0.037 mole) in DMSO (20 ml.) is treated with NaH (57%) in oil (1.6 g., 0.037 mole) with intermittent cooling to moderate the resulting vigorous reaction. After 2 hr., the mixture is poured into 150 ml. of H2O and the product isolated according to the procedure of Example 25. Crystallization from isopropyl ether affords 5.9 (50%) of analytically pure 2'-[2-(1-methyl-2-piperidyl)ethyl]picolinanilide, m.p. 65.5°-67° C. (corr.).
Reaction SMILES: [CH2:1]([PH2:5])[CH:2]([CH3:4])[CH3:3].[CH:6]([CH:8]=[O:9])=[O:7]>O1CCCC1>[CH2:1]([P:5]1[CH:6]([OH:7])[CH:8]([OH:9])[P:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH:6]([OH:7])[CH:8]1[OH:9])[CH:2]([CH3:4])[CH3:3]
Reactant: O=CC=O
Reactant: CC(C)CP
Solvent: C1CCOC1
Product: CC(C)CP1C(O)C(O)P(CC(C)C)C(O)C1O
Yield: 97 %

Procedure:
In a suitable autoclave, equipped with mechanical stirring and external heating are added 200 parts of mono-isobutylphosphine (85%) and 300 parts of tetrahydrofuran, as solvent. With no external heating applied to the reactor, 275 parts of a 40% aqueous glyoxal solution are added with stirring at 20°-25° C. The resultant solid product is filtered, and dried to give 276 parts (97% yield) of 1,4-diisobutyl-2,3,5,6-tetrahydroxy-1,4-diphosphorinane, m.p. 173°-175° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:23])=[C:16]([NH:20][CH:21]=[O:22])[C:17]([CH3:19])=[CH:18][C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:24](Cl)(=[O:26])[CH3:25]>>[C:24]([C:18]1[C:13]2[O:12][CH2:11][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=3)[C:14]=2[C:15]([CH3:23])=[C:16]([NH:20][CH:21]=[O:22])[C:17]=1[CH3:19])(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: Cc1cc2c(c(C)c1NC=O)C(c1ccc(C(C)C)cc1)CO2
Product: CC(=O)c1c(C)c(NC=O)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Yield: 48 %

Procedure:
Using N-(3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)formamide obtained in Example 58 and acetyl chloride, the title compound was obtained in the same manner as in Example 38. Yield: 48%. Melting point: 177-179° C. (ethyl acetate-hexane).
Reaction SMILES: N(C(C)C)(C(C)C)CC.[N:10]([CH2:19][C:20]#[CH:21])([Si:15]([CH3:18])([CH3:17])[CH3:16])[Si:11]([CH3:14])([CH3:13])[CH3:12].I[Si:23]([CH3:26])([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[CH3:16][Si:15]([CH3:18])([CH3:17])[N:10]([CH2:19][C:20]#[C:21][Si:23]([CH3:26])([CH3:25])[CH3:24])[Si:11]([CH3:12])([CH3:13])[CH3:14]
Reactant: C#CCN([Si](C)(C)C)[Si](C)(C)C
Reactant: C[Si](C)(C)I
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)C#CCN([Si](C)(C)C)[Si](C)(C)C
Yield: 177.9 %

