Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].Br[C:6]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10]([CH:18]([CH3:21])[C:19]#[N:20])=[CH:11]2.Cl>C(Cl)Cl.C1(C)C=C(C)C=C(C)C=1>[CH3:17][O:16][C:15]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([CH:18]([CH3:21])[C:19]#[N:20])[CH:9]=[CH:8]2
Reactant: COc1ccc2cc(C(C)C#N)ccc2c1Br
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1cc(C)cc(C)c1
Solvent: ClCCl
Product: COc1ccc2cc(C(C)C#N)ccc2c1
Temperature: 0 °C
Yield: 71 %

Procedure:
10 Grams of anhydrous aluminum chloride are added portionwise and under stirring to a solution containing 14.5 g of 2-(5-bromo-6-methoxy-2-naphthyl)propionitrile dissolved in 60 ml of methylene chloride and 8.3 ml of mesitylene, while keeping the temperature at about 20° C. The reaction mixture is kept at this temperature under stirring for 1 hour and then is slowly poured into a mixture made of 60 g of crushed ice and of 20 ml of a 6N aqueous solution of hydrochloric acid. The layers are separated after 15 minutes of stirring and the aqueous layer is discarded. The organic layer is twice washed with 25 ml of a 6N aqueous solution of hydrochloric acid, then with 25 ml of water and is dried over anhydrous sodium sulfate. The organic solution is evaporated to dryness under vacuum and the residue is crystallized from tetrachloroethylene obtaining 7.5 g of product with a yield of 71%.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:28])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[O:24][CH2:25][CH:26]=[CH2:27])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH2:25]([O:24][C:18]1[C:19]([Cl:23])=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:28])[CH:26]=[CH2:27]
Reactant: C=CCOc1c(Cl)cccc1C(=O)NC1(C(=O)OCC)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCOc1c(Cl)cccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
The mixture of 2-(2-allyloxy-3-chloro-benzoylamino)-indan-2-carboxylic acid ethyl ester (17) (140 mg, 0.35 mmol) and KOH (500 mg, 8.9 mmol) is dissolved in EtOH (5 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until pH˜3. After filtration, the solid is purified by HPLC to give a pure product (18) as white solid (88 mg, 68%).
Reaction SMILES: [N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1/[CH:11]=[N:12]/[C:13]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]#[N:16])=[N+]=[N-]>C1(C)C=CC=CC=1>[Cl:21][C:20]1[C:13]([N:12]2[CH:11]=[C:5]3[CH:6]=[N:7][CH:8]=[C:9]([F:10])[C:4]3=[N:1]2)=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16]
Reactant: N#Cc1cccc(Cl)c1/N=C/c1cncc(F)c1N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: N#Cc1cccc(Cl)c1-n1cc2cncc(F)c2n1
Yield: 54.8 %

Procedure:
A solution of 2-{[1-(4-azido-5-fluoropyridin-3-yl)-meth-(E)-ylidene]-amino}-3-chlorobenzonitrile (5.16 g, 17.2 mmol) in toluene (60 mL) was heated at 105° C. for 5 hours. The resultant mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-5% methanol in DCM) to afford the title compound as a beige solid (2.57 g, 55% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.42 (d, J=2.6 Hz, 1H), 9.26 (d, J=2.5 Hz, 1H), 8.33 (d, J=3.8 Hz, 1H), 8.24-8.19 (m, 2H), 7.92 (t, J=8.1 Hz, 1H).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:29])[C:4]1([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:9][CH2:8][C:7]([C:10]2[NH:11][C:12]3[C:17]([C:18]=2[CH:19]2[CH2:21][CH2:20]2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:6][CH2:5]1>CO.[Pd]>[CH2:22]([C:4]1([N:3]([CH3:2])[CH3:29])[CH2:5][CH2:6][CH:7]([C:10]2[NH:11][C:12]3[C:17]([C:18]=2[CH:19]2[CH2:21][CH2:20]2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:8][CH2:9]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CN(C)C1(Cc2ccccc2)CC=C(c2[nH]c3ccccc3c2C2CC2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN(C)C1(Cc2ccccc2)CCC(c2[nH]c3ccccc3c2C2CC2)CC1
Reaction time: 5 h
Yield: 50 %

