Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH:7]=O)=[N:4][CH:3]=1.N1C=CC=CC=1.[OH:15][NH2:16].Cl>CCO.C(Cl)Cl>[CH3:1][C:2]1[S:6][C:5]([CH:7]=[N:16][OH:15])=[N:4][CH:3]=1
Reactant: NO
Reactant: Cc1cnc(C=O)s1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cnc(C=NO)s1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 5-methylthiazole-2-carbaldehyde (6.1 g, 48 mmol) in EtOH (30 mL), was added pyridine (4 mL, 49 mmol) and HONH2.HCl (3.3 g, 47 mmol). The mixture was stirred at ambient temperature for 12 hours. The reaction mixture was diluted with DCM and extracted with water. The organic solution was dried, filtered and concentrated to give the crude oxime. Yield: 6 g LCMS: (ES+) m/z=143.8 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:29]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[Cl:23])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccccc4Cl)c3O2)cc1
Yield: 72.3 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (3.00 g, 7.83 mmol) with 3-chlorophenylboronic acid (1.84 g, 11.74 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.308 g, 0.391 mmol), and potassium carbonate (2.70 g, 19.57 mmol) generally according to the procedure described for Intermediate 37 provided 2.35 g (72%) of (±)-[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a tan solid. mp 100-103° C.; Anal. calcd. for C22H19ClO4S: C, 63.69; H, 4.62. Found: C, 63.43; H, 4.69.
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[CH:6][N:5]=[C:4]([C:9]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([F:20])=[CH:17][CH:18]=3)[CH2:13][CH2:12]2)=[O:10])[CH:3]=1.[NH:21]1[CH2:26][CH2:25][CH:24]([N:27]2[C:35]3[C:30](=[N:31][CH:32]=[CH:33][CH:34]=3)[NH:29][C:28]2=[O:36])[CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].CN1C(=O)CCC1>O>[F:20][C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[N:11]([C:9]([C:4]1[CH:3]=[C:2]([N:21]3[CH2:22][CH2:23][CH:24]([N:27]4[C:35]5[C:30](=[N:31][CH:32]=[CH:33][CH:34]=5)[NH:29][C:28]4=[O:36])[CH2:25][CH2:26]3)[C:7]([I:8])=[CH:6][N:5]=1)=[O:10])[CH2:12][CH2:13]2
Reactant: O=C(c1cc(Cl)c(I)cn1)N1CCc2cc(F)ccc21
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)c(I)cn1)N1CCc2cc(F)ccc21
Temperature: 130 °C
Reaction time: 10 h

Procedure:
0.50 g (1.2 mmol) (4-chloro-5-iodo-pyridin-2-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone, 0.27 g (1.2 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one, 0.26 g (1.9 mmol) potassium carbonate and 3.5 mL NMP were combined and stirred at 130° C. for 10 h. After the addition of water the precipitate formed was suction filtered and dried.
Reaction SMILES: [P:1](Cl)(Cl)Cl.[CH:5]([C:22]1[CH:27]=[C:26]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:25]=[C:24]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:23]=1[OH:36])([C:7]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=[C:9]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:8]=1[OH:21])[CH3:6].[OH:37][N:38]1[C:43]([CH3:45])([CH3:44])[CH2:42][CH:41]([OH:46])[CH2:40][C:39]1([CH3:48])[CH3:47]>C(N(CC)CC)C>[C:28]([C:26]1[CH:25]=[C:24]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:23]2[O:36][P:1]([O:46][CH:41]3[CH2:42][C:43]([CH3:44])([CH3:45])[N:38]([OH:37])[C:39]([CH3:48])([CH3:47])[CH2:40]3)[O:21][C:8]3[C:9]([C:17]([CH3:20])([CH3:18])[CH3:19])=[CH:10][C:11]([C:13]([CH3:16])([CH3:14])[CH3:15])=[CH:12][C:7]=3[CH:5]([CH3:6])[C:22]=2[CH:27]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: ClP(Cl)Cl
Reactant: CC(c1cc(C(C)(C)C)cc(C(C)(C)C)c1O)c1cc(C(C)(C)C)cc(C(C)(C)C)c1O
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Solvent: CCN(CC)CC
Product: CC1c2cc(C(C)(C)C)cc(C(C)(C)C)c2OP(OC2CC(C)(C)N(O)C(C)(C)C2)Oc2c1cc(C(C)(C)C)cc2C(C)(C)C