Procedure:
A reactor with a capacity of 40 mL, equipped with a magnetic stirrer was filled, under argon atmosphere, with 0.0085 g (0.015 mmol) of [{Ir(μ-Cl)(CO)2}2], and then with 25 mL of anhydrous and deoxidized toluene and 0.7 g (5.4 mmol) of NEt(i-Pr)2. The whole mixture was stirred until the starting iridium(I) complex was dissolved, and then 0.598 g (3 mmol) of (Me3Si)2NCH2C≡CH and 0.96 g (4.8 mmol) of ISiMe3 were added to the resulting mixture. The reaction was carried out at a temperature of 80° C. until complete conversion of (Me3Si)2NCH2C≡CH. After the reaction was completed, in order to remove the catalyst from the reaction mixture the solvent was evaporated at a reduced pressure along with any residual unreacted substrates, and then anhydrous pentane was added to the residue. The resulting suspension was filtered and the resulting deposit was rinsed with two portions of a solvent. The solvent was initially evaporated from the filtrate, and the residual product was distilled by means of the “trap-to-trap” technique at a reduced pressure to obtain 1.45 g of 1-(N,N-bis(trimethyl-silyl)amino)-3-trimethylsilylprop-2-yne, obtained with a yield of 96%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C(Cl)(=O)C(Cl)=O.Cl.[CH:19]1[C:29]2[CH2:28][CH2:27][C:26]3[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=3[N:24]([C:34]([NH:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH2:43])=[O:35])[C:23]=2[CH:22]=[CH:21][CH:20]=1>>[CH:19]1[C:29]2[CH2:28][CH2:27][C:26]3[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=3[N:24]([C:34]([NH:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:9](=[O:11])[CH:8]=[CH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[O:35])[C:23]=2[CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)C=Cc1cccnc1
Reactant: NCCCCCCNC(=O)N1c2ccccc2CCc2ccccc21
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Product: O=C(C=Cc1cccnc1)NCCCCCCNC(=O)N1c2ccccc2CCc2ccccc21

Procedure:
Batch size: 2.2 g (14.8 mmol) 3-(3-pyridyl)-acrylic acid, 2.5 g (19.7 mmol) oxalyl chloride, 4.5 g (44.5 mmol) TEA and 5.0 g (13.4 mmol) 6-(10,11-dihydro-dibenzo[b,f]azepin-5-yl-carbonylamino)-hexylamine hydrochloride.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[O:18][CH3:19]>>[C:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[O:18][CH3:19])(=[O:3])[CH3:2]
Reactant: COc1cc(C(=O)O)ccc1O
Reactant: CC(=O)OC(C)=O
Product: COc1cc(C(=O)O)ccc1OC(C)=O
Temperature: 25 °C

Procedure:
Acetic anhydride (72.9 g, 67.4 mL) is added under nitrogen at room temperature to 4-hydroxy-3-methoxybenzoic acid (97.7 g) in xylenes (817 g, 950 mL) while stirring. The stirred mixture is heated to 115°-125° C. and heated at 120°-125° C. for 4 to 20 hours under nitrogen. Part of the liquid is then removed by distillation at about 150° bath temperature to a volume of about 700 ml and the mixture is cooled to room temperature to obtain a slurry of 4-acetoxy-3-methoxybenzoic acid which is again diluted with additional xylenes (224 g, 226 mL). N,N-dimethylformamide (DMF, 1.9 g, 2.0 mL) is added followed by dropwise addition, over 2.5 hours, of oxalyl chloride (90.6 g, 62.2 mL). The reaction mixture is stirred at room temperature for 24 hours to obtain a solution of 4-acetoxy-3-methoxybenzoyl chloride which is used as such in the next step. The xylenes solution is cooled to -14° to -20° C. with a brine solution and diisopropylamine (169 g, 234 mL) is added dropwise over a 45 minute period, at a rate so that the temperature does not exceed 0° C. The reaction mixture is allowed to warm to room temperature and is stirred at room temperatue (17°-20° C.) for 21 hours. The resulting slurry is filtered under vacuum, and the filter cake is further slurried with xylenes (430 mL) and filtered.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][CH2:13][C:14]#[C:15][C:16]1[CH:25]=[CH:24][C:19]([C:20](OC)=[O:21])=[CH:18][CH:17]=1)=[O:11].[NH2:26][OH:27].[OH-].[Na+].Cl>C1COCC1.CO>[OH:27][NH:26][C:20](=[O:21])[C:19]1[CH:24]=[CH:25][C:16]([C:15]#[C:14][CH2:13][NH:12][C:10]([C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)=[O:11])=[CH:17][CH:18]=1
Reactant: NO
Reactant: COC(=O)c1ccc(C#CCNC(=O)c2cc3ccccc3s2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NO)c1ccc(C#CCNC(=O)c2cc3ccccc3s2)cc1
Reaction time: 14 h

