Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[NH2:1][C:2]1[N:7]=[C:6]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[F:13])[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1
Reactant: OB(O)c1ccccc1F
Reactant: CSc1nc(N)nc(Cl)c1C#N
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CSc1nc(N)nc(-c2ccccc2F)c1C#N

Procedure:
From 2-amino-4-chloro-6-methylsulfanyl-pyrimidine-5-carbonitrile, o-fluorobenzeneboronic acid, tetrakis(triphenylphosphine)palladium(O) and potassium carbonate in toluene. ES-MS m/e (%): 261 (M+H+, 100).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:9]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:39]=[CH:38][C:21]([O:22][C:23]3[N:27]([CH2:28][C:29](OCC)=[O:30])[C:26]4[CH:34]=[CH:35][CH:36]=[CH:37][C:25]=4[N:24]=3)=[CH:20][CH:19]=2)[C:10]1=[O:40])[CH3:8].[Cl-].[Cl-].[Ca+2]>C1COCC1>[CH2:7]([N:9]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:19]=[CH:20][C:21]([O:22][C:23]3[N:27]([CH2:28][CH2:29][OH:30])[C:26]4[CH:34]=[CH:35][CH:36]=[CH:37][C:25]=4[N:24]=3)=[CH:38][CH:39]=2)[C:10]1=[O:40])[CH3:8]
Reactant: CCOC(=O)Cn1c(Oc2ccc(-n3c(=O)n(CC)c4cccnc43)cc2)nc2ccccc21
Agent: [Al+3]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCn1c(=O)n(-c2ccc(Oc3nc4ccccc4n3CCO)cc2)c2ncccc21
Yield: 55.1 %

Procedure:
Lithium aluminum hydride (33.2 mg) was added to a solution of ethyl {2-[4-(1-ethyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)phenoxy]-1H-benzimidazol-1-yl}acetate (200 mg) in THF (4 mL) at 0° C. The mixture was stirred at room temperature under a dry atmosphere (CaCl2 tube) for 30 min. The mixture was quenched with EtOAc and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10%-50% EtOAc in hexane) to give 1-ethyl-3-(4-{[1-(2-hydroxyethyl)-1H-benzimidazol-2-yl]oxy}phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (100 mg) as colorless crystals.
Reaction SMILES: [OH-].[Na+].O.[CH2:4]1[C@@H:9]2[C:10]3[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=3[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:8]2[CH2:7][CH2:6][N:5]1[CH2:23][CH2:24][O:25][CH2:26][C:27]([O:29]CC)=[O:28].Cl>C(O)C>[CH2:4]1[C@@H:9]2[C:10]3[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=3[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:8]2[CH2:7][CH2:6][N:5]1[CH2:23][CH2:24][O:25][CH2:26][C:27]([OH:29])=[O:28]
Reactant: CCOC(=O)COCCN1CCN2c3ccccc3Cc3ccccc3[C@H]2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)COCCN1CCN2c3ccccc3Cc3ccccc3[C@H]2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
65 ml of a 10% w/v aqueous solution of sodium hydroxide and 200 ml of water were added to a solution of 44.85 g of ethyl (S)-2-(1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepin-2-yl)ethoxyacetate (prepared as described in Example 58) in 450 ml of ethanol, and the mixture was stirred at room temperature for 2 hours. At the end of this time, it was adjusted to a pH value of 4 by the addition of concentrated hydrochloric acid and concentrated by evaporation under reduced pressure. The crystals which precipitated were collected by filtration and recrystallized from water to give 39.20 g (yield 90%) of the title compound as the monohydrate, melting at 105°-108° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH:7]=O)=[CH:5][N:6]=1.N1C=CC=CC=1.C(O)(=O)[CH2:16][C:17]([OH:19])=[O:18].S(=O)(=O)(O)O>N1C=CC=CC=1.O>[CH3:1][C:2]1[S:3][C:4]([CH:7]=[CH:16][C:17]([OH:19])=[O:18])=[CH:5][N:6]=1
Reactant: O=C(O)CC(=O)O
Reactant: Cc1ncc(C=O)s1
Agent: O=S(=O)(O)O
Solvent: c1ccncc1
Solvent: O
Product: Cc1ncc(C=CC(=O)O)s1
Temperature: 25 °C
Yield: 72 %

