Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OCCCC)(=O)C=C.[C:10]([O:15][CH3:16])(=O)[C:11](C)=C.[C:17]([O:21][CH2:22][CH2:23][OH:24])(=O)C=C.C(O)(=O)C=C.C(OOC(C)(C)C)(C)(C)C>C(OCCO)CCC>[CH2:10]([O:15][CH2:16][CH2:17][O:21][CH2:22][CH2:23][OH:24])[CH3:11]
Reactant: C=C(C)C(=O)OC
Reactant: C=CC(=O)OCCO
Agent: C=CC(=O)O
Agent: C=CC(=O)OCCCC
Agent: CC(C)(C)OOC(C)(C)C
Solvent: CCCCOCCO
Product: CCOCCOCCO
Yield: 5.8 %

Procedure:
70 g of ethylene glycol monobutyl ether, 70 g of diethylene glycol monoethyl ether and 150 g of the polyether A1) described in example 2 were weighed into a 4 liter reaction vessel equipped with stirring, cooling and heating devices and heated to 155° C. A mixture of 360 g of butyl acrylate, 420 g of methyl methacrylate and 75 g of hydroxyethyl acrylate was then added over a period of 2 hours, while simultaneously adding 25.7 g of di-tert.-butyl peroxide dissolved in 8 g of ethylene glycol monobutyl ether and 8 g of diethylene glycol monoethyl ether to form copolymer A2). Immediately thereafter, a mixture of 139 g of butyl acrylate, 195 g of methyl methacrylate, 82 g of hydroxyethyl acrylate and 34 g of acrylic acid was added over a period of 1 hour, while simultaneously adding 19.3 g of di-tert.-butyl peroxide dissolved in 5.5 g of ethylene glycol monobutyl ether and 5.5 g of diethylene glycol monoethyl ether over a period of 1.5 hours to form copolymer A3). After stirring for a further 2 hours at 150° to 155° C., the temperature was reduced to 100° C., 52.5 g of dimethylethanolamine were added and the mixture dispersed in 1670 g of distilled water. The resulting aqueous binder dispersion A) had a solids content of 44%, an organic solvent content of 4.8%, an acid number of 21 and an OH number of 106.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][CH2:14][CH2:15][C:16](O)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(O)C>[CH2:1]([N:8]1[C:12]([CH2:13][CH2:14][CH:15]=[C:16]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC(CCCc1cncn1Cc1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCO
Product: C(CCc1cncn1Cc1ccccc1)=C(c1ccccc1)c1ccccc1

Procedure:
1-benzyl-5-(4-hydroxy-4,4-diphenylbutyl)-1H-imidazole (1,3 g) is refluxed in 20 ml of ethanol containing 5% (w/w) hydrogen chloride for 1 hour. The solvent is evaporated and the HCl-salt of the product is precipitated with ethyl acetate. Yield 1,1 g, m.p. 161°-168° C.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[O:6][C:7]=1[CH2:8][OH:9])[CH3:2].[CH3:20][O:21][C:22](=[O:33])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][C:26]=1[CH3:32].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH3:20][O:21][C:22](=[O:33])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:9][CH2:8][C:7]2[O:6][C:5]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)=[N:4][C:3]=2[CH2:1][CH3:2])=[CH:27][C:26]=1[CH3:32]
Reactant: CCc1nc(-c2ccc(C(F)(F)F)cc2)oc1CO
Reactant: COC(=O)CCc1ccc(O)cc1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCc1nc(-c2ccc(C(F)(F)F)cc2)oc1COc1ccc(CCC(=O)OC)c(C)c1
Reaction time: 8 h

Procedure:
To a solution of [4-Ethyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-methanol (0.108 g, 0.400 mmole) and 3-(4-Hydroxy-2-methyl-phenyl)-propionic acid methyl ester (0.078 g, 0.400 mmole) in toluene (2 mL) at room temperature, is added tributylphosphine followed by a solution of 1,1′-(azodicarbonyl)-dipiperidine (0.201 g, 0.8 mmole) in toluene (2 mL). The reaction is stirred overnight, then diluted with hexane (10 mL). The precipitate is removed through filtration and the filtrate is concentrated, loaded to a silica gel column, eluted with ethyl acetate in hexane (0-15%) and concentrated to provide the titled compound as a white solid. Mass [EI+] 448 (M++H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:11]3[CH:12]=[C:13]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=3)[N:9]=[CH:10][C:3]=12.CC1(C)C(C)(C)[O:25][B:24](B2OC(C)(C)C(C)(C)O2)[O:23]1.C([O-])(=O)C.[K+].C(Cl)Cl>CS(C)=O>[S:17]([C:13]1[CH:12]=[C:11]([N:8]2[C:4]3=[N:5][CH:6]=[CH:7][C:2]([B:24]([OH:25])[OH:23])=[C:3]3[CH:10]=[N:9]2)[CH:16]=[CH:15][CH:14]=1)(=[O:19])(=[O:18])[NH2:20]
Reactant: NS(=O)(=O)c1cccc(-n2ncc3c(I)ccnc32)c1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc(-n2ncc3c(B(O)O)ccnc32)c1
Temperature: 84 °C