Procedure:
The above-named compound is prepared using the general procedure of Example 1 by reacting 4.4 ml of phosphorous trichloride, 21.94 grams of 2,2'-ethylidenebis(4,6-di-tert-butylphenol), 19.3 ml of triethylamine and 6.68 grams of 1,4-dihydroxy-2,2,6,6-tetramethylpiperidine.
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([O:9][CH3:10])=[O:8])[CH2:5][NH:4][C:3]1=[O:11].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].Br[C:23]1[N:28]=[CH:27][CH:26]=[CH:25][N:24]=1>C1COCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.ClCCl>[CH3:1][N:2]1[CH:6]([C:7]([O:9][CH3:10])=[O:8])[CH2:5][N:4]([C:23]2[N:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[C:3]1=[O:11]
Reactant: COC(=O)C1CNC(=O)N1C
Reactant: Brc1ncccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)C1CN(c2ncccn2)C(=O)N1C
Temperature: -40 °C
Reaction time: 1 h
Yield: 30.5 %

Procedure:
A suspension of methyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (316 mg, 2 mmol) (prepared as described in step (ii) of Example 8) in THF (10 ml) was stirred at −40° C. Lithium hexamethyldisilazide (2 ml, 1M solution in THF) was added dropwise and the mixture was stirred at −40° C. for 15 minutes and then at −70° C. for 1 hour. A solution of 2-bromopyrimidine (318 mg, 2 mmol) in THF (1 ml) was added dropwise and the reaction was stirred at −70° C. for 1 hour and then warmed to 0° C. over 1 hour and then stirred at room temperature overnight. The reaction mixture was diluted with citric acid solution and dichloromethane. The organic layer was separated, washed with water and brine, dried and evaporated. The residue was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give crude methyl 3-methyl-2-oxo-1-(2-pyrimidinyl)-4-imidazolidinecarboxylate (144 mg) which was used in the next step, LC/MS [M+H]+=237. (ii) A stirred solution of methyl 3-methyl-2-oxo-1-(2-pyrimidinyl)-4-imidazolidinecarboxylate (144 mg, 0.6 mmol) in THF (1.5 ml) at 0° C. was treated with lithium hydroxide (72 mg, 3 mmol) in water (1 ml) and the reaction mixture was stirred at 0-5° C. for 1 hours. The reaction was acidified to pH 2 with 2N hydrochloric acid and the solvent was evaporated. The residue dried to give 3-methyl-2-oxo-1-(2-pyrimidinyl)-4-imidazolidinecarboxylic acid which was used crude in the next step, LC/MS [M+H]+=223.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[F:11][CH2:12][C:13](=O)[CH2:14][C:15]([O:17][CH3:18])=[O:16].[NH2:20][C:21]([CH3:29])=[CH:22][C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24]>C(OCC)(=O)C>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:22]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])=[C:21]([CH3:29])[NH:20][C:13]([CH2:12][F:11])=[C:14]1[C:15]([O:17][CH3:18])=[O:16]
Reactant: CC(N)=CC(=O)OC(C)C
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: COC(=O)CC(=O)CF
Solvent: CCOC(C)=O
Product: COC(=O)C1=C(CF)NC(C)=C(C(=O)OC(C)C)C1c1cccc(Cl)c1Cl
Reaction time: 2.5 h
Yield: 38.4 %