Procedure:
The free base from Example 33 (210 mg, 0.567 mmol) was dissolved in methanol (35 ml), and palladium on charcoal (5 per cent strength; 90 mg) was added. The reaction mixture was hydrogenated under 3 bar for 5 h. The catalyst was separated off over Celite and the filtrate was concentrated. The solid residue (185 mg) was separated by chromatography [silica gel 60 (40 g); ethyl acetate/methanol 10:1 (250 ml), ethyl acetate/methanol 4:1 (250 ml)]. 1-Benzyl-4-(3-cyclopropyl-1H-indol-2-yl)-N,N-dimethylcyclohexanamin (more polar diastereoisomer) was obtained in a yield of 50% (105 mg) with a melting point of 65-70° C. The less polar diastereoisomer was isolated in a yield of 26% (54 mg) together with by-products. This fraction was purified again by chromatography [silica gel 60 (20 g); trichloromethane/methanol 40:1 (250 ml)]. The less polar diastereoisomer was obtained by this procedure in a yield of 43 mg (20%) with traces of an impurity and was employed in this form for the citrate preparation.
Reaction SMILES: C([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:17])[CH:14]=2)[CH2:9]1)C1C=CC=CC=1.[H][H].CC(C)=O.[ClH:24]>C(O)C.[OH-].[OH-].[Pd+2]>[ClH:24].[F:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:16]2
Reactant: [H][H]
Reactant: Fc1ccc2c(c1)CN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCO
Product: Fc1ccc2c(c1)CNC2
Temperature: 25 °C

Procedure:
A suspension of 20% palladium hydroxide on carbon (4.0 g) and N-benzyl-5-fluoroisoindoline (D7) (44.6 g) in ethanol (475 ml) and conc. hydrochloric acid (d=1.18, 25 ml) was stirred with hydrogen at 50 psi for 18 h at 45° C. The mixture was cooled to ambient temperature and filtered to remove the catalyst. The filtrate was evaporated in vacuo to give a solid which was stirred with acetone (300 ml) for 0.5 h and filtered to give the title compound (D8) as a solid (29.3 g). 1H NMR δ (D6-DMSO): 10.0 (2H, br, s), 7.41-7.46 (1H, m), 7.15-7.29 (2H, m), 4.49 (2H, s), 4.46 (2H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][C:10]=1[O:24][CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1.O>[CH2:1]([O:8][C:9]1[C:19]([C:20]([F:21])([F:22])[F:23])=[CH:18][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[O:24][CH3:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(OC)c(OCc2ccccc2)c(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(=O)O)cc(C(F)(F)F)c1OCc1ccccc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 93.5 %

Procedure:
Ethyl 4-benzyloxy-3-methoxy-5-trifluoromethylbenzoate (704 mg) was dissolved in tetrahydrofuran (6 mL) and water (2 mL), and lithium hydroxide monohydrate (333 mg) was added to the solution, and then the mixture was stirred at 60° C. for 3 hours. After the organic solvent was distilled off, the mixture was acidified with 1N hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (606 mg) as a colorless crystal.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][C:24]([NH2:26])=[O:25])[CH:21]=2)[NH:16][CH:15]=1.O.NN.CO.[ClH:32]>C(O)C.C(OCC)(=O)C>[ClH:32].[NH2:3][CH2:12][CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][C:24]([NH2:26])=[O:25])[CH:21]=2)[NH:16][CH:15]=1
Reactant: NC(=O)Cc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Agent: Cl
Agent: NN
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: NCCc1c[nH]c2ccc(CC(N)=O)cc12