Procedure:
To a solution of methyl 4-[3-(benzothiophen-2-ylcarbonylamino)prop-1-ynyl]-benzoate (0.5 mmol) in THF/methanol (10 ml/10 ml) was added 50 wt. % aqueous hydroxylamine (3 ml) followed by 1M aqueous NaOH (1 ml) adjusting the pH to 10-11. The reaction mixture was stirred for ˜14 h, neutralized to pH=7-8 with 6M aqueous HCl, and concentrated in vacuo. The precipitate was collected and purified by HPLC providing the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[CH:11]([O:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:26]=[C:27]=[O:28])(=[O:25])=[O:24])=[O:16])([CH3:13])[CH3:12]>C(Cl)Cl>[CH3:9][O:8][C:6]1[N:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:1][C:27]([NH:26][S:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:15]([O:14][CH:11]([CH3:13])[CH3:12])=[O:16])(=[O:25])=[O:24])=[O:28])[N:7]=1
Reactant: COc1nc(C)nc(N)n1
Reactant: CC(C)OC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: ClCCl
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)OC(C)C)n1
Yield: 51.1 %

Procedure:
To 26.8 g of 2-amino-4-methoxy-6-methyl-1,3,5-triazine in 300 ml anhydrous methylene chloride was added 67.0 g of 2-isopropoxycarbonylbenzenesulfonyl isocyanate in 100 ml anhydrous methylene chloride. The resultant suspension was stirred at ambient temperature for 72 hours, and filtered to yield 40.0 g of the desired product as a white solid, m.p. 193°-196° C. The solid showed infrared absorption peaks at 1700 and 1710 cm-1 consistent for N-[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)aminocarbonyl]-2-(isopropoxycarbonyl)benzenesulfonamide.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[NH:10][C@H:11]1[CH2:16][CH2:15][C@@H:14]([NH:17][CH:18]([CH3:20])[CH3:19])[CH2:13][C@H:12]1[CH2:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[BH3-][C:36]#N.[Na+]>CO.O>[CH2:1]([O:8][C:9](=[O:32])[NH:10][C@H:11]1[CH2:16][CH2:15][C@@H:14]([N:17]([CH:18]([CH3:20])[CH3:19])[CH3:36])[CH2:13][C@H:12]1[CH2:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)N[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](CS(=O)(=O)c2ccc(Br)cc2)C1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)N(C)[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](CS(=O)(=O)c2ccc(Br)cc2)C1
Reaction time: 0.17 h
Yield: 94.4 %

Procedure:
The above derivative (118ba) (1.96 g) was dissolved in MeOH (15 ml) prior to the addition of 37% formaldehyde in water (1.41 ml). After 10 min, NaBH3CN (708 mg) was added. After 2 h, the reaction was concentrated. EtOAc was added and the organic layer was washed with H2O, brine, dried, filtered, and concentrated to give [(1S,2R,4R)-2-(4-Bromo-benzenesulfonylmethyl)-4-(isopropyl-methyl-amino)-cyclohexyl]-carbamic acid benzyl ester (1.9 g), MS found: (M+H)+=539.3.
Reaction SMILES: [CH3:1][C:2]1[C:19]([CH3:20])=[CH:18][C:5]([O:6][CH2:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[C:4]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)(=[O:24])=[O:23])[CH:3]=1.Br[CH2:32][C@@H:33]([CH3:53])[CH2:34][O:35][Si:36]([C:49]([CH3:52])([CH3:51])[CH3:50])([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Si:36]([O:35][CH2:34][C@H:33]([CH3:53])[CH2:32][N:21]([S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)(=[O:23])=[O:24])[C:4]1[CH:3]=[C:2]([C:1]2[CH:18]=[CH:19][CH:2]=[CH:3][CH:4]=2)[C:19]([C:20]2[CH:16]=[CH:17][CH:8]=[CH:9][CH:10]=2)=[CH:18][C:5]=1[O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=1)([C:49]([CH3:52])([CH3:51])[CH3:50])([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: C[C@H](CBr)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: COC(=O)c1ccc(COc2cc(C)c(C)cc2NS(=O)(=O)c2ccccn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(COc2cc(-c3ccccc3)c(-c3ccccc3)cc2N(C[C@@H](C)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)S(=O)(=O)c2ccccn2)cc1
Reaction time: 4 h
Yield: 139.6 %