Procedure:
To a 48 mL pressure bottle was added 3-(4-iodo-1H-pyrazolo[3,4-b]pyridin-1-yl)benzenesulfonamide, “dot” 2 1-methyl-2-pyrrolidinone complex (60 mg, 0.100 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (94.7 mg, 0.373 mmol), potassium acetate (24.4 mg, 0.249 mmol) and anhydrous DMSO (Volume: 2 mL). The reaction mixture was purged well with argon and treated with PdCl2(dppf).CH2Cl2 (12.5 mg, 0.017 mmol). The reaction mixture was then heated to 84° C. for 1 h to give the desired intermediate. LC/MS (Condition B): ret. T=2.4 min, (M+H)+ 318.98.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].[F:16][C:17]1[C:18](F)=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=[O:21].O>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][C:22]2[CH:23]=[CH:24][C:17]([F:16])=[CH:18][C:19]=2[CH:20]=[O:21])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=Cc1cccc(F)c1F
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc(F)cc2C=O)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To stirred solution of 4-cyanophenol (Aldrich, 5.00 g, 42 mmol) in DMF (100 mL), potassium carbonate (63 mmol) and 2-4, difluoro-benzaldehyde (Aldrich, 5.97 g, 42 mmol) were added and the mixture was stirred at 90° C. overnight. The mixture was cooled to room temperature and poured into water. The solid was filtered and dried to give a pale yellow solid. 5.2 g MS (H+), 242.
Reaction SMILES: [CH2:1]([OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[C:19]([O:18][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCC/C=C\CCCCCCCCCCO
Solvent: c1ccncc1
Product: CCCCC/C=C\CCCCCCCCCCOC(C)=O
Yield: 42 %

Procedure:
The obtained (Z)-11-heptadecenol (Formula II, R=CH3) is added to a mixture of 5 ml. of dry pyridine and 3.5 ml of acetic anhydride, and the mixture is stirred at 0° C. for 3 hours. The solution is poured onto ice and extracted with methylene chloride. The extract is washed with water, 3% aqueous sulfuric acid and again with water, dried over magnesium sulfate, filtered, and the solvent is evaporated. The residue is distilled in fine vacuo. 2.25 g (42%) of (Z)-11-heptadecenyl acetate (Formula I, R=CH3) are obtained; this compound is identical with the product obtained in step (A) above.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].Br[CH2:12]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[O:10]1[C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[O:1][CH2:12]1
Reactant: BrCBr
Reactant: N#Cc1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc2c(c1)OCO2
Temperature: 120 °C
Yield: 94.8 %