Procedure:
A solution of 3-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-1H-indole-5-acetamide (8.0 g) in ethanol (500 ml) containing hydrazine hydrate (5.76 g), was heated under reflux for 2 h. The solvent was removed by evaporation, the residue was suspended in ethyl acetate (500 ml) and washed with saturated potassium carbonate solution (300 ml). The organic phase was separated and the aqueous phase again extracted with ethyl acetate (200 ml). Evaporation of the dried (Na2SO4) combined organic extracts gave an off-white solid. This was dissolved in ethyl acetate (90 ml) containing methanol (10 ml) and ethereal hydrogen chloride was added until no more solid deposited. Crystallisation from ethyl acetate-methanol gave the title compound as off-white granules (3.2 g) m.p. 225°-7° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[C:10]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1)([OH:12])=[O:11]>>[C:10]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[N:5][C:4]2[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=2)=[CH:15][CH:14]=1)([OH:12])=[O:11]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: O=Cc1ccc(C(=O)O)cc1
Product: O=C(O)c1ccc(C=Nc2ccc(Cl)c(Cl)c2)cc1

Procedure:
Equimolar amounts of 3,4-dichloroaniline and p-carboxybenzaldehyde are stirred together at room temperature to give a nearly quantitative yield of N-(p-carboxybenzylidene)-3,4-dichloroaniline that is recrystallized from ethanol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10](=[O:18])[C@@H:9]2[CH2:19][CH2:20][C@H:21]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[C:4]([OH:37])[CH:3]=1.[C:38](OC(=O)C)(=[O:40])[CH3:39]>ClCCl.CN(C)C1C=CN=CC=1>[C:38]([O:37][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[C@@H:8]1[C@@H:9]([CH2:19][CH2:20][C@H:21]([O:29][Si:30]([C:33]([CH3:34])([CH3:36])[CH3:35])([CH3:32])[CH3:31])[C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[C:10](=[O:18])[N:11]1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:40])[CH3:39]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CC[C@H]1C(=O)N(c2ccccc2)[C@@H]1c1ccc(Br)cc1O)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1cc(Br)ccc1[C@@H]1[C@@H](CC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(F)cc2)C(=O)N1c1ccccc1
Yield: 78.2 %

Procedure:
(3R,4S)-4-(4-Bromo-2-hydroxyphenyl)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-1-phenylazetidin-2-one (293 mg, 0.50 mmol) was dissolved in anhydrous dichloromethane (3 mL). 4-Dimethylaminopyridine (183 mg, 1.5 mmol) was added followed by acetic anhydride (280 μL, 302 mg, 3.0 mmol). After 1 h the reaction was filtered through a plug of silica gel and eluted with dichloromethane. The solvent was concentrated, azeotroped with toluene and purified by chromatography (40 g silica gel, 1% to 85% ethyl acetate-hexane) to afford 5-bromo-2-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}phenyl acetate (245 mg, 78% yield); Rf 0.47 (1:4 ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.38-7.16 (m, 9H), 7.14-6.94 (m, 3H), 4.69 (t, J=5.4 Hz, 1H), 4.64 (d, J=2.3 Hz, 1H), 3.06 (ddd, J=4.7, 2.3, 2.2 Hz, 1H), 2.30 (s, 3H), 1.97-1.78 (m, 4H), 0.89 (s, 9H), 0.032 (s, 3H), −0.14 (s, 3H) ppm; MS [M−OSi(CH3)2C(CH3)3]+ 493.8.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]=[C:18]3[S:22][C:21](=[O:23])[NH:20][C:19]3=[O:24])=[CH:13][N:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[Na].[Hg]>[C:1]1([CH2:7][CH2:8][CH:9]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH:18]3[S:22][C:21](=[O:23])[NH:20][C:19]3=[O:24])=[CH:13][N:12]=2)[OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1NC(=O)C(=Cc2ccc(C(=O)CCc3ccccc3)nc2)S1
Agent: [Hg]
Agent: [Na]
Solvent: CO
Product: O=C1NC(=O)C(Cc2ccc(C(O)CCc3ccccc3)nc2)S1
Reaction time: 4 h
Yield: 35.7 %

Procedure:
To a solution of the title product of Example 67 (260 mg, 0.77 mmol) in methanol (10 ml) was added 3% sodium amalgam (4 g) and the reaction was stirred for 4 hours. The methanol was decanted, evaporated and the resultant solid diluted with water (10 ml). The aqueous solution was adjusted to pH 2 with 1N HCl and extracted with CH2Cl2 (3×10 ml) which was discarded. After neutralization of the aqueous layer to pH 7 with NaHCO3, it was then re-extracted with CH2Cl2 (3×10 ml). These combined organic layers were dried (MgSO4), filtered and concentrated to afford the desired product (94 mg, 36%) isolated as a foam.
Reaction SMILES: [Cl-:1].[NH4+].[CH3:3][C:4]1[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[C:8]([CH3:15])[C:5]=1[NH:6][CH3:7].Cl>C(O)C.[Zn]>[ClH:1].[ClH:1].[NH2:12][C:10]1[CH:11]=[C:4]([CH3:3])[C:5]([NH:6][CH3:7])=[C:8]([CH3:15])[CH:9]=1
Reactant: CNc1c(C)cc([N+](=O)[O-])cc1C
Reactant: [Cl-]
Agent: Cl
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Product: CNc1c(C)cc(N)cc1C

Procedure:
A suspension of 15.5 g of powdered zinc and 0.6 g of ammonium chloride is heated to reflux. After the source of heat has been removed, 0.02 mole (3.6 g) of 2,6-dimethyl-4-nitro-N-methylaniline is added so as to maintain reflux. At the end of the addition, the reaction mixture is filtered boiling into a solution of 0.05 mole of hydrochloric acid in 14 ml of absolute ethanol; the dihydrochloride crystallises from the filtrate. After recrystallisation from an alcohol-water mixture, a white product is obtained:
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[C:6](Cl)[N:5]=1)[CH3:2]>O>[CH2:1]([N:3]([CH2:17][CH3:18])[C:4]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[C:6]([N:13]2[CH2:14][CH2:15][N:10]([CH3:8])[CH2:11][CH2:12]2)[N:5]=1)[CH3:2]
Reactant: CCN(CC)c1nc(Cl)cc(N2CCNCC2)n1
Solvent: O
Product: CCN(CC)c1nc(N2CCNCC2)cc(N2CCN(C)CC2)n1

Procedure:
2-Diethylamino-4,6-dichloropyrimidine (10 g) is reacted with piperazine (14.45 g) in ethanol (200 ml) at reflux for 2 hr. The mixture is concentrated and the product isolated by silica gel chromatography giving 2-diethylamino-4-piperazino-6-chloropyrimidine. The 2-diethylamino-4-piperazino-6-chloropyrimidine (8 g) is heated neat at 70° for 16 hr. Then water (2.5 ml) is added and the mixture is heated at 100° for 50 hr. The mixture is chromatographed on silica gel, the appropriate fractions are pooled and concentrated to give the title compound, NMR (CDCl3) 1.15, 2.80, 2.85, 2.90, 3.30, 3.70 and 4.95 δ.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:2]1.Cl[C:34]([CH2:36][O:37]C(=O)C)=[O:35]>>[OH:37][CH2:36][C:34]([N:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:2]1)=[O:35]
Reactant: O=C(NCC1CCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CC(=O)OCC(=O)Cl
Product: O=C(NCC1CCN(C(=O)CO)C1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12

Procedure:
Starting from 4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (pyrrolidin-3-ylmethyl)-amide (example A146) and acetic acid chlorocarbonyl-methyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[C:21]([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[CH:20]=[CH:19][C:3]=1[CH2:4][NH:5][C:6](=[O:18])[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([CH3:15])=[C:9]([O:16][CH3:17])[CH:8]=1.[CH:29](=O)[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.COC1C=C(C=C(OC)C=1C)C(NCC1C=CC(C2N=C(C)ON=2)=CC=1NCCC1C=CC=CC=1)=O>>[CH3:17][O:16][C:9]1[CH:8]=[C:7]([CH:12]=[C:11]([O:13][CH3:14])[C:10]=1[CH3:15])[C:6]([NH:5][CH2:4][C:3]1[CH:19]=[CH:20][C:21]([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)=[CH:22][C:2]=1[NH:1][CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:18]
Reactant: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2N)cc(OC)c1C
Reactant: O=CCCc1ccccc1
Agent: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2NCCc2ccccc2)cc(OC)c1C
Product: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2NCCCc2ccccc2)cc(OC)c1C

Procedure:
Compound 1g (50 mg, 0.13 mmol) was reductively aminated with hydrocinnamaldehyde (0.020 mL, 0.15 mmol) following a procedure analogous to the preparation of compound 9a to afford compound 10a. ESI-MS m/e 501.4 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([CH2:31][O:32][CH2:33][CH3:34])([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>C(#N)C>[CH2:33]([O:32][CH2:31][C@@:13]12[CH2:12][N:11]([S:8]([C:5]3[CH:6]=[N:7][C:2]([N:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH2:20][CH2:19][C:18]1=[CH:17][C:16]1[N:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[N:22]=[CH:23][C:15]=1[CH2:14]2)[CH3:34]
Reactant: C1CCNC1
Reactant: CCOC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(Cl)nc1)C2
Solvent: CC#N
Product: CCOC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCCC3)nc1)C2

Procedure:
A solution of (R)-6-(6-chloropyridine-3-sulfonyl)-4a-ethoxymethyl-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triazacyclopenta[b]naphthalene (0.013 g) and pyrrolidine (0.025 mL) in acetonitrile was heated at 100° C. in a microwave reactor for 10 minutes. The solution was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (5:1 by volume), to afford the title compound as a clear gum (0.0080 g). LCMS (Method B): 538 (M+H)+, Retention time 4.0 minutes.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][OH:12]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH:11]=[O:12]
Reactant: O=[N+]([O-])c1ccc(CO)c(F)c1
Solvent: ClCCl
Product: O=Cc1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
Add borane-tetrahydrofuran complex (16.21 mL, 1 M) to a mixture of 2-fluoro-4-nitro-benzoic acid (1.2 g) and tetrahydrofuran (10 mL) at 0° C. Heat at 80° C. for 3 hours. Cool at room temperature and add 1 N aqueous hydrochloric acid (20 mL) and extract with ethyl acetate. Wash with saturated aqueous sodium bicarbonate and dry the remaining organic phase over sodium sulfate and concentrate under reduced pressure to provide (0.91 g, 83%) of an oil. Add (2-fluoro-4-nitro-phenyl)-methanol (0.91 g) to a mixture of dioxide manganese (1.1 g) in 20 ml of dichloromethane. Stir at room temperature overnight and filter over Celite®. Concentrate under reduced pressure to provide (0.27 g, 30%) of the title compound as an oil.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([Cl:10])=[N:5][CH:6]=[N:7][C:8]=1Cl.[NH2:11][C:12]1[CH:13]=[C:14]([NH:19][C:20](=[O:34])[C:21]2[CH:26]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:24]=[C:23]([F:33])[CH:22]=2)[CH:15]=[CH:16][C:17]=1[CH3:18].C(NC(C)C)(C)C.CCCC(C)C>C(OCC)C.O.C(O)CCC>[NH2:2][C:3]1[C:8]([NH:11][C:12]2[CH:13]=[C:14]([NH:19][C:20](=[O:34])[C:21]3[CH:26]=[C:25]([N:27]4[CH2:28][CH2:29][O:30][CH2:31][CH2:32]4)[CH:24]=[C:23]([F:33])[CH:22]=3)[CH:15]=[CH:16][C:17]=2[CH3:18])=[N:7][CH:6]=[N:5][C:4]=1[Cl:10]
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: Cc1ccc(NC(=O)c2cc(F)cc(N3CCOCC3)c2)cc1N
Agent: Cl
Solvent: CC(C)NC(C)C
Solvent: CCCC(C)C
Solvent: O
Product: Cc1ccc(NC(=O)c2cc(F)cc(N3CCOCC3)c2)cc1Nc1ncnc(Cl)c1N
Temperature: 25 °C
Yield: 52.3 %

Procedure:
Ethereal hydrogen chloride solution (1M, 1.5 ml) was added to a mixture of 5-amino-4,6-dichloropyrimidine (0.512 g), N-(3-amino-4-methylphenyl)-3-fluoro-5-morpholinobenzamide (0.514 g) and n-butanol (10 ml) and the resultant mixture was stirred and heated to reflux for 24 hours. Di-isopropylamine (1 ml) was added and the mixture was allowed to cool to ambient temperature. Water and a mixture of diethyl ether and isohexane were added and the precipitated solid was collected and dried. There was thus obtained the title compound (0.373 g); NMR Spectrum: 2.12 (s, 3H), 3.22 (m, 4H), 3.74 (m, 4H), 5.28 (s, 2H), 6.87 (d, 1H), 7.11 (d, 1H), 7.22 (d. 1H), 7.27 (s, 1H), 7.52 (d, 1H), 7.69 (s, 1H), 7.73 (s, 1H), 8.03 (s, 1H), 10.15 (s, 1H); Mass Spectrum: M−H − 455 & 457.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[Br:33]N1C(=O)CCC1=O>O.C(Cl)(Cl)Cl>[Br:33][CH2:11][C:10]([C:3]1[CH:4]=[C:5]([F:9])[C:6]([CH3:8])=[CH:7][C:2]=1[F:1])=[O:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1cc(F)c(C)cc1F
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: O
Solvent: Cc1cccc(C)n1
Solvent: ClC(Cl)Cl
Product: Cc1cc(F)c(C(=O)CBr)cc1F
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
To a chloroform (3.5 mL) solution of 1-(2,5-difluoro-4-methylphenyl)ethanone (0.23 g), under ice cooling in a nitrogen atmosphere, 2,6-lutidine (0.27 mL) and trimethylsilyl trifluoromethanesulfonate (0.32 mL) were added, and the resultant was stirred for 30 minutes. Then, N-bromosuccinimide (0.27 g) was added thereto, and the resultant was stirred for 30 minutes under ice cooling. Water was added to the reaction solution, and the resultant was stirred for 15 minutes, followed by extraction with chloroform. An organic layer was separated using a phase separator, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (OH-type silica gel; hexane/ethyl acetate-gradient elution=99/1→95/5) to obtain the title compound (0.31 g) as a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:5][CH:4]=1)=O.C[Mg]Br.[Cl-].[NH4+].[CH2:21]([O:23]CC)C>>[OH:23][CH2:21][CH2:1][C:3]1[CH:15]=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:5][CH:4]=1
Reactant: CCOCC
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)cc1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)(C)OC(=O)c1ccc(CCO)cc1

Procedure:
t-Butyl p-formylbenzoate (20 g, 97 mmol) was dissolved in dry diethyl ether (300 ml), followed by the dropwise addition of methylmagnesium bromide ethereal solution, 33 ml) under cooling with ice and stirring. The obtained mixture was stirred for one hour and poured into a saturated aqueous solution of ammonium chloride, and the obtained mixture was extracted with ether. The ethereal phase was washed with water, dried and distilled to remove the solvent. The pale-yellow viscous liquid residue thus obtained was subjected to silica gel column chromatography and eluted with a solvent (ethyl acetate/hexane=1:4) to give 21.8 g of t-butyl 4-(hydroxyethyl)benzoate.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][CH2:15][C@@H:14]1[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>>[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][CH2:15][C@@H:14]1[CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:2]3[O:1][CH:5]=[CH:4][N:3]=3)=[CH:31][CH:32]=2)=[CH:24][CH:25]=1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Cc2ccc(I)cc2)cc1
Reactant: c1cocn1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Cc2ccc(-c3ncco3)cc2)cc1
Yield: 23 %

Procedure:
The title compound (20 mg, 23%) was prepared from oxazole (60 mg, 0.81 mmol) and (R)-2-[4-(4-iodo-benzyl)-phenoxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.1 g, 0.2 mmol) using the procedure of Example 146, step 1; 1HNMR (400 MHz, CDCl3) δ 7.95 (d, J=8.4 Hz, 2H), 7.68 (d, J=0.8 Hz, 1H), 7.26 (m, 2H), 7.21 (d, J=0.8 Hz, 1H), 7.10 (d, J=8 Hz, 2H), 6.86 (br d, J=7.2 Hz, 2H), 4.10 (br, 2H), 3.96 (s, 2H), 3.9-3.75 (br, 2H), 3.40 (br, 2H), 2.03-1.84 (br, 4H), 1.46 (s, 9H).