Procedure:
2,3-Dichlorobenzaldehyde (1.75 g, 10 mmoles), methyl 4-fluoro-3-oxobutanoate (1.34 g, 10 mmoles) and 1-methylethyl 3-amino-2-butenoate (1.43 g, 10 mmoles) were heated with stirring at 90° for 2.5 hours. The reaction mixture was dissolved in ethyl acetate and chromatographed on silica eluting with petroleum ether (60°-80°)/ethyl acetate mixtures. Pure fractions were combined and evaporated to dryness. The title compound (1.6 g) was obtained by crystallisation from 2-propanol. mp 148°-9°.
Reaction SMILES: O.[CH3:2][CH:3]([CH3:5])[O-:4].[CH3:6][CH:7](C)[O-:8].C[CH:11](C)[O-:12].CC(C)[O-].[Ti+4:18].CC(O)(CC(C)(O)CCCC)C>CC(O)C>[CH3:2][CH:3]([O:4][C:7]([CH3:6])=[O:8])[CH2:5][O:12][CH3:11].[Ti:18]
Reactant: [Ti+4]
Reactant: CC(C)[O-]
Agent: CCCCC(C)(O)CC(C)(C)O
Solvent: O
Solvent: CC(C)O
Product: COCC(C)OC(C)=O
Product: [Ti]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-propanol (IPA) solution (500 g) of deionized water (27 g) was agitated with IPA solution (500 g) of a titanium tetraisopropoxide (284 g) and dropped at room temperature for 2 hours. 2,4-dimethyl-2,4-octanediol (180 g) was added to a solution obtained and agitated at room temperature for 30 minutes. After the solution was concentrated under reduced pressure at 30° C., it was heated to 60° C. and heating was continued under reduced pressure to generate no distillate. Then, PGMEA (1,200 g) was added thereto and heated under reduced pressure at 40° C. until no BOH was distilled to obtain a PGMEA solution of a titanium-containing compound [B-I] (1,000 g) (compound concentration: 25%). The molecular weight (Mw) of the compound measured in terms of polystyrene was 1,200.
Reaction SMILES: C1(B([O:14][B:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)C2C=CC=CC=2)C=CC=CC=1.O[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1[O:36][C:37]2[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=2[N:39]=1>O1CCCC1>[C:22]1([B:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[O:14][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]2[O:36][C:37]3[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=3[N:39]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Oc1ccccc1-c1nc2ccccc2o1
Reactant: c1ccc(B(OB(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc(B(Oc2ccccc2-c2nc3ccccc3o2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of diphenylborinic anhydride (5.0 g; 0.014 mole) in tetrahydrofuran (20 ml) was added to a solution of 2-(2′-hydroxyphenyl)benzoxazole (3.1 g; 0.014 mole) in tetrahydrofuran (10 ml). The reaction mixture was refluxed under nitrogen for 2 h and allowed to cool to room temperature, then kept in the refrigerator for 18 h. The product was filtered off under suction, washed with methanol and dried under vacuum at 80° C. for 6 h. Yield 4.4 g (84%). The product was further purified by sublimation (85%). M.p 195° C. (DSC, onset); Tg 59° C. Elemental analysis:
Reaction SMILES: [N+](C1C=CC(COC(N2C[C@@H](S)C[C@H]2C(N2CCN(C(=O)COCCNC(OCC3C=CC([N+]([O-])=O)=CC=3)=O)CC2)=O)=O)=CC=1)([O-])=O.[CH2:48]([CH2:50][NH2:51])[OH:49].[C:52]1(=O)[O:57][C:55](=[O:56])[C:54]2=[CH:58][CH:59]=[CH:60][CH:61]=[C:53]12>C1(C)C=CC=CC=1>[C:52]1(=[O:57])[N:51]([CH2:50][CH2:48][OH:49])[C:55](=[O:56])[C:54]2=[CH:58][CH:59]=[CH:60][CH:61]=[C:53]12
Reactant: NCCO
Reactant: O=C1OC(=O)c2ccccc21
Agent: O=C(NCCOCC(=O)N1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)OCc1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCO

Procedure:
(2S, 4S )-1-(p-nitrobenzyloxycarbonyl)-2-(4-(2-(2-(p-nitrobenzyloxycarbonylamino) ethoxy)acetyl)piperazine-1-yl) carbonyl-4-mercaptopyrrolidine ##STR12## 1) A 6.11 g portion of ethanolamine and 14.81 g of phthalic anhydride were stirred in 100 ml of toluene for 3 hours with heating. After concentration of the reaction solution, a residue was crystallized from chloroform, collected by filtration and then dried to yield 17.2 g of white 2-phthalimidoethanol.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]([C:11]2[C:12]([C:18]([F:21])([F:20])[F:19])=[N:13][C:14](Cl)=[N:15][CH:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[C:26]#[N:27]>C(#N)C>[CH3:4][CH2:3][CH2:2][CH:1]([CH3:7])[CH3:6].[CH:1]1([CH2:7][NH:8][C:9]([C:11]2[C:12]([C:18]([F:21])([F:20])[F:19])=[N:13][C:14]([NH:22][C:23]3[CH:30]=[CH:29][CH:28]=[C:25]([C:26]#[N:27])[CH:24]=3)=[N:15][CH:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NCC1CCCCC1)c1cnc(Cl)nc1C(F)(F)F
Reactant: N#Cc1cccc(N)c1
Solvent: CC#N
Product: CCCC(C)C
Product: N#Cc1cccc(Nc2ncc(C(=O)NCC3CCCCC3)c(C(F)(F)F)n2)c1
Temperature: 200 °C
Yield: 118 %

Procedure:
To a solution of 2-chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid cyclohexylmethyl-amide (50 mg) in acetonitrile (0.5 ml) was added 3-aminobenzonitrile (92 mg, ex Aldrich) and the solution heated at 200° C. under microwave conditions for 45 minutes. Acetonitrile was removed under reduced pressure and ethyl acetate (5 ml) added. The solution was washed sequentially with 2N hydrochloric acid (2×3 ml) and water (3×3 ml), dried (MgSO4), evaporated and the residue purified using silica gel chromatography with 1:1 ethyl acetate:isohexane to afford the title compound (37 mg).
Reaction SMILES: C(N(CC)CC)C.ClCCl.[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N:18]2[CH2:22][C@@H:21]([O:23][CH2:24][CH2:25][OH:26])[C@H:20]([O:27][CH2:28][O:29][CH3:30])[CH2:19]2)[N:13]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>O>[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N:18]2[CH2:22][C@@H:21]([O:23][CH2:24][CH2:25][O:26][S:32]([CH3:31])(=[O:34])=[O:33])[C@H:20]([O:27][CH2:28][O:29][CH3:30])[CH2:19]2)[N:13]=1
Reactant: COCO[C@@H]1CN(c2cccc(Br)n2)C[C@H]1OCCO
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCO[C@@H]1CN(c2cccc(Br)n2)C[C@H]1OCCOS(C)(=O)=O
Reaction time: 0.25 h

Procedure:
7.9 ml of triethylamine was slowly added to a solution of 70 ml of dichloromethane containing 13.14 g of 2-bromo-6-[(3R,4R)-3-methoxymethyloxy-4-(2-hydroxyethyl)oxypyrrolidine-1-yl]pyridine in an ice bath. Then, 3.2 ml of methanesulfonyl chloride was slowly added thereto, followed by stirring for 15 minutes. Then, the reaction solution was poured into water and extracted twice with dichloromethane. The organic phase was washed with brine and the solvent was removed. The residue was filtered through NH-silica gel, to give 15.66 g of the target compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9]2)=[CH:4][C:3]=1[F:22].[CH2:23]([O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[C:30]([N+:37]([O-])=O)[CH:29]=1)[CH2:24][CH2:25][CH3:26]>>[NH2:37][C:30]1[CH:29]=[C:28]([O:27][CH2:23][CH2:24][CH2:25][CH3:26])[CH:36]=[CH:35][C:31]=1[C:32]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:9]2)=[CH:4][C:3]=1[F:22])=[O:33]
Reactant: CCCCOc1ccc(C(=O)O)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2ccc(N)c(F)c2)C1
Product: CCCCOc1ccc(C(=O)Nc2ccc(N3CCC(CNC(=O)OC(C)(C)C)C3)cc2F)c(N)c1

Procedure:
tert-Butyl [1-(4-amino-3-fluorophenyl)pyrrolidin-3-yl]methylcarbamate was reacted with 4-butoxy-2-nitrobenzoic acid by method E, followed by hydrogenation. This resulted in the product with the molecular weight of 500.62 (C27H37FN4O4); MS (ESI): 501 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]=1[OH:16])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]=1[OH:16]
Reactant: O=[N+]([O-])c1cccc(-c2ccccc2)c1O
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(-c2ccccc2)c1O
Yield: 90 %