Procedure:
A mixture of 29 g of 2-methyl-5-thiazolecarboxaldehyde, 30 ml of pyridine, 29 g of malonic acid and 30 drops of pyridine was heated at 100°-110° C. for 5 hours and after cooling to room temperature, the mixture was poured into 500 ml of water. The pH of the solution was adjusted to 3 by addition of N sulfuric acid and the precipitate formed was recovered by vacuum filtration and was dried to obtain 27.8 g of 3-(2-methyl-5-thiazolyl)-2-propenoic acid which were crystallized from 10% aqueous ethanol to obtain 23.8 g of the said product melting at 204° C.
Reaction SMILES: Cl.[CH2:2]([C:6]1[N:11]=[C:10]([C:12]([NH2:14])=[NH:13])[CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].[O-]CC.[Na+].[Na].CO[CH:22](OC)[CH2:23][C:24](=O)[CH3:25]>C(O)C.CC(C)=O.CCCCCC.C(O)(=O)C>[CH2:2]([C:6]1[N:11]=[C:10]([C:12]2[N:14]=[C:24]([CH3:25])[CH:23]=[CH:22][N:13]=2)[CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5]
Reactant: COC(CC(C)=O)OC
Reactant: CCCCc1cccc(C(=N)N)n1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: CCO
Product: CCCCc1cccc(-c2nccc(C)n2)n1
Yield: 68 %

Procedure:
To 6-n-butyl-2-picoline amidine hydrochloride (3 g) were added sodium ethoxide solution in ethanol prepared from ethanol (100 ml) and metallic sodium (0.65 g) and then 1,1-dimethoxy-3-butanone (purity 90 %, 2.16 g). The mixture was heated under refluxing for three hours, and was left to stand at room temperature. After acetic acid was added into the mixture to be weak acidic condition, the mixture was concentrated under reduced pressure. The residue was dissolved in chloroform (200 ml), followed by washing with water (50 ml) and drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue obtained was subjected to silica gel column chromatography (eluent; hexane:acetone=2:1) to obtain 2-(6-n-butyl-2-pyridinyl)-4-methylpyrimidine (2.17 g, yield: 68 %).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N+:13]([O-])([OH:15])=[O:14].Cl>S(=O)(=O)(O)O>[N+:13]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][C@@H:2]([C:10]([OH:12])=[O:11])[NH2:1])=[CH:5][CH:6]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Agent: O=S(=O)(O)O
Product: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Yield: 43 %

Procedure:
Using the procedure of Bergel and Stock as set forth in J. Chem. Soc., 2409-2417 (1954) L-phenylalanine (50 g) was treated with a mixture of concentrated sulfuric acid (150 ml), and fuming nitric acid (28 ml) to produce the nitro compound Yield 26.9 g (43%) mp 232°-234° C., [α]D25 =+9.6° (c=1.77, 1N HCl).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([C:10]([OH:12])=O)[CH2:7][C:6]=2[CH:13]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[N:43]1([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([C:10]([N:46]3[CH2:45][CH2:44][N:43]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:48][CH2:47]3)=[O:12])[CH2:7][C:6]=2[CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)C1Cc2cc(Cl)ccc2O1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C2Cc3cc(Cl)ccc3O2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
To a solution of 5-chloro-2,3-dihydro-1-benzofuran-2-carboxylic acid (1 g, 5 mmol) in N,N-dimethylformamide (10 ml) was added EDAC.HCl (1.45 g, 7.56 mmol, 1.5 eq), HOBt (1.02 g, 7.55 mmol, 1.5 eq), triethylamine (1.52 g, 15.0 mmol, 3 eq) and tert-butyl piperazine-1-carboxylate (935 mg, 5.02 mmol, 1 eq). The resulting solution was stirred overnight at room temperature, quenched with water (200 ml), and then extracted with ethyl acetate (3×200 ml). The combined organic layer was washed with brine (3×100 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude material was purified by silica gel chromatography using 10%-20% ethyl acetate in petroleum ether to elute. The product-containing fractions were combined and concentrated under vacuum to afford tert-butyl 4-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)carbonyl]piperazine-1-carboxylate as a off-white solid (1.2 g, 65%). (ES, m/z): [M+H]+ 367; 1H NMR (300 MHz, CDCl3): δ 7.05-7.22 (m, 2H), 6.72 (d, J=8.4 Hz, 1H), 5.38-5.45 (m, 1H), 3.75-3.90 (m, 3H), 3.25-3.70 (m, 7H), 1.50 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[CH:9][N:10]=[C:4]2[CH:3]=1.C([O-])(=O)C.[Na+].[Br:16]Br.C(=O)([O-])O.[Na+]>CO>[Br:16][C:8]1[N:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]2=[N:10][CH:9]=1
Reactant: Cc1ccn2ccnc2c1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1ccn2c(Br)cnc2c1
Reaction time: 0.33 h
Yield: 98.3 %