Procedure:
596 mg of methyl 4-({4,5-dimethyl-2-[(pyridin-2-ylsulfonyl)amino]phenoxy}methyl)benzoate was dissolved in 5.96 mL of DMF, and 820 mg of {[(2S)-3-bromo-2-methylpropyl]oxy}(tert-butyl)diphenylsilane and 1.37 g of cesium carbonate were added thereto, followed by stiffing at 80° C. for 4 hours. To the reaction liquid was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=60:40) to obtain 840 mg of methyl 4-[(2-{[(2R)-3-{[tert-butyl(diphenyl)silyl]oxy}-2-methylpropyl](pyridin-2-ylsulfonyl)amino}-4,5-diphenylphenoxy)methyl]benzoate.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=2)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-:34].[Li+]>C(COC)OC.O>[C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@@H:17]([OH:21])[CH2:18][C@@H:19]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=1)[C:20]([OH:22])=[O:34])([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: [OH-]
Reactant: COc1ccc(C[C@@H]2C[C@@H]([C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)OC2=O)cc1OC
Agent: [Li+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(C[C@H](C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1OC

Procedure:
In analogy with Example 44d), 778 mg of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-3(R)-[(3,4-dimethoxyphenyl)methyl]dihydrofuran-2-(3H)-one in 27.67 ml of dimethoxyethane and 13.91 ml of water are hydrolysed with 6.83 ml of 1M lithium hydroxide solution to give the title compound, which is subjected directly to further processing. TLC Rf (C)=0.07.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH:7]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[N:19]2[CH:23]=[C:22]([C:24]3[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=3)[N:21]=[CH:20]2)[NH:12][N:11]=1)([CH3:9])[CH3:8].[CH2:30]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1F)[C:35]#[N:36])[CH3:31].O>CS(C)=O>[CH2:30]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[N:12]1[C:13]2[C:18](=[C:17]([N:19]3[CH:23]=[C:22]([C:24]4[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=4)[N:21]=[CH:20]3)[CH:16]=[CH:15][CH:14]=2)[C:10]([CH:7]([CH3:9])[CH3:8])=[N:11]1)[C:35]#[N:36])[CH3:31]
Reactant: CC(C)c1n[nH]c2cccc(-n3cnc(-c4cnn(C)c4)c3)c12
Reactant: CCc1cc(C#N)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CCc1cc(C#N)ccc1-n1nc(C(C)C)c2c(-n3cnc(-c4cnn(C)c4)c3)cccc21
Temperature: 130 °C
Reaction time: 0.17 h
Yield: 53.4 %

Procedure:
Cesium carbonate (850 mg) was added to a solution of compound (5a) (200 mg) in DMSO (2.2 mL), and the mixture was heated to 130° C. The mixture was stirred for 10 minutes and 3-ethyl-4-fluorobenzonitrile (292 mg) was added thereto. The resulting mixture was stirred at the same temperature for 1.5 hours. After completion of the reaction, the reaction solution was allowed to standing still for cooling, and water was poured thereto. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine and dried by the addition of anhydrous sodium sulfate. After removal of the solvent by evaporation, the residue was purified by neutral silica gel column chromatography (chloroform/ethyl acetate/methanol) to obtain compound (6a) (151.8 mg, yield 54%) as a white foamy substance.
Reaction SMILES: [OH:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([C:8]2[CH:28]=[CH:27][C:11]([CH2:12][S:13][C:14]3[N:23]([CH3:24])[C:22](=[O:25])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[CH3:26])[N:15]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.Cl.[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][Cl:36].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[ClH:36].[CH3:24][N:23]1[C:22](=[O:25])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[CH3:26])[N:15]=[C:14]1[S:13][CH2:12][C:11]1[CH:27]=[CH:28][C:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:35][CH2:34][N:33]([CH3:37])[CH3:32])=[CH:30][CH:29]=2)=[CH:9][CH:10]=1
Reactant: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(O)cc4)cc3)n(C)c(=O)c12
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(OCCN(C)C)cc4)cc3)n(C)c(=O)c12
Temperature: 80 °C
Reaction time: 20 h
Yield: 50.1 %