Procedure:
To a solution of 2-nitro-6-phenylphenol(900 mg, 4.2 mmol) in methanol(50 ml) was added 10% Pd/C (100 mg). The mixture was flushed with argon, then hydrogen was bubbled through the solution for 10 min. and a hydrogen atmosphere was maintained at balloon pressure overnight. The mixture was filtered through celite and the celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5% MeOH/CH2Cl2) gave the desired product(700 mg, 90%). 1H NMR (CD3OD): δ 7.55-7.27 (m, 5H), 6.77-6.61 (m, 3H)
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[N:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[C:26]3[N:30]=NN[N:27]=3)=[CH:18][CH:19]=2)[C:11]2[C:10]([C:31]([O:33]C(OC(OC3CCCCC3)=O)C)=[O:32])=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=1.CCOC1N(CC2C=CC(C3C=CC=CC=3C3NN=NN=3)=CC=2)C2C([C:76]([OH:78])=[O:77])=CC=CC=2N=1>>[CH3:1][CH2:2][O:3][C:4]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[C:26]3[N:27]=[C:76]([OH:78])[O:77][N:30]=3)=[CH:16][CH:15]=2)[C:11]2[C:10]([C:31]([OH:33])=[O:32])=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=1
Reactant: CCOc1nc2cccc(C(=O)OC(C)OC(=O)OC3CCCCC3)c2n1Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1
Reactant: CCOc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Product: CCOc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2noc(O)n2)cc1

Procedure:
TCV-116 or candesartan,
Reaction SMILES: [C:1]([Si:5]([CH3:15])([CH3:14])[O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:16]([CH:18]1[O:20][CH2:19]1)Br>>[C:1]([Si:5]([CH3:15])([CH3:14])[O:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:16][CH:18]2[CH2:19][O:20]2)=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: BrCC1CO1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(O)cc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(OCC2CO2)cc1
Yield: 21 %

Procedure:
Synthesis followed SP3a, using 4.1 mmol 4-(tert-Butyl-dimethyl-silanyloxy)-phenol and racemic epibromohydrine to give the title compound upon purification by Flash Master Personal (20 g silica gel cartridge, PE to PE/ethyl acetate 15:1) with 21% yield.
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:18][O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=C[CH:21]=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.Cl.OC(COC1C=CC([Cl:55])=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1.Cl.OC(COC1C=CC=CC=1C)CNC(C)(C)CC1C=CC(OC)=CC=1.Cl.OC(COC1C=CC(C(C)(C)C)=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1>>[ClH:55].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:21]=[CH:26][CH:27]=[CH:28][C:29]=1[CH:24]([CH3:25])[CH3:23])[CH2:4][NH:5][C:6]([CH3:16])([CH3:17])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(Cl)cc2)cc1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2cccc3ccccc23)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccc(C(C)(C)C)cc2)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccccc2C)cc1
Agent: Cl
Product: COc1ccc(CC(C)(C)NCC(O)COc2ccccc2C(C)C)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 356 (M−15,1), 251 (19), 250 (100), 163 (5), 122 (5), 121 (53), 114 (8), 104 (6),103 (6), 91 (24), 77 (14).
Reaction SMILES: [O:1]=[C:2]1[C:6]2=[CH:7][N:8]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][CH:24]=[N:23]4)=[CH:18][CH:17]=3)[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]2=[N:4][N:3]1[CH2:27][C:28]([O:30]CC)=[O:29].[OH-].[Li+].Cl>O1CCOCC1.ClCCl>[O:1]=[C:2]1[C:6]2=[CH:7][N:8]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][CH:24]=[N:23]4)=[CH:18][CH:17]=3)[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]2=[N:4][N:3]1[CH2:27][C:28]([OH:30])=[O:29]
Reactant: CCOC(=O)Cn1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(O)Cn1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Reaction time: 18 h

Procedure:
Ethyl (3-oxo-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-3,5-dihydro-2H-pyrazol[4,3-c]quinolin-2-yl)acetate (Example 524, 10 mg, 0.023 mmol) was suspended in dioxane (2 mL), treated with an lithium hydroxide (22 μL, 1 N aqueous, 0.023 mmol, 1.05 equiv) and stirred vigorously for 18 hours. The mixture was diluted with dichloromethane until homogeneous (2 mL) and stirred for an additional 6 hours. The mixture was treated with hydrochloric acid (1 drop from 9″ pipette, 12 N aqueous) and concentrated in vacuo, providing the titled compound: 1H-NMR (400 MHz, d6-DMSO) δ 9.06 (1H, s), 8.44 (1H, d, J=2.7 Hz), 8.15 (1H, d, J=7.9 Hz), 7.81 (2H, d, J=8.8 Hz), 7.74 (1H, d, J=8.5 Hz), 7.71 (1H, d, J=1.3 Hz), 7.58 (1H, t, 7.8 Hz), 7.50 (1H, t, J=7.3 Hz), 7.43 (2H, d, J=8.5 Hz), 7.14 (1H, hr s), 6.52 (1H, m), 5.74 (2H, s), 4.59 (2H, s) ppm; high resolution mass spectrometry (ES+) m/z 400.1412 [(M+H)+; calculated for C22H18N5O3: 400.1404].
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][NH2:17]>CN(C)C=O>[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][NH:17][C:10]([C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[NH:1][CH:2]=[CH:3]2)=[O:12]
Reactant: CN(C)CCN
Reactant: O=C(O)c1cccc2cc[nH]c12
Solvent: CN(C)C=O
Product: CN(C)CCNC(=O)c1cccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.6 %

Procedure:
Indole-7-carboxylic acid (3.20 g, 0.020 mole) was dissolved in 50 ml of dimethylformamide (DMF) and 3.3 g (0.020 mole) of N,N'-carbonyldiimidazolewas added. After stirring for 2 hours at room temperature, 2.0 g (0.023 mole) of N,N-dimethylethylenediamine was added, and stirring was continuedfor an additional 1 hour. At the end of this time the solvent was removed at a pressure of 0.1 mm Hg (50° C.) and the remaining residue was triturated with a minimum of H2O and the crude product was filtered off and dried and concentrated to give a solid. Recrystallization from ether-pentane gave 2.20 g of N-[2-(dimethylamino)ethyl]-1H-indole-7-carboxamide (48%), m.p. 100°-102° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[C:12]2[N:17]=[CH:16][C:15]([CH2:18][NH2:19])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N:28]1[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[C:36](O)=[O:37])=[CH:30][CH:29]=1.N1(O)C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>C(OCC)(=O)C.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[C:12]2[N:17]=[CH:16][C:15]([CH2:18][NH:19][C:36](=[O:37])/[CH:35]=[CH:34]/[C:31]3[CH:32]=[CH:33][N:28]=[CH:29][CH:30]=3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)/C=C/c1ccncc1
Reactant: NCc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(/C=C/c1ccncc1)NCc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 65 %

Procedure:
To a dichloromethane (1 ml) solution of the [6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methylamine (41 mg, 0.10 mmol) obtained in Example 63, (E)-3-(pyridin-4-yl)acrylic acid (15 mg, 0.10 mmol), benzotriazol-1-ol (14 mg, 0.10 mmol) and N-methylmorpholine (0.011 ml, 0.10 mmol) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (19 mg, 0.10 mmol) at 0° C. The resulting mixture was stirred at room temperature for 19 hours. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel chromatography. The fraction obtained from the ethyl acetate eluate was concentrated under reduced pressure. The solid thus obtained was washed with diethyl ether and collected by filtration to give the title compound (35 mg, 0.065 mmol, 65%) as a white solid.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12].O>C(Cl)Cl>[C:11]([NH:15][C:7](=[O:8])[C:4]1[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)N
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(C(=O)NC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 95 %

Procedure:
To a solution of p-toluoyl chloride (34.2 ml, 259 mmol) in DCM (250 ml), charged to a 500 mL round bottom, t-butylamine (57.3 ml, 543 mmol) was added slowly at 0° C. The reaction mixture was stirred at 0° C. for 45 min. The reaction mixture was then partioned between additional DCM and water. The organic layer was then washed with water 2 and brine. The organic layer was then dried over magnesium sulfate and concentrated under vacuum to give a white solid N-tert-butyl-4-methylbenzamide (47.07 g, 95.1% yield). MS (M+H)+ 192.