Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([Sn](CCCC)(CCCC)CCCC)=[N:6][C:7]=2[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.Br[C:42]1[CH:50]=[N:49][CH:48]=[C:47]2[C:43]=1[CH:44]=[CH:45][NH:46]2>>[CH3:1][N:2]1[C:10]([CH2:11][N:12]2[CH2:13][CH2:14][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:16][CH2:17]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([C:42]1[CH:50]=[N:49][CH:48]=[C:47]3[NH:46][CH:45]=[CH:44][C:43]=13)=[N:6][C:7]=2[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1
Reactant: Brc1cncc2[nH]ccc12
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-c3cncc4[nH]ccc34)nc21

Procedure:
2-(1-((9-methyl-6-morpholino-2-(tributylstannyl)-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (150 mg) was reacted with 4-bromo-6-azaindole via General Procedure G to afford 118 (31.8 mg) following reverse phase purification. MS (Q1) 491.2 (M)+. 1H NMR (400 MHz, DMSO) δ 11.70 (s, 1H), 9.14 (s, 1H), 8.79 (s, 1H), 7.70 (t, 1H), 7.43 (s, 1H), 4.30 (s, 4H), 4.02 (s, 1H), 3.89 (s, 3H), 3.83-3.76 (m, 4H), 3.73 (s, 2H), 2.92 (t, 2H), 1.97 (dd, 16.9, 2H), 1.69 (t, 2H), 1.40-1.09 (m, 3H), 1.02 (s, 6H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][C:7]([CH3:13])=[C:6]([C:14]1[CH:25]=[CH:24][C:17]([O:18][CH2:19][CH2:20][CH2:21][C:22]#[N:23])=[CH:16][CH:15]=1)[C:5]2=O.O.[NH2:28][NH2:29]>>[Cl:1][C:2]1[C:11]([OH:12])=[CH:10][C:9]([OH:8])=[C:4]([C:5]2[C:6]([C:14]3[CH:25]=[CH:24][C:17]([O:18][CH2:19][CH2:20][CH2:21][C:22]#[N:23])=[CH:16][CH:15]=3)=[C:7]([CH3:13])[NH:29][N:28]=2)[CH:3]=1
Reactant: Cc1oc2cc(O)c(Cl)cc2c(=O)c1-c1ccc(OCCCC#N)cc1
Reactant: NN
Solvent: O
Product: Cc1[nH]nc(-c2cc(Cl)c(O)cc2O)c1-c1ccc(OCCCC#N)cc1
Yield: 31.5 %

Procedure:
This compound was synthesised in the same manner as described above. 4-[4-(6-Chloro-7-hydroxy-2-methyl-4-oxo-4H-chromen-3-yl)-phenoxy]-butyronitrile (0.55, 1.49 mmol), hydrazine hydrate (6 ml). The quenched reaction was extracted into ethyl acetate, washed (water), dried (MgSO4), and the solvent removed under vacuum to give a brown oil which was purified by column chromatography to give 4-{4-[3-(5-Chloro-2,4-dihydroxy-phenyl)-5-methyl-1H-pyrazol-4-yl]-phenoxy}-butyronitrile as a white solid (0.18 g, 31.5%); Rf 0.5 Ethyl acetate/Hexane (70/30).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:6][CH2:7][CH3:8])[C:3](Cl)=[O:4].[OH-].[NH4+:11]>>[CH3:1][C:2]([CH3:9])([CH2:6][CH2:7][CH3:8])[C:3]([NH2:11])=[O:4]
Reactant: [NH4+]
Reactant: CCCC(C)(C)C(=O)Cl
Agent: [OH-]
Product: CCCC(C)(C)C(N)=O
Temperature: 1 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
Ammonium hydroxide (250 ml) was stirred and cooled to 1° C. and 2,2-dimethyl valeroyl chloride (49.7 g, 95%, 318 mmol) was added dropwise over 30 minutes. After stirring at room temperature for an additional 1/2 hour, the white solid product was recovered by filtration, washed with water and allowed to air dry to give 35.4 g (86%) of the desired amide, mp 94°-95° (lit. mp 95°-96° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([OH:15])[CH:10]=[CH:11][C:12]=2[C:13]#[N:14])=[CH:4][CH:3]=1.O1CCC[CH2:17]1.CC(C)([O-])C.[K+].CI>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([O:15][CH3:17])[CH:10]=[CH:11][C:12]=2[C:13]#[N:14])=[CH:4][CH:3]=1
Reactant: N#Cc1ccn(O)c1-c1ccc(Cl)cc1
Reactant: C1CCOC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: COn1ccc(C#N)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a stirred solution of 2-(p-chlorophenyl)-1-hydroxypyrrole-3-carbonitrile (2.88 g, 0.0132 mol) and anhydrous tetrahydrofuran is added potassium tert-butoxide (1.55 g, 0.0138 mol). After 30 minutes, methyl iodide (2.06 g, 0.9 mL, 0.0145 mol) is added and the resulting slurry is stirred at room temperature for hours, diluted with water and extracted with ether. The combined ether extracts are washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to yield a solid. Crystallization of the solid from ether/hexanes gives the title compound as a brown solid (2.35 g, 77%), mp 105°-106° C.
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:12][N:11]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27]1[C:39]2[NH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]=2[C:30]([O:40][CH:41]2[O:43][C@H:42]2[CH3:44])=[CH:29][CH:28]=1>CO>[CH2:1]([N:8]([CH:9]1[CH2:12][N:11]([S:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:20][CH:21]=2)(=[O:15])=[O:14])[CH2:10]1)[CH2:44][CH:42]([OH:43])[CH2:41][O:40][C:30]1[C:31]2[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[NH:38][C:39]=2[CH:27]=[CH:28][CH:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCOc1ccc(S(=O)(=O)N2CC(NCc3ccccc3)C2)cc1
Reactant: C[C@@H]1OC1Oc1cccc2[nH]c3ccccc3c12
Solvent: CO
Product: CCCCOc1ccc(S(=O)(=O)N2CC(N(Cc3ccccc3)CC(O)COc3cccc4[nH]c5ccccc5c34)C2)cc1
Yield: 105.7 %

Procedure:
To a solution of benzyl-[1-(4-butoxy-benzenesulfonyl)-azetidin-3-yl]-amine (0.14 g, 0.37 mmol) in methanol (2 ml) was added (2S)-3-(9H-carbazol-4-yloxy)-methyl oxirane (0.11 g, 0.45 mmol) and the mixture was stirred at reflux for 3 days. The methanol was then evaporated, and the residue was washed with a mixture of ether and hexanes to give 0.24 g of an off-white solid; m.p. 65-67° C.; MS (ES) m/z 614.2 (MH+); HRMS (ES) Calcd. for C35H40N3O5S (MH+): 614.2689, Found: 614.2706.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:12][CH2:11][C:8]([C:13]([OH:15])=O)([CH2:9][CH2:10]1)[CH2:7][CH2:6]2)=[O:4].C(Cl)(=O)C(Cl)=O.[CH3:22][N:23](C=O)C.CN>C(Cl)Cl>[CH3:22][NH:23][C:13]([C:8]12[CH2:11][CH2:12][C:5]([C:3]([O:2][CH3:1])=[O:4])([CH2:10][CH2:9]1)[CH2:6][CH2:7]2)=[O:15]
Reactant: COC(=O)C12CCC(C(=O)O)(CC1)CC2
Reactant: CN(C)C=O
Agent: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CNC(=O)C12CCC(C(=O)OC)(CC1)CC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-(Methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid 1-A (Chapman, N. B. et al. J. Org. Chem., 1970, 35, 917) (4.0 g, 18.9 mmol) was dissolved in 12 mL of anhydrous methylene chloride under nitrogen atmosphere, treated with oxalyl chloride (2M in methylene chloride, 28 mL, 56 mmol) and subsequently with 0.5 ml of DMF. The reaction was stirred at room temperature under nitrogen atmosphere for 90 min, then evaporated and placed under vacuum for 20 min. The acid chloride was dissolved in anhydrous methylene chloride (75 mL), cooled in an ice-bath, and then treated dropwise with a solution of methylamine (2M in THF, 57 mL, 113 mmol). Upon addition of the amine, the cooling bath was removed and the reaction stirred at ambient temperature for 30 min. The mixture was diluted with 1000 mL of methylene chloride and washed with 1N aqueous HCl, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated. Product was purified by flash silica gel chromatography, eluting with 0-5% MeOH/CH2Cl2 gradient to yield methyl 4-[(methylamino)carbonyl]bicyclo[2.2.2]octane-1-carboxylate 1-B as a white solid. MS (ESI+)=226.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[CH:11][CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:18]([O:20][C:21]([C:23]1[NH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([NH2:32])=[CH:27][CH:26]=2)=[O:22])[CH3:19]>>[CH2:18]([O:20][C:21]([C:23]1[NH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([NH:32][C:15]([C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:14]=1)=[O:17])=[CH:27][CH:26]=2)=[O:22])[CH3:19]
Reactant: O=C(O)c1cccc(-c2cc(Cl)cc(Cl)c2)n1
Reactant: CCOC(=O)c1cc2cc(N)ccc2[nH]1
Product: CCOC(=O)c1cc2cc(NC(=O)c3cccc(-c4cc(Cl)cc(Cl)c4)n3)ccc2[nH]1

Procedure:
Carboxylic acid (131) (50 mg, 0.19 mmol) was coupled to aniline (58) (42 mg, 0.21 mmol) using Method D to give the crude product.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])=[CH:17][CH:16]=2)=[C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:7]=1.[CH3:35][Sn](C)(C)C>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.C1(C)C=CC=CC=1>[CH3:35][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[O:26][C:27]=3[CH3:28])=[CH:19][CH:20]=2)=[C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:7]=1
Reactant: C[Sn](C)(C)C
Reactant: COC(=O)Cc1cc(Br)ccc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)Cc1cc(C)ccc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Yield: 32 %

Procedure:
Methyl 2-[5-bromo-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate (1.00 g), tetramethyltin (0.73 g), tetrakis(triphenylphosphine)palladium (0.11 g) and toluene (50 mL) were stirred with heating under reflux under an argon atmosphere for 40 hrs. The reaction mixture was concentrated and the residue was subjected to silica gel column chromatography to give crystals (0.28 g, 32%) of methyl 2-[5-methyl-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate from a fraction eluted with ethyl acetate-hexane (1:6, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 80-81° C.
Reaction SMILES: [CH2:1]([Si:6]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][CH2:10][CH:9]([CH:12]2[CH2:17][CH2:16][C:15](=O)[CH:14]=[CH:13]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[F:25][C:26]1[CH:31]=[CH:30][C:29]([Li])=[CH:28][CH:27]=1>>[CH2:1]([Si:6]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][CH2:10][CH:9]([C:12]2[CH2:17][CH2:16][C:15]([C:29]3[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: [Li]c1ccc(F)cc1
Reactant: CCCCC[Si]1(c2ccccc2)CCC(C2C=CC(=O)CC2)CC1
Product: CCCCC[Si]1(c2ccccc2)CCC(C2=CC=C(c3ccc(F)cc3)CC2)CC1
Yield: 74 %

Procedure:
In the same manner as in Example 1, 50.0 g of 4-(4-n-pentyl-4-phenyl-4-silacyclohexyl)-2-cyclohexenone was subjected to coupling reaction with 4-fluorophenyllithium, followed by dehydration reaction in the presence of an acid catalyst to obtain 45.5 g of 1-(4-n-pentyl-4-phenyl-4-silacyclohexyl)-4-(4-fluorophenyl)-1,3-cyclohexadiene (yield: 74%). The results of IR analysis of the compound are shown below.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[O:17][C:18]4[C:23]([C:24](=[O:26])[CH:25]=3)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=4[N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:36]1([N:42]=[C:43]=[O:44])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH:36]1([NH:42][C:43]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]4[O:17][C:18]5[C:23]([C:24](=[O:26])[CH:25]=4)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=5[N:29]4[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]4)=[O:15])=[CH:11][CH:12]=3)[CH2:2][CH2:3]2)=[O:44])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CCNCC4)cc3)cc(=O)c2c1
Reactant: O=C=NC1CCCCC1
Product: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CCN(C(=O)NC5CCCCC5)CC4)cc3)cc(=O)c2c1

Procedure:
This compound was prepared from 6-methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (Example 43) and commercially available cyclohexyl isocyanate (Aldrich) via the parallel synthesis described above. MS—base peak at m/z=603 by positive ion CI
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:16]([O:18][C:19]([C:21]1([CH2:36]I)[CH2:25][CH2:24][N:23]([C:26](=[O:35])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH2:22]1)=[O:20])[CH3:17]>>[CH2:16]([O:18][C:19]([C:21]1([CH2:36][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[N:9]=[CH:10][C:11]([C:14]#[N:15])=[CH:12][N:13]=3)=[CH:6][CH:7]=2)[CH2:25][CH2:24][N:23]([C:26](=[O:35])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH2:22]1)=[O:20])[CH3:17]
Reactant: N#Cc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccccc2OC)C1
Product: CCOC(=O)C1(COc2ccc(-c3ncc(C#N)cn3)cc2)CCN(C(=O)c2ccccc2OC)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 2-(4-hydroxy-phenyl)-pyrimidine-5-carbonitrile and 3-iodomethyl-1-(2-methoxy-benzoyl)-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 15) to afford the racemate as a white solid (53 mg, 30%)
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[N:4][CH:5]=[C:6]([NH2:8])[CH:7]=1.[Br:15]N1C(=O)CCC1=O>C(#N)C>[Br:15][C:5]1[C:6]([NH2:8])=[CH:7][C:2]([Cl:1])=[C:3]([O:9][CH2:10][C:11]([F:13])([F:14])[F:12])[N:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cnc(OCC(F)(F)F)c(Cl)c1
Solvent: CC#N
Product: Nc1cc(Cl)c(OCC(F)(F)F)nc1Br
Yield: 100.2 %

Procedure:
3-Chloro-5-amino-2-(2,2,2-trifluoroethoxy)-pyridine (3.05 g) obtained in Step B was brominated with N-bromosuccinimide (2.4 g) in acetonitrile (68 ml) as described in Example 14, Step C to give 2-bromo-5-chloro-6-trifluoroethoxy-pyridin-3-yl-amine (4.12 g) as a red oil. MS (ES+) 305/307/309 (MH+); 346/348/350 (MH++CH3CN); 1H NMR (400 MHz, CDCl3) 3.80 (br s, 2H), 4.65 (q, 2H), 7.10 (s, 1H).
Reaction SMILES: [OH2:1].[CH2:2]([CH:5]1[CH2:10][C:9](=[O:11])[O:8][C:6]1=[O:7])[CH:3]=[CH2:4]>>[CH2:2]([CH:5]([CH2:10][C:9]([OH:8])=[O:11])[C:6]([OH:1])=[O:7])[CH:3]=[CH2:4]
Reactant: C=CCC1CC(=O)OC1=O
Reactant: O
Product: C=CCC(CC(=O)O)C(=O)O
Temperature: 25 °C
Yield: 98.6 %

Procedure:
Water (321 g, 321 mL, 1.78 moles) was placed in a 1 L, 3-neck RBF and briefly vacuumed to remove oxygen. Then allyl succinic anhydride (50 g, 42.7 mL, 357 mmoles) was added and the reaction solution heated to 110 C overnight. The reaction solution was then cooled to room temperature and the volatiles removed from a sample to prepare for FTIR analysis. After confirming the anhydride had been converted to carboxylic acid, the volatiles were removed by vacuum transfer while stirring the reaction solution at 30 C. The reaction flask temperature was maintained with a temperature controller while being monitored using a thin wire thermocouple placed between the heating mantle and reaction flask. As the product began to solidify, the solids were broken up to facilitate drying. After the majority of the water had been removed, the flask was connected directly to the Schlenk line to achieve a pressure <20 mtorr overnight. The product is a white solid (55.6 g, 352 mmoles, 98.5% yield). 1H NMR (DMSO-d6, δ): 2.07 to 2.35 and 2.42 to 2.52 (m, 4H, CH2═CHCH2CH(CO2H)CH2CO2H), 2.66 to 2.74 (m, 1H, CH2CH(CO2H)CH2), 5.00 to 5.09 (m, 2H, CH2═CHCH2) 5.6 to 5.78 (m, 1H, CH2═CHCH2CH). IR (cm−1, diamond): 2300 to 3700 (broad CO2H), 3029 w (sp2 C—H), 2978w, 2921w (sp3 C—H), 1689 s (C═O).
Reaction SMILES: [OH-].[Na+].[C@@H:3]1([C:11]([O:13]CC)=[O:12])[CH2:5][C@H:4]1[C:6]([O:8][CH2:9][CH3:10])=[O:7]>CCO>[CH2:9]([O:8][C:6]([C@@H:4]1[CH2:5][C@H:3]1[C:11]([OH:13])=[O:12])=[O:7])[CH3:10]
Reactant: CCOC(=O)[C@@H]1C[C@H]1C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)[C@@H]1C[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
1N Sodium hydroxide (81 mL, 81.36 mmol) was added to a solution of diethyl trans-cyclopropane-1,2-dicarboxylate (15.15 g, 81.36 mmol) in EtOH (100 mL) at 0° C., and the mixture was stirred at 0° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, 2M hydrochloric acid and NaCl were added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5→100% ethyl acetate/hexane) to give trans-2-(ethoxycarbonyl)cyclopropanecarboxylic acid (11.20 g, 70.8 mmol, 87%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([OH:19])[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4].[CH3:29][S:30](Cl)(=[O:32])=[O:31].CCN(CC)CC>C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:18][C@H:17]([O:19][S:30]([CH3:29])(=[O:32])=[O:31])[C:16](=[O:20])[C@H:15]2[C@@:6]1([CH3:28])[CH2:7][CH2:8][C@@H:9]1[C@:14]2([CH3:21])[CH2:13][C@@H:12]([C:22]2[CH:26]=[CH:25][O:24][CH:23]=2)[O:11][C:10]1=[O:27])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H](O)C(=O)[C@@H]2[C@@]3(C)C[C@@H](c4ccoc4)OC(=O)[C@H]3CC[C@]21C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@H](c3ccoc3)C[C@]21C
Yield: 32 %

Procedure:
A solution of 8a (0.05 g, 0.13 mmol), methanesulfonyl chloride (1 mL) and NEt3 (2 mL) in CH2Cl2 (30 mL) was stirred at room temperature overnight and then the mixture was washed with saturated NaHCO3 (20 mL) and saturated NaCl (2×15 mL) and dried (Na2SO4). The solvent was removed under reduced pressure. The resulting crude solid was purified by column chromatography (eluent: ethyl acetate/n-hexanes) to afford 0.02 g (32%) of a white solid, mp 147-150° C.; 1H NMR (CDCl3): δ 1.14 (3H, s, H-19); 1.47 (3H, s, H-20); 1.50-1.70 (3H, m, H-7α,β and H-11β); 1.81 (1H, m, H-6α); 2.11 (1H, dd, J=2.9, 11.3 Hz, H-8); 2.16 (1H, s, H-10); 2.19 (1H, m, H-6β); 2.42 (1H, dd, J=13.2, 13.2 Hz, H-3α); 2.50 (1H, m, H-3β); 2.52 (1H, dd, J=4.8, 13.2 Hz, H-11α); 2.75 (1H, dd, J=3.6, 13.2 Hz, H-4); 3.25 (3H, s, CH3SO2); 3.74 (3H, s, CO2CH3); 5.07 (1H, dd, J=8.0, 12.2 Hz, H-2); 5.55 (1H, dd, J=5.1, 11.7 Hz, H-12); 6.41 (1H, dd, J=0.9, 1.8 Hz, H-14); 7.42 (1H, dd, J=1.8, 1.8 Hz, H-15); 7.45 (1H, br d).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][C:11]#[N:12])=[N:6][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.C(OCC)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1
Reactant: Cc1cc(N)cnc1CCCC#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(N)cnc1CCCCN
Yield: 88.4 %

Procedure:
5-Amino-2-(3-cyanopropyl)-3-methylpyridine (23.0 g) was reduced with lithium aluminium hydride (12.47 g) in a mixture of tetrahydrofuran (750 ml) and diethylether (750 ml) over 3 hours, to give 5-amino-2-(4-aminobutyl)-3-methylpyridine (20.8 g) as an amber oil. N.M.R. (CDCl3):- assignment, δ (p.p.m.) multiplicity; -- CH2CH2CH2NH2, 1.3 - 1.9, m; 3--CH3, 2.22, s; CH2 (CH 2)2CH2NH2, 2.6-2.8, m; 5-NH2, ca 3.5, broad resonance; 4-pyridyl proton, 6.77, d; 6-pyridyl proton, 7.88, d;
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][NH:6][C:7](=[O:30])[NH:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[C:18]([Cl:26])[CH:17]=2)[CH:12]=[CH:11][C:10]=1[N+:27]([O-:29])=[O:28])[CH3:2].[C:32](=[O:37])=[N:33][C:34](Cl)=[O:35]>C1(C)C=CC=CC=1>[Cl:26][C:18]1[CH:17]=[C:16]([O:15][C:13]2[CH:12]=[CH:11][C:10]([N+:27]([O-:29])=[O:28])=[C:9]([N:8]3[C:34](=[O:35])[NH:33][C:32](=[O:37])[N:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:31])[C:7]3=[O:30])[CH:14]=2)[CH:21]=[CH:20][C:19]=1[C:22]([F:23])([F:24])[F:25]
Reactant: CCOC(=O)CNC(=O)Nc1cc(Oc2ccc(C(F)(F)F)c(Cl)c2)ccc1[N+](=O)[O-]
Reactant: O=C=NC(=O)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)Cn1c(=O)[nH]c(=O)n(-c2cc(Oc3ccc(C(F)(F)F)c(Cl)c3)ccc2[N+](=O)[O-])c1=O
Temperature: 60 °C

Procedure:
A mixture of N-{{5-[(2-chloro-α,α,α-trifluoro-p-tolyl)oxy]-2-nitrophenyl}carbamoyl}glycine ethyl ester (75.0 g, 0.162 mol) and N-(chlorocarbonyl) isocyanate (35.0 g, 0.332 mol) in toluene is heated at 60° C. overnight, treated with additional N-(chlorocarbonyl) isocyanate (4.25 g), heated at 60° C. for 4 hours, cooled to room temperature and filtered to obtain a solid. The solid is washed with petroleum ether and dried to give the title product as a white solid which is identified by 1H and 13CNMR spectral analyses.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:3]=1[C:4]([C:6]1[C:11]([C:12]([O:14]C)=[O:13])=[CH:10][N:9]=[CH:8][C:7]=1[OH:16])=[O:5].[OH-].[Na+].Cl>O.CO>[F:1][C:2]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:3]=1[C:4]([C:6]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][N:9]=[CH:8][C:7]=1[OH:16])=[O:5]
Reactant: COC(=O)c1cncc(O)c1C(=O)c1cc(Cl)ccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cncc(O)c1C(=O)c1cc(Cl)ccc1F
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
Methyl 4-(2'-fluoro-5'-chlorobenzoyl)-5-hydroxynicotinate of Preparative Example 25 (1.2 g) is added to a solution of sodium hydroxide (0.67 g) in water (4 mL) and methanol (12 mL). A yellow solution is obtained after 5 min. The mixture is stirred at room temperature for 1.25 h. The resulting solution is acidified with 1N hydrochloric acid (14 mL) to pH=2 and the mixture is allowed to stand overnight. The white solid is collected by filtration and washed with water (3×5 mL) and dried to yield 4-(2'-fluoro-5'-chlorobenzoyl)-5-hydroxynicotinic acid (1.04 g).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[S:16][CH3:17])[NH:5][C:4]=2[CH:3]=1.S(OC)(O[CH3:22])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[CH3:22][O:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[S:16][CH3:17])[NH:5][C:4]=2[CH:3]=1
Reactant: CSc1cccc2c1Sc1ccc(O)cc1N2
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc2c(c1)Nc1cccc(SC)c1S2
Yield: 50.5 %

Procedure:
2-Methoxy-6-methylthiophenothiazine (m.p. 152°-154°C.; 20.1 g.) is prepared by methylation of 2-hydroxy-6-methylthiophenothiazine (37.8 g.) by means of dimethyl sulphate (22.2 g.) in the presence of sodium carbonate (30.1 g.) in acetone.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[CH:4][CH:3]=1.Br[C:11]([F:18])([F:17])[C:12]([N:14]([CH3:16])[CH3:15])=[O:13].C([O-])([O-])=O.[K+].[K+].O>CC(N(C)C)=O>[F:17][C:11]([F:18])([O:9][C:5]1[CH:6]=[C:7]([F:8])[C:2]([Br:1])=[CH:3][CH:4]=1)[C:12]([N:14]([CH3:16])[CH3:15])=[O:13]
Reactant: CN(C)C(=O)C(F)(F)Br
Reactant: Oc1ccc(Br)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN(C)C(=O)C(F)(F)Oc1ccc(Br)c(F)c1
Temperature: 100 °C
Yield: 85 %

Procedure:
A mixture of 4-bromo-5-fluoro-phenol (4.0 g, 20.7 mmol), 2-bromo-2,2-difluoro-N,N-dimethyl-acetamide (4.4 g, 21.6 mmol) and K2CO3 (3.2 g, 23.2 mmol) in 20 mL of DMAC was heated to 100° C. for 120 min. The mixture was then poured on 50 mL of H2O and extracted with TBME (2×50 mL). The combined organic layers were washed with 10% NaOH (50 mL), water and brine and dried over MgSO4. The product (5.7 g, >96% purity by NMR, 17.6 mmol, 85% yield) was obtained as a yellow oil that solidified upon standing.