Procedure:
To a solution of 3,4 Dihydroxy benzonitrile (5.0 g, 37.0 mmol) in 20 ml of DMF was added dibromomethane (19.25 g, 110.0 mmol) and potassium carbonate (25.50 g, 184.90 mmol). The reaction mixture was heated at 120° C. for 2 h under the nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), reaction mixture was cooled to room temperature. Water (50 ml) was added to the reaction mixture and extracted the compound with ethyl acetate (3×100 mL). The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure to give the title compound as yellow solid (5.16 g, 94.8%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:17](I)[CH3:18].O>CN(C)C=O>[CH2:17]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[N:10][C:2]=1[Cl:1])[CH3:18]
Reactant: O=C(O)c1cccnc1Cl
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2-chloronicotinic acid (5 g, 31.7 mmol, Aldrich) in dimethylformamide (50 mL) were added potassium carbonate (6.579 g, 47.6 mmol) and ethyl iodide (3.8 mL, 47.7 mmol), respectively. The reaction mixture was stirred at room temperature for 3 d. Water (˜50 mL) was added and the product was extracted with ethyl ether (2×75 mL). The combined organic phases were washed with brine (1×50 mL), dried over anhydrous magnesium sulfate. The solids were filtered off, and the filtrate was concentrated under reduced pressure to give 2-chloronicotinic acid ethyl ester as yellow oil. It was then dissolved in ethanol (50 mL) and sodium ethoxide (17.8 mL, 47.6 mmol, 21% in ethanol, Aldrich) was added dropwise. Precipitation was seen as sodium ethoxide was added. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated and the residue partitioned between methylene chloride (150 mL) and water (50 mL). The aqueous layer was extracted with methylene chloride (1×50 mL). The combined organic layers were washed with brine (1×20 mL) and dried over anhydrous magnesium sulfate. The solids were filtered off, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (120 g of silica gel, 10-30% ethyl acetate in hexane) to give 2-ethoxynicotinic acid ethyl ester as an orange oil (4.04 g, 65% yield for 2 steps).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[C:26]([O:37][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40])[CH:25]=1)=[O:23])[CH2:9][CH2:10][NH:11][C:12](=[O:20])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].CO.[Cl-].[Na+]>CC(O)C>[C:38]([O:37][C:26]1[CH:25]=[C:24]([CH:22]([OH:23])[CH2:21][N:8]([CH2:9][CH2:10][NH:11][C:12](=[O:20])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:29]=[CH:28][C:27]=1[O:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:35])[CH3:33])(=[O:43])[C:39]([CH3:40])([CH3:41])[CH3:42]
Reactant: CC(C)(C)C(=O)Oc1ccc(C(=O)CN(CCNC(=O)Cc2ccccc2)Cc2ccccc2)cc1OC(=O)C(C)(C)C
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)O
Product: CC(C)(C)C(=O)Oc1ccc(C(O)CN(CCNC(=O)Cc2ccccc2)Cc2ccccc2)cc1OC(=O)C(C)(C)C
Temperature: -10 °C
Yield: 82.2 %

Procedure:
A suspension of 2-{N-benzyl-N-[2-(2-phenylacetamido)ethyl]amino}-3',4'-bis(pivaloyloxy)acetophenone (2.0 g.) in 2-propanol (20 ml.) was cooled to a -10° C. and sodium borohydride (0.34 g.) added in two portions interspersed by a portion of methanol (4 ml.). After 30 minutes at -10° C. a saturated aqueous solution (150 ml.) of sodium chloride (brine) was added and the mixture was extracted with ether (3×80 ml.). Evaporation of the dried (MgSO4) ethereal extracts gave 1-[3,4-bis(pivaloyloxy)phenyl]-2-[2-(2-phenylacetamido)-N-benzyl-ethylamino]ethanol (1.65 g.) which was dissolved without purification in ethanol (40 ml.). To this solution was added benzyl bromide (0.37 ml., 0.0031 mole) and the mixture was then hydrogenated in the presence of 10% palladium-carbon (0.4 g.) at atmospheric pressure and room temperature during 2 hours. The catalyst was separated, washed with ethanol (10 ml.) and the ethanol washings and reaction solution were evaporated together. The residue was triturated with ether (20 ml.) containing several drops of ethanol to give 1-[3,4-bis(pivaloyloxy)phenyl]-2-[2-(2-phenylacetamido)ethylamino]ethanol hydrobromide, (1.2 g.), m.p. 110°-115° C., identical with that obtained in Example 1.
Reaction SMILES: CC1C=NC2C(C=1C)=CC=C1C=2N=CC(C)=C1C.[CH:19]1([N:23]2[CH2:29][CH2:28][CH2:27][N:26]([C:30]([N:32]3[CH2:35][CH:34]([OH:36])[CH2:33]3)=[O:31])[CH2:25][CH2:24]2)[CH2:22][CH2:21][CH2:20]1.Br[C:38]1[CH:39]=[C:40]2[C:45](=[CH:46][CH:47]=1)[N:44]=[C:43]([CH3:48])[CH:42]=[CH:41]2>>[CH:19]1([N:23]2[CH2:29][CH2:28][CH2:27][N:26]([C:30]([N:32]3[CH2:33][CH:34]([O:36][C:38]4[CH:39]=[C:40]5[C:45](=[CH:46][CH:47]=4)[N:44]=[C:43]([CH3:48])[CH:42]=[CH:41]5)[CH2:35]3)=[O:31])[CH2:25][CH2:24]2)[CH2:22][CