Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]([NH:7][O:8][C@H:9]1[C@H:14]([O:15][CH3:16])[C@H:13]([O:17][CH3:18])[C@@H:12]([O:19][CH3:20])[C@H:11]([CH3:21])[O:10]1)=[O:6].[H-].[Na+].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[N:37]=[CH:36][N:35]([C:38]3[CH:43]=[CH:42][C:41]([O:44][C:45]([F:48])([F:47])[F:46])=[CH:40][CH:39]=3)[N:34]=2)=[CH:29][CH:28]=1>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]([N:7]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[N:37]=[CH:36][N:35]([C:38]3[CH:43]=[CH:42][C:41]([O:44][C:45]([F:47])([F:46])[F:48])=[CH:40][CH:39]=3)[N:34]=2)=[CH:29][CH:28]=1)[O:8][C@H:9]1[C@H:14]([O:15][CH3:16])[C@H:13]([O:17][CH3:18])[C@@H:12]([O:19][CH3:20])[C@H:11]([CH3:21])[O:10]1)=[O:6]
Reactant: COC(=O)CC(=O)NO[C@@H]1O[C@@H](C)[C@H](OC)[C@@H](OC)[C@H]1OC
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(CBr)cc3)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CC(=O)N(Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)O[C@@H]1O[C@@H](C)[C@H](OC)[C@@H](OC)[C@H]1OC
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 33.7 %

Procedure:
To a solution of N-((2S,3R,4R,5S,6S)-3,4,5-trimethoxy-6-methyl-tetrahydropyran-2-yloxy)-malonamic acid methyl ester (P-5; 108 mg, 0.34 mmol) in dry THF (3 mL) was added 60% NaH (14.4 mg, 0.36 mmol) giving gas evolution. To this mixture was added 3-(4-bromomethylphenyl)-1-(4-trifluoromethoxyphenyl)-1H-[1,2,4]triazole (P-7; 106 mg, 0.26 mmol), and the resulting mixture was heated to 50° C. for 21 h. The mixture was then allowed to cool to room temperature and diluted with EtOAc and washed with H2O. The aqueous fraction was extracted with EtOAc. The organic fractions were combined, washed with brine, dried with anhydrous Na2SO4 and evaporated at room temperature under vacuum. The resulting crude material was purified by silica gel chromatography (eluting with 100% Hexane going to 50% EtOAc in Hexane over 15 min and then going to 100% EtOAc over an additional 20 min). The title product (56 mg, 34%) was isolated as a colorless glass: 1H NMR (300 MHz, CDCl3) δ 8.58 (s, 1H), 8.17 (d, J=8.4 Hz, 2H), 7.90-7.70 (m, 2H), 7.41 (dd, J=9.9, 8.4 Hz, 4H), 5.42-5.09 (m, 2H), 4.76 (d, J=15.9 Hz, 1H), 3.83-3.05 (m, 18H), 1,41-1.20 (m, 3H); 13C NMR (151 MHz, CDCl3) δ 167.80, 148.87, 141.93, 137.72, 135.95, 130.20, 128.71, 127.19, 122.81, 121.66, 119.95, 105.05, 82.11, 81.97, 79.79, 76.81, 70.28, 70.04, 60.48, 59.63, 59.20, 58.37, 52.76, 41.66, 30.10, 18.58; ESIMS m/z 639 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][Br:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: BrCCCCCCCCCCCCBr
Reactant: CCOC(=O)c1ccc(-c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(-c2ccc(OCCCCCCCCCCCCBr)cc2)cc1
Yield: 67 %

Procedure:
An acetone solution of 90 m moles(21.8 g) of the above 4'-hydroxybiphenyl-4-carboxylic acid ethyl ester, 0.15 mole(49.2 g) of 1,12-dibromododecane, and 0.4 mole(55.3 g) of potassium carbonate was refluxed for four hours. The reaction sloution was filtered. The filtrate was concentrated, and then purified by column chromatography, to obtain 29.5 g of 4'-(12-bromododecyloxy)biphenyl-4-carboxylic acid ethyl ester [m.p. 88.6°-90.5° C⟧ (yield: 67%)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([C@H:26]([NH:38][C:39](=[O:49])[O:40][C@@H:41]1[C@H:48]2[C@H:44]([O:45][CH2:46][CH2:47]2)[O:43][CH2:42]1)[C@H:27]([OH:37])[CH2:28][NH:29][O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C>CN(C)C1C=CN=CC=1.O1CCCC1>[CH2:19]([C@H:26]([NH:38][C:39](=[O:49])[O:40][C@@H:41]1[C@H:48]2[C@H:44]([O:45][CH2:46][CH2:47]2)[O:43][CH2:42]1)[C@H:27]([OH:37])[CH2:28][N:29]([S:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1)(=[O:17])=[O:16])[O:30][CH:31]1[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CNOC1CCCCC1)O[C@H]1CO[C@H]2OCC[C@H]21
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CN(OC1CCCCC1)S(=O)(=O)c1ccc(OCc2ccccc2)cc1)O[C@H]1CO[C@H]2OCC[C@H]21
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.3 %

Procedure:
A mixture of 4-benzyloxybenzenesulfonyl chloride (65 mg; 0.230 mmol), (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-[(cyclohexyloxy)amino]-2-hydroxypropylcarbamate (100 mg, 0.230 mmol), diisoproylethylamine (0.042 mL, 0.242 mmol) and 4-dimethylaminopyridine (˜1 mg) in anhydrous tetrahydrofuran (3 mL) was stirred at ambient temperature under an Argon atmosphere for 16 hours. An additional quantity of 4-benzyloxybenzenesulfonyl chloride (13 mg, 0.046 mmol) and 4-dimethylaminopyridine (˜1 mg) was added and the reaction was heated at reflux for approximately 2 hours. After cooling to ambient temperature, the reaction mixture was partitioned between ethyl acetate and aqueous hydrochloric acid. The phases were separated and the organic layer was then washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The crude product was purified on flash grade silica gel eluting with 1:1 ethyl acetate:hexane. Fractions containing the product were combined and evaporated in vacuo and dried under high vacuum to provide (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-[{[4-(benzyloxy)phenyl]sulfonyl}(cyclohexyloxy)amino]-2-hydroxypropylcarbamate (143 mg, 91%). H1-NMR (chloroform-D3): 1.27 (m, 6H), 1.61 (m, 5H), 2.07 (m, 2H), 2.91 (m, 4H), 3.10 (b, 1H), 3.68 (m, 2H), 3.89 (m, 4H), 4.19 (m, 1H), 4.84 (m, 1H), 5.01 (m, 1H), 5.12 (s, 2H), 5.64 (d, 1H), 7.05 (d, 2H), 7.28 (m, 10H), 7.71 (d, 2H). MS(ESI): 703(M+Na).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:12]=[CH:11][N:10]([C:13]3[N:21]=[CH:20][CH:19]=[CH:18][C:14]=3[C:15]([OH:17])=O)[N:9]=2)[CH2:4][CH2:3]1.[NH2:22][CH:23]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:24]([OH:28])[C:25]([NH2:27])=[O:26]>ClCCl>[NH2:27][C:25](=[O:26])[CH:24]([OH:28])[CH:23]([NH:22][C:15](=[O:17])[C:14]1[CH:18]=[CH:19][CH:20]=[N:21][C:13]=1[N:10]1[CH:11]=[CH:12][C:8]([CH:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)=[N:9]1)[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CN1CCC(c2ccn(-c3ncccc3C(=O)O)n2)CC1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Solvent: ClCCl
Product: CN1CCC(c2ccn(-c3ncccc3C(=O)NC(Cc3ccccc3)C(O)C(N)=O)n2)CC1
Yield: 47 %

Procedure:
Coupling of 2-(3-(1-methylpiperidin-4-yl)-1H-pyrazol-1-yl)nicotinic acid (360 mg, 1.257 mmol) and 3-amino-2-hydroxy-4-phenylbutanamide (293 mg, 1.509 mmol) in dichloromethane (50 mL) according to the procedure described for example 1.3 and recrystallization from ethylacetate afforded 273 mg of the title compound; ESI-MS [M+H]+: 463.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22]([OH:24])=O)[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2.[CH:27]12[CH2:35][CH:31]([CH2:32][NH:33][CH2:34]1)[CH2:30][N:29]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:28]2>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22]([N:33]3[CH2:34][C@H:27]4[CH2:35][C@H:31]([CH2:30][N:29]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:28]4)[CH2:32]3)=[O:24])[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: C[C@@H](C(=O)O)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C2)C1
Product: C[C@@H](C(=O)N1C[C@@H]2C[C@@H](CN(C(=O)OC(C)(C)C)C2)C1)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O

Procedure:
Using (2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoic acid and 3,7-diazabicyclo[3.3.1]nonane-3-carboxylic acid, 1,1-dimethylethyl ester* and the synthetic procedure described in Example 1, the title compound was prepared. * Reference for 3,7-Diazabicyclo[3.3.1]nonane-3-carboxylic acid, 1,1-dimethylethyl ester: Alstermark, C; Andersson, K; Bjore, A; Bjorsne, M; Lindstedt, A. E; Nilsson, G; Polla, M; Strandlund, G; Ortengren, Y. PCT Int. Appl. (2000), WO 0077000.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:10][C:11]3[C:16]([C:17](=[O:19])[CH:18]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:7][CH:8]=1>I.CC(O)=O.O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:10][C:11]3[C:16]([C:17](=[O:19])[CH:18]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:7][CH:8]=1
Reactant: COc1ccc(-c2cc(=O)c3ccccc3o2)nc1
Agent: I
Solvent: O
Solvent: CC(=O)O
Product: O=c1cc(-c2ccc(O)cn2)oc2ccccc12
Temperature: 25 °C
Yield: 36.2 %

Procedure:
2-(5-Methoxy-pyridin-2-yl)-chromen-4-one (790 mg, 3.12 mmol) in HI (10 mL) and AcOH (4 mL) was heated at reflux for 6 h. Reaction mixture was cooled to rt, diluted with water, neutralized and extracted with EtOAc to give crude product. This was purified by column chromatography using 5% MeOH in dichloromethane to give (270 mg, 36%) of 2-(5-Hydroxy-pyridin-2-yl)-chromen-4-one. MS (ES) m/z: 240.09 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10]N=C2CCCCCCC2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[CH:21](O)([CH3:23])[CH3:22]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:10][C:21]3[CH2:23][CH2:8][CH2:9][CH2:4][CH2:5][CH2:6][C:22]=3[C:8]=2[CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)O
Reactant: O=[N+]([O-])c1ccc(ON=C2CCCCCCC2)cc1
Agent: Cl
Product: O=[N+]([O-])c1ccc2oc3c(c2c1)CCCCCC3

Procedure:
The core molecule was synthesized by the following procedure. Potassium t-butoxide (5.9 g, 53 mmol) was added in portions to a cooled (5° C.) solution of cycloheptanone oxime (7.5 g, 53 mmol) in DMF (100 mL). The cooled reaction mixture was stirred for 50 minutes and then 1-chloro-4-nitrobenzene (7.9 g, 50 mmol) in DMF (25 mL) was added over 5 minutes. The reaction mixture was stirred at ˜10° C. for 30 minutes and then allowed to warm to room temperature and stirred for an additional 4 hours. The reaction mixture was concentrated under reduced pressure and the crude material was dissolved in ether and washed with water and brine. The organic phase was dried (Na2SO4) and concentrated to provide cyclooctanone O-(4-nitro-phenyl)-oxime (5.7 g). Cyclooctanone O-(4-nitro-phenyl)-oxime (5.3 g, 20 mmol) was dissolved in warm isopropanol (120 mL) and 12 N hydrochloric acid (6.8 mL) was added. The reaction mixture was heated to reflux for 5 hours and then cooled in an ice bath. The solid was collected by filtration, washed with water and cold isopropanol, and dried in an oven. The crude solid was purified by flash column chromatography (elution with 2% ethyl acetate-hexanes) to give 2-nitro-6,7,8,9,10,11-hexahydro-benzo[b]-cycloocta[d]furan (3.5 g, 14 mmol). A mixture of 2-nitro-6,7,8,9,10,11-hexahydro-benzo[b]-cycloocta[d]furan (3.4 g, 14 mmol) and Raney nickel (-4.1 g wet weight) in ethanol (170 mL) was hydrogenated at 50 PSI on a Parr shaker overnight. The mixture was filtered through Celite® and the filtrate was concentrated. The crude solid was purified by flash column chromatography (elution with 20% ethyl acetate-hexanes) to give 6,7,8,9,10,11-Hexahydro-benzo[b]-cycloocta[d]furan-2-ylamine (2.3 g). Mp 97-98° C.
Reaction SMILES: Cl.C[NH:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]23[CH2:20][CH:15]4[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]4)[CH2:12]2)[CH2:18]3)=[CH:6][CH:5]=1.N1C=CC=CC=1.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>O>[C:28]([NH:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]23[CH2:12][CH:13]4[CH2:19][CH:17]([CH2:16][CH:15]([CH2:14]4)[CH2:20]2)[CH2:18]3)=[CH:8][CH:9]=1)([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)Cl
Reactant: CNc1ccc(OC23CC4CC(CC(C4)C2)C3)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(OC23CC4CC(CC(C4)C2)C3)cc1
Reaction time: 18 h

Procedure:
A solution of the free base from 2.82 g. of the N-methyl-4-(1-adamantyloxy)aniline hydrochloride in 20 ml. pyridine was treated dropwise with 1.64 ml. ClCO2C2H5. Following 18 hours standing in the cold the mixture was poured into ice:H2O. This was extracted with Et2O and the organic layer washed in turn with H2O, cold 2.5 N HCl, H2O NaHCO3 and brine. The extract was then taken to dryness to leave behind N-methyl, N-carbethoxy-4-(1-adamantyloxy)aniline as an oil.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:25][CH2:24][CH:23]([N:26]([CH3:28])[CH3:27])[CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[Cl:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:30][C:31]1[CH:36]=[C:35]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:25][CH2:24][CH:23]([N:26]([CH3:27])[CH3:28])[CH2:22]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:29])[CH2:3][CH2:4]2)=[O:9])[CH:34]=[CH:33][CH:32]=1
Reactant: CN(C)C1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)C1
Reactant: OB(O)c1cccc(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)C1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2cccc(Cl)c2)C1
Yield: 30 %

Procedure:
The title compound was synthesized in analogy to example 66, from (RS)-(4,4-difluoro-piperidin-1-yl)-[5-(3-dimethylamino-pyrrolidine-1-carbonyl)-1H-indol-2-yl]-methanone (example 42, intermediate a)), 3-chlorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (30%).
Reaction SMILES: CO[CH:3]([O:6][CH3:7])[O:4][CH3:5].C([C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:12][CH:11]=1)=O>CO>[CH3:7][O:6][CH:3]([O:4][CH3:5])[C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:12][CH:11]=1
Reactant: COC(OC)OC
Reactant: O=Cc1ccc(/C=C/C(=O)O)cc1
Solvent: CO
Product: COC(OC)c1ccc(/C=C/C(=O)O)cc1
Temperature: 0 °C

Procedure:
38.81 mL (0.354 mmol) of trimethylorthoformate is added to a suspension of 25 g (0.141 mol) of (E)-3-(4-formylphenyl)acrylic acid in 350 mL of methanol and the mixture is refluxed for 48 hours. After cooling, the reaction mixture is filtered and the filtrate is evaporated down. The residue is taken up in 500 mL of dichloromethane and filtered through CELITE® filter aid. The filtrate is evaporated down to 150 mL and cooled to 0° C. The precipitate formed is filtered off, washed with dichloromethane/petroleum ether (1:1), and dried at 60° C. in the circulating air dryer. Yield: 12.05 g (31.5% of theory); C12H14O4 (M=222.24); calc.: molecular ion peak (M+H)+: 245; found: molecular ion peak (M+H)+: 245; Rf value: 0.6 (silica gel, petroleum ether/ethyl acetate (1:1)).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]=[CH:8]2.[NH2-:13].[Na+].C(OCC)(=O)C.[BrH:21]>C1(C)C(C)=CC=CC=1>[BrH:21].[NH2:13][C:8]1[C:9]2[C:4](=[C:3]([OH:2])[CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: [NH2-]
Reactant: COc1cccc2cnccc12
Agent: Br
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: Nc1nccc2c(O)cccc12
Temperature: 140 °C
Reaction time: 1 h

Procedure:
900 mg (5.66 mmol) of 5-methoxyisoquinoline was dissolved in 20 ml of xylene. 4.26 ml (28.3 mmol) of N,N,N′,N′-tetramethylenediamine and 1.17 g (30.0 mmol) of sodium amide were added to the obtained solution, and they were stirred at 140° C. for 1 hour. After the treatment with ethyl acetate as the extraction solvent in an ordinary manner, 10 ml of hydrobromic acid was added to the obtained crude product and they were heated under reflux for 6 hours. The solvent was evaporated to obtain the title compound.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:14])[O:12][CH3:13])=[C:6]([CH3:15])[CH:5]=1.Cl[CH2:17][C:18]1[S:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1>O.CN(C)C=O>[S:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=[C:18]1[CH2:17][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:14])[O:12][CH3:13])=[C:6]([CH3:15])[CH:5]=1
Reactant: COC(=O)Nc1ccc(O)cc1C
Reactant: ClCc1nc2ccccc2s1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Nc1ccc(OCc2nc3ccccc3s2)cc1C
Reaction time: 0.33 h
Yield: 58.7 %

Procedure:
A solution of 3.6 g of potassium hydroxide in 10 ml of water was added to a solution of 10.0 g of methyl N-(4-hydroxy-2-methylphenyl)carbamate [prepared as described in Example 15(a) above] in 30 ml of dimethylformamide and 6 ml of water cooled in an ice-water bath. The resulting mixture was stirred at the same temperature for 20 minutes, and then a solution of 10.0 g of 2-chloromethylbenzothiazole in 25 ml of dimethylformamide was added to the reaction mixture. The temperature of the resulting mixture was elevated to room temperature and the mixture was stirred for 1 hour, at the end of which time the temperature was elevated further to 60° C. and the reaction mixture stirred for a further 2 hours. The reaction mixture was then poured into water to give a crystalline precipitate which was washed with water and further washed with diethyl ether and then recrystallised from ethyl acetate to give 10.5 g (yield 59%) of the title compound as a crystalline solid having a melting point of 147° to 149° C. The proton nuclear magnetic resonance spectrum was identical to that for the title compound of Example 21.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH2:16](O)[CH3:17]>>[CH2:16]([O:9][C:8](=[O:10])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:17]
Reactant: O=C(O)Cc1ccccc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccccc1

Procedure:
A solution of phenylacetic acid (50 g, 0.36 mol) in ethanol (150 mL) is treated with catalytic amount of sulfuric acid (4 mL). The reaction mixture is refluxed for 4 h. The reaction is then concentrated in vacuo. The residue is dissolved in diethyl ether (300 mL) and washed with saturated aqueous sodium bicarbonate solution (2×50 mL) and water (1×100 mL). The organic layer dried over sodium sulfate filtered and concentrated in vacuo to give phenylacetic acid ethyl ester as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 1.2 (t, J=7.2, 3H), 3.6 (s, 2H), 4.1 (q, J=7.2, 2H), 7.3 (m, 5H); MS 165 [M+1]+.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15]C[C@@H:13]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH2:12]2)=[N:8][C:9]=1[NH2:10].C([O:28]C(N1CCO[C@@H](C(O)=O)C1)=O)(C)(C)C>>[ClH:1].[ClH:1].[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15][O:28][C@@H:13]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH2:12]2)=[N:8][C:9]=1[NH2:10]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](C(=O)O)C1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Agent: Cl
Product: Nc1ccc(N2CCO[C@@H](C(=O)N3CCCC3)C2)nc1N

Procedure:
The title compound was prepared by a method analogous to the one used for Intermediate 1, but using (R)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid for Step 1. 1H NMR (400 MHz, CD3OD) δ 1.81-2.03 (m, 4H) 3.37-3.51 (m, 3H) 3.60-3.73 (m, 3H) 3.75-3.85 (m, 2H) 3.90-3.97 (m, 2H) 4.49 (dd, 1H) 6.40 (d, 1H) 7.73 (d, 1H).
Reaction SMILES: C[O-].[Na+].Cl.Cl.[CH2:6]([NH:13][NH2:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:15]([C:17](=[C:20](SC)[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:18]#[N:19])#[N:16]>CO.C(O)C>[NH2:19][C:18]1[N:13]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:14]=[C:20]([NH:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:17]=1[C:15]#[N:16]
Reactant: CSC(Nc1ccccc1)=C(C#N)C#N
Reactant: NNCc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: N#Cc1c(Nc2ccccc2)nn(Cc2ccccc2)c1N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
With ice-cooling, 19.3 ml of a 5.4N sodium methanolate solution in 20 ml of methanol (purissimum) are added to 9.9 g of benzylhydrazine dihydrochloride in 20 ml of methanol (purissimum) and the reaction mixture is stirred for approx. 15 minutes at room temperature and then introduced into a solution of 4.65 g of 2-cyano-3-methylmercapto-3-phenylamino-acrylonitrile in 150 ml of absolute ethanol. The mixture is heated under reflux for approx. 17 hours and cooled to room temperature and insoluble material is filtered off with suction. The filtrate is concentrated by evaporation using a rotary evaporator and the brown oily residue is chromatographed on 190 g of silica gel, methylene chloride/ethyl acetate mixtures being used as eluant. 5-Amino-1-benzyl-4-cyano-3-phenylamino-pyrazole is obtained; m.p. 139-140° C., FAB-MS: (M+H)+ =290 (C17H15N5).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Mg].CN(C)[CH:14]=[O:15]>C1COCC1.BrCCBr>[Cl:8][C:6]1[CH:7]=[C:2]([CH:3]=[C:4]([O:9][CH3:10])[CH:5]=1)[CH:14]=[O:15]
Reactant: CN(C)C=O
Reactant: COc1cc(Cl)cc(Cl)c1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: COc1cc(Cl)cc(C=O)c1
Temperature: 0 °C
Yield: 54 %

Procedure:
3,5-Dichloroanisole (74.0 g, 419 mmol) in THF (200 mL) was added dropwise to magnesium metal (14.2 g, 585 mmol, pre-washed with 0.5 N HCl) in THF (100 mL) at 25° C. After the addition, 1,2-dibromoethane (3.9 g, 20.8 mmol) was added dropwise. The resultant dark brown mixture was heated at reflux for 3 h. The mixture was cooled to 0° C., and N,N-dimethylformamide (60 mL) was added in one portion. The mixture was partitioned with diethyl ether (3×400 mL) and 6N HCl (500 mL). The combined organic extracts were washed with brine (300 mL), dried (Na2SO4), filtered and concentrated in vacuo to give an oil. Flash chromatography (2×) on silica get eluting with Hex:EtOAc (4:1) afforded the sub-title compound (38.9 g, 54%) as a yellow oil.
Reaction SMILES: [P:1]([O-:18])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:19](=[O:24])[CH2:20][CH2:21][CH2:22][CH3:23]>C(Cl)(Cl)Cl>[OH:24][CH:19]([P:1](=[O:18])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Reactant: CCCCC=O
Solvent: ClC(Cl)Cl
Product: CCCCC(O)P(=O)(OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
The general method of F. Texier-Boullet and A. Foucaud [Synthesis, 1982, 916] was employed. A mixture of dibenzyl phosphite (7.73 ml, 0.035 mole) and valeraldehyde (11.15 ml, 0.105 mole) was stirred at room temperature and basic alumina (35 g) added in one portion. After standing overnight at room temperature chloroform was added and the alumina collected and washed with chloroform. The filtrate was evaporated to dryness and the resulting oil chromatographed on silica gel with gradient elution (50% pentane/ethyl acetate-ethyl acetate) to give the title compound as a colourless oil (9.17 g, 76%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7](C(=O)C(F)(F)F)[C:8]2[C:13]([C:14]=1[NH2:15])=[CH:12][C:11]([Cl:16])=[CH:10][CH:9]=2)=[O:5])[CH3:2].C(O)C.C(=O)([O-])[O-].[K+].[K+]>O>[NH2:15][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:16])[CH:12]=2)[NH:7][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)c1c(N)c2cc(Cl)ccc2n1C(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1[nH]c2ccc(Cl)cc2c1N
Temperature: 70 °C
Reaction time: 1.75 h
Yield: 71.2 %

Procedure:
Heat at 70° C. and stir a mixture of 3-amino-5-chloro-1-(2,2,2-trifluoro-ethanoyl)-1H-indole-2-carboxylic acid ethyl ester (3.34 g, 10 mmol), ethanol (50 mL), and potassium carbonate (1.50 g, 10.85 mmol). After 1.75 h, add water (20 mL), and after another hour add additional potassium carbonate (0.58 g, 4.20 mmol). Cool the reaction mixture to ambient temperature and partition between water/ethyl acetate. Separate the organic layer, dry over MgSO4, filter and concentrate to afford 1.70 g of the title compound as a solid. MS 239(M+H).