Procedure:
A cooled (−10° C.) suspension of 7-methylimidazo[1,2-α]pyridine (26 g, 0.2 mol) and sodium acetate (24.3 g, 0.3 mol) in methanol (150 ml) was treated with bromine (ca. 10 ml, 0.2 mol) added dropwise until the first permanent colour change occurred. Stirring was continued for a further 20 minutes before the reaction was poured into saturated aqueous sodium hydrogencarbonate (2 l). The resulting solid was filtered, washed with water and dried. Trituration with 5% ether in isohexane furnished 3-bromo-7-methylimidazo[1,2-α]pyridine as a red-brown powder (41.5 g, 100%). 1H NMR (360 MHz, CDCl3) δH 2.43 (3H, s), 6.76 (1H, d, J 7), 7.37 (1H, s), 7.53 (1H, s), 7.55 (1H, s), 8.00 (1H, d, J 7); m/z (ES+) 210/212 (M++H).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH2:2][CH3:3].[OH-].[Na+].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17]Br>C(Cl)Cl.O.S(=O)(=O)(O)[O-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:1][CH2:2][CH3:3]
Reactant: BrCCCCBr
Reactant: CCCc1ccccc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCCc1ccccc1OCCCCBr
Yield: 101 %

Procedure:
The title compound was prepared according to the procedure of Example 7 using 2-n-propylphenol (10 g, 0.073 mol) in methylene chloride (100 ml), sodium hydroxide (6.0 g, 0.146 mol) in water (100 ml), 1,4-dibromobutane (55 g, 0.255 mol) and tetra-n-butylammonium bisulfate (26 g, 0.073 mol). The crude product was distilled (b.p. 110°-112°/0.25 mm Hg) to give 20 g (80%) of the title compound.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].CS(C)=O.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]O.C(N(CC)CC)C>C(Cl)Cl>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]1[O:5][CH2:1][CH2:2][O:3]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: OCCCCCCCCCBr
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: BrCCCCCCCCC1OCCO1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a cooled (−78° C.) solution of oxalyl chloride (11.66 g, 92 mmol) in DCM (250 mL), a solution of dimethylsulfoxide (DMSO) (13.0 mL, 183 mmol) in DCM (50 mL) was added over 15 minutes. After a further 5 minutes, a solution of 9-bromononanol (10.25 g, 45.9 mmol) in DCM (50 mL) was added dropwise over 15 minutes. The resulting reaction mixture was stirred at this temperature for 45 minutes. Triethylamine (32 mL, 230 mmol) was added, and the reaction mixture stirred at this temperature for 10 minutes. The coolant was removed and allowed to warm to RT. The reaction mixture was stirred at RT for 40 minutes and then diluted with water. The organic phase was removed and washed with 10% aqueous potassium hydrogen sulfate and dried (magnesium sulfate). The suspension was filtered and the filtrate evaporated under reduced pressure to afford the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16]C2C=CC=CC=2)[CH:12]=[C:11]([O:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[C:10]=1[C:33]1[O:37][N:36]=[C:35]([C:38](OCC)=[O:39])[CH:34]=1)C1C=CC=CC=1>C(N)C.C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:12]=[C:11]([O:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[C:10]=1[C:33]1[O:37][N:36]=[C:35]([C:38]([NH:36][CH2:35][CH3:34])=[O:39])[CH:34]=1)[C:14]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1cc(-c2c(OCc3ccccc3)cc(OCc3ccccc3)cc2Oc2ccc([N+](=O)[O-])cc2)on1
Agent: CCN
Solvent: C1CCOC1
Product: CCNC(=O)c1cc(-c2c(OCc3ccccc3)cc(OCc3ccccc3)cc2Oc2ccc([N+](=O)[O-])cc2)on1
Yield: 160.2 %