Procedure:
2-[4-(4-Hydroxybenzoyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (306 mg), 2-dimethylaminoethyl chloride hydrochloride (218 mg), and potassium carbonate (316 mg) were dissolved in DMF (5 ml) and the solution was stirred at 80° C. for 20 hours. This reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, and dried. Then, hydrogen chloride/ethyl acetate was added and the precipitated hydrochloride was collected by filtration to provide the title compound as colorless solid (193 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([C:15]#[N:16])=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)[CH3:2].O[C:19]1C=C[CH:25]=[C:24]2[C:20]=1[CH:21]=[CH:22][NH:23]2>>[C:15]([CH:5]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=2)=[C:19]2[C:1](=[C:2]3[CH:25]=[CH:24][N:23]=[C:22]3[CH:21]=[CH:20]2)[O:3][C:4]1=[O:17])#[N:16]
Reactant: CCOC(=O)C(C#N)=Cc1cccc(OC)c1
Reactant: Oc1cccc2[nH]ccc12
Product: COc1cccc(C2=c3ccc4c(c3OC(=O)C2C#N)C=CN=4)c1

Procedure:
Alternatively, compounds of Formula III can be prepared as shown in Schemes 3 and 4. Condensation of 3,5-dimethoxybenzaldehyde with ethyl cyanoacetate in the presence of a base such as piperidine produces the 3-(3,5-dimethoxyphenyl)-2-cyano-acrylic acid ethyl ester. Treatment of the ester with 3-methoxyphenol in the presence of NaH produces the 3-cyano-7-methoxy-4-(3,5-dimethoxyphenyl)-2-oxo-2H-chromene. Similarly, reaction of 3-(3-methoxy-phenyl)-2-cyano-acrylic acid ethyl ester with 4-hydroxyindole produces 3-cyano-4-(3-methoxyphenyl)-2-oxo-2H-pyrrolo[2,3-h]chromene.
Reaction SMILES: C1(C)C=CC(S(CC[O:12][C:13](=[O:54])[CH2:14][O:15][C:16]2[CH:21]=[C:20]([CH3:22])[C:19]([S:23]([N:26]3[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[N:28]=[C:27]3[S:35]([CH2:37][C:38]3[C:43]([CH3:44])=[C:42]([O:45][CH2:46][C:47]([F:50])([F:49])[F:48])[CH:41]=[CH:40][N:39]=3)=[O:36])(=[O:25])=[O:24])=[C:18]([CH:51]([CH3:53])[CH3:52])[CH:17]=2)(=O)=O)=CC=1.C([O-])(O)=O.[Na+:60]>CC#N.O>[Na+:60].[CH3:44][C:43]1[C:38]([CH2:37][S:35]([C:27]2[N:26]([S:23]([C:19]3[C:20]([CH3:22])=[CH:21][C:16]([O:15][CH2:14][C:13]([O-:54])=[O:12])=[CH:17][C:18]=3[CH:51]([CH3:53])[CH3:52])(=[O:24])=[O:25])[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[N:28]=2)=[O:36])=[N:39][CH:40]=[CH:41][C:42]=1[O:45][CH2:46][C:47]([F:49])([F:48])[F:50]
Reactant: Cc1ccc(S(=O)(=O)CCOC(=O)COc2cc(C)c(S(=O)(=O)n3c(S(=O)Cc4nccc(OCC(F)(F)F)c4C)nc4ccccc43)c(C(C)C)c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(OCC(=O)[O-])cc(C(C)C)c1S(=O)(=O)n1c(S(=O)Cc2nccc(OCC(F)(F)F)c2C)nc2ccccc21
Temperature: 65 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
To a solution of 4-[2-{3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl-methanesulfinyl}-benzimidazole-1-sulfonyl]-3-isopropyl-5-methylphenoxyacetic acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 68, 1.6 g, 1.95 mmol) in 15 mL of CH3CN was added the solution of NaHCO3 (200 mg, 2.34 mmol, 1.2 eq) in 8 mL of H2O. The mixture was heated to 65° C. for 1.5 h. Thereafter all volatile materials were removed under vacuum, the mixture was washed with ether (2×), and then the aqueous layer was lyophilized overnight. The solid was dissolved in 110 mL of ether-EtOAc (10:1), and then the mixture was filtered to remove insoluble material. The filtrate was concentrated and the residual oil was dissolved in 10 mL of ether-EtOAc (10:1). Hexane was added to the mixture to precipitate a white solid. The precipitate was filtered, washed with hexane, and dried under vacuum to yield 1.0 g (77%) of 4-[2-{3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl-methanesulfinyl}-benzimidazole-1-sulfonyl]-3-isopropyl-5-methylphenoxyacetic acid sodium salt (Compound 39) as a white solid.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24]Br)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[Cl:28][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]2[C:38]=1[N:37]=[C:36]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)[CH:35]=[CH:34]2>>[F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24][N:42]2[CH2:43][CH2:44][N:39]([C:36]3[CH:35]=[CH:34][C:33]4[C:38](=[C:29]([Cl:28])[CH:30]=[CH:31][CH:32]=4)[N:37]=3)[CH2:40][CH2:41]2)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: Clc1cccc2ccc(N3CCNCC3)nc12
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2Oc2ccccc21
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3ccc4cccc(Cl)c4n3)CC2)c2ccccc2Oc2ccccc21

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-xanthene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 8-chloro-2-piperazin-1-yl-quinoline. Melting point: 68° C. C33H32ClF3N4O2 (M=609.09) Calc.: molecular peak (M+H)+: 609/611. Found: molecular peak (M+H)+: 609/611.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:21]=[C:22]([S:27]([NH:30][CH3:31])(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[CH3:26]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:21]=[C:22]([S:27]([NH:30][CH3:31])(=[O:28])=[O:29])[CH:23]=[CH:24][C:25]=1[CH3:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: CNS(=O)(=O)c1ccc(C)c(Br)c1
Product: CNS(=O)(=O)c1ccc(C)c(C#Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)c1

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 3-bromo-N,4-dimethylbenzenesulfonamide (Combiblocks), the title compound was obtained as an orange sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(O[C:10]([C:12]1[C:13]([CH3:24])=[N:14][N:15]([C:17]2[C:22](Br)=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:16]=1)=[O:11])C.O1[CH2:29][CH2:28][CH2:27]C1>>[CH:27]1([C:22]2[C:17]([N:15]3[CH:16]=[C:12]([CH2:10][OH:11])[C:13]([CH3:24])=[N:14]3)=[N:18][CH:19]=[CH:20][CH:21]=2)[CH2:28][CH2:29]1
Reactant: C1CCOC1
Reactant: CCOC(=O)c1cn(-c2ncccc2Br)nc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1nn(-c2ncccc2C2CC2)cc1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a stirred suspension of lithium aluminium hydride (0.44 g, 11.7 mmol) in dry tetrahydrofuran (25 mL) is added a solution of 1-(3-bromo-pyridin-2-yl)-3-methyl-pyrazole-4-carboxylic acid ethyl ester (1.6 g, 5.8 mmol) in dry tetrahydrofuran (5 mL) under nitrogen atmosphere at −78° C. After complete addition the reaction mixture is warmed to room temperature then stir overnight. The reaction mixture is quenched with 1N sodium hydroxide then filtered through the celite. The organic layer is separated and the aqueous layer is extracted with ethyl acetate. The combined organic layer is washed with water and brine, dried on sodium sulfate, filtered and concentrated to yield 1.1 g (84%) of [1-(3-cyclopropyl-pyridin-2-yl)-3-methyl-pyrazol-4-yl]-methanol. MS (m/z): 230 (M+1).