Procedure:
A solution of ethyl 5-[2,4-bis(benzyloxy)-6-(4-nitrophenoxy)phenyl]isoxazole-3-carboxylate (1.8 g, 3.2 mmol) in 2 M ethylamine/THF solution (100 mL) in a stopped flask was heated at 100° C. for 5 hours. The solvent was removed and the residue was crystallized from a small volume of methanol to provide the title compound (1.45 g, 83% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[CH2:6][CH:7]3[CH:11]([CH:12]([C:13]4[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=4)[C:4]=2[CH:3]=1)[CH2:10][NH:9][CH2:8]3.[CH2:22]=O>C(O)=O>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[CH2:6][CH:7]3[CH:11]([CH:12]([C:13]4[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=4)[C:4]=2[CH:3]=1)[CH2:10][N:9]([CH3:22])[CH2:8]3
Reactant: Clc1ccc(C2c3cc(Cl)ccc3CC3CNCC32)cc1
Reactant: C=O
Solvent: O=CO
Product: CN1CC2Cc3ccc(Cl)cc3C(c3ccc(Cl)cc3)C2C1

Procedure:
A mixture of 1.5 g of (3aRS,4SR,9aSR)-6-chloro-4-(p-chlorophenyl)-3a,4,9,9a-tetrahydro-benz[f]isoindoline, 10 cc of 100% formic acid and 10 cc of a 40% aqueous formaldehyde solution is heated to the boil at reflux for 2 hours in an atmosphere of nitrogen. The mixture is concentrated by evaporation, the residue is taken up in water, the solution is made alkaline with concentrated caustic soda solution and is extracted with methylene chloride. Ether is added to the dried extracts until they are turbid, filtration through Hyflo and concentration by evaporation are effected, whereby the title compound is obtained as residue. M.P. 133°-135° (after crystallization from ether).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[C:19]2[O:21][CH2:22][O:23][C:18]2=[CH:17][C:4]=1[CH:5]=[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[BH4-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:20]=[C:19]2[O:21][CH2:22][O:23][C:18]2=[CH:17][C:4]=1[CH2:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(=Cc1cc2c(cc1OC)OCO2)C(=O)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(Cc1cc2c(cc1OC)OCO2)C(=O)OCC
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.7 %

Procedure:
To a solution of the diethyl 2-(2-methoxy-4,5-methylenedioxybenylidene)-malonate (23.4 g, 0.073 mol) in ethanol (100 ml) was added sodium borohydride (2.8 g, 0.073 mol) and the mixture was stirred at rt for 5 h. The reaction was quenched with water and extracted with ethyl acetate (3×200 mL). The combined organic extracts were dried (Na2SO4) and evaporated to afford the title compound as an oil (20.3 g, 86%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][C@@H:11]([OH:13])[CH2:10][N:9]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[CH:6][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH-].[Na+]>C(Cl)Cl.[Cl-].[Na+].O>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][C:11](=[O:13])[CH2:10][N:9]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1c1cccc(F)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(=O)C[C@@H]1c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.1 %

Procedure:
(2R,4R)-tert-Butyl 2-(3-fluorophenyl)-4-hydroxypyrrolidine-1-carboxylate (1.4 g, 4.98 mmol) and Dess-Martin periodinane (2.53 g, 5.97 mmol) were mixed in 50 mL DCM and stirred at ambient temperature overnight. For workup, 20 mL 1N NaOH was added to reaction, and stirred for 30 minutes, followed by addition of 20 mL brine. The reaction mixture was extracted with several portions of DCM. The combined organic extracts were filtered through a Phase Separator filter paper, concentrated, and purified by reverse phase chromatography, eluting with 20-70% acetonitrile/water to yield the product as yellow oil (600 mg, 43% yield.)
Reaction SMILES: [K].[Cl:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[OH:11].[Br:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>>[Cl:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[O:11][CH2:16][CH2:15][CH2:14][CH2:13][Br:12]
Reactant: BrCCCCBr
Reactant: COc1ccc(O)c(Cl)c1
Agent: [K]
Product: COc1ccc(OCCCCBr)c(Cl)c1

Procedure:
The intermediate 4-(2-chloro-4-methoxyphenoxy)butyl bromide was prepared from the potassium salt of 2-chloro-4-methoxyphenol and 1,4-dibromobutane.
Reaction SMILES: [C:1]([C@H:5]1[C@@H:11]([C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][CH:13]=2)[CH2:10][C@H:9]2[N:19]([CH3:20])[C@@H:6]1[CH2:7][CH2:8]2)([O:3]C)=[O:2]>O.O1CCOCC1>[C:1]([C@H:5]1[C@@H:11]([C:12]2[CH:13]=[CH:14][C:15]([I:18])=[CH:16][CH:17]=2)[CH2:10][C@H:9]2[N:19]([CH3:20])[C@@H:6]1[CH2:7][CH2:8]2)([OH:3])=[O:2]
Reactant: COC(=O)[C@H]1[C@@H](c2ccc(I)cc2)C[C@@H]2CC[C@H]1N2C
Solvent: C1COCCO1
Solvent: O
Product: CN1[C@H]2CC[C@@H]1[C@@H](C(=O)O)[C@@H](c1ccc(I)cc1)C2

Procedure:
A round bottom flask filled with a solution of 100 mg of 2β-Carbomethoxy-3β-(4-Iodophenyl)tropane in 10 mL of 1:1 water/dioxane was heated to a gentle reflux for two days. The solvent was then removed and the white residue was triturated with hot ethyl acetate twice. The remaining solid was dried under in vacuo to yield 90 mg of CIT-acid 7, (93%) as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[N:9]([CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][CH:19]([NH:22][CH2:23][C:24]4[CH:25]=[CH:26][C:27]5[O:28][CH2:29][C:30](=[O:34])[NH:31][C:32]=5[N:33]=4)[CH2:18][CH2:17]3)[C:8]=2[CH:35]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO>[OH:3][CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[N:9]([CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][CH:19]([NH:22][CH2:23][C:24]4[CH:25]=[CH:26][C:27]5[O:28][CH2:29][C:30](=[O:34])[NH:31][C:32]=5[N:33]=4)[CH2:18][CH2:17]3)[C:8]=2[CH:35]=1)[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)N(CCN1CCC(NCc3ccc4c(n3)NC(=O)CO4)CC1)C(=O)CO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1ccc2c(c1)N(CCN1CCC(NCc3ccc4c(n3)NC(=O)CO4)CC1)C(=O)CO2

Procedure:
6-[({1-[2-(6-Acetyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (Example 45) (309 mg, 0.645 mmol) was reduced with sodium borohydride (47 mg, 2 equivalents) in methanol (12 mL) at 0° C. After quenching the reaction with water, the reaction mixture was concentrated under reduced pressure and extracted with chloroform. The chloroform layer was washed with brine and dried over magnesium sulfate and concentrated to dryness to give the as an off-white solid, 202 mg (95%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[N:12]=[C:11]([CH3:13])[C:10]([C:14]([OH:16])=O)=[CH:9][N:8]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([NH2:28])[CH:23]=[CH:22]2.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CN(C=O)C>[O:18]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([NH:28][C:14]([C:10]1[C:11]([CH3:13])=[N:12][C:7]([C:2]3[N:1]=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:8][CH:9]=1)=[O:16])[CH:23]=[CH:22]2)[CH3:17]
Reactant: COc1ccc2c(ccn2N)c1
Reactant: Cc1nc(-c2ncccn2)ncc1C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: COc1ccc2c(ccn2NC(=O)c2cnc(-c3ncccn3)nc2C)c1
Temperature: 50 °C
Yield: 116.1 %

Procedure:
A solution of 2-pyrimidin-2-yl-4-methyl-pyrimidine-5-carboxylic acid (496 mg, 2.30 mmol) and 5-methoxy-indol-1-ylamine (0.98 mmol) in anhydrous DMF (10 mL) is stirred at 50° C. for 30 min. DMTMM (555 mg, 2.01 mmol) is added and stirred at 50° C. for an hour. DMF is evaporated off. The residue is mixed with water (40 mL) and stirred at rt for 20 minutes. The solid is collected by filtration, washed with water (3×5 mL) and dried in vacuum to afford 2-pyrimidin-2-yl-4-methyl-pyrimidine-5-carboxylic acid (5-methoxyl-indol-1-yl)-amide (410 mg) as a solid. MS: 361 (M+H); 1H NMR (300 MHz, CD3OD): δ 2.93(s, 3H), 4.84(s, 3H), 7.04(t, H), 6.50(d, H), 6.92(d, H), 7.14(s, H), 7.26-7.37(m, 2H), 7.72 (t, H), 9.09 (d, 2H), 9.27(s, H).
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:23])[CH:17]([NH2:22])[CH2:18][CH:19]([CH3:21])[CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[F:24][C:25]1[CH:26]=[C:27]([CH2:32][C:33](O)=[O:34])[CH:28]=[C:29]([F:31])[CH:30]=1>>[CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:23])[CH:17]([NH:22][C:33](=[O:34])[CH2:32][C:27]2[CH:26]=[C:25]([F:24])[CH:30]=[C:29]([F:31])[CH:28]=2)[CH2:18][CH:19]([CH3:20])[CH3:21])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CC(C)CC(N)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: CC(C)CC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1

Procedure:
2-Amino-4-methyl-pentanoic acid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide was coupled with (3,5-Difluoro-phenyl)-acetic acid to provide the title compound: C13 NMR (100 MHz, CDCl3) 22.5, 22.9, 24.2, 25.0, 26.6, 26.7, 42.9, 43.1, 51.9, 56.0, 59.3, 67.3, 102.9, 105.5, 112.3, 112.6, 131.9, 137.4, 169.1, 169.4; MS m/z 476.3 (M+1).
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].C(Br)[C:13]1[CH:18]=[CH:17][CH:16]=CC=1>O1CCCC1>[CH2:8]([C:1]([CH2:13][CH2:18][CH2:17][CH3:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]#[N:9])[CH2:1][CH2:2][CH3:3]
Reactant: N#CCc1ccccc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCC(C#N)(CCCC)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a flame dried 500 ml three neck round bottomed flask, equipped with a dry argon inlet, magnetic stir bar, and thermometer, is added benzyl cyanide ((1), 5.0 gm.; 0.043 mol) and tetrahydrofuran (100 ml). To the reaction is slowly added sodium hydride (60% in oil) (7.2 gm, 0.1075 mol) over one hour. Once addition is complete the reaction is stirred at room temperature for 1 hour. To the reaction is added benzyl bromide (18.4 gm; 0.043 mol) and the reaction is stirred at 50° C. for 18 hours. The reaction is evaporated to dryness, residue dissolved in toluene and washed with 1N HCl. Organic phase is dried with Na2SO4, filtered and evaporated to yield α,α-dibutyl-benzeneacetonitrile (2), wt=7.7 gm (65%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[CH:4]=[O:5].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:3]=1[CH:4]=[O:5]
Reactant: CCCCCCCCCBr
Reactant: O=Cc1c(O)cccc1Cl
Product: CCCCCCCCCOc1cccc(Cl)c1C=O

Procedure:
2-chloro-6-hydroxy-benzaldehyde was alkylated with 1-bromononane as in Example 1 to give 2-chloro-6-nonyloxy benzaldehyde. Reduction with sodium borohydroxide as in Example 1 gave 2-chloro-6-nonyloxy benzyl alcohol which on treatment with triphenylphosphine hydrobromide in acetonitrile as in Example 1 yielded [[2-chloro-6-nonyl-oxy]phenyl]methyl]triphenyl phosphonium bromide. Condensation with 7-formyl-3-methyl-2,4,6-octatrienoic acid ethyl ester as described in Example 3 produced (All E)-9-[2-chloro-6-(nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoic acid ethyl ester. The ester was subjected to hydrolysis, as in Example 5, the produce (All-E)-9-[2-chloro-6-(nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoic acid mp 129-131° (from ethyl acetate/hexane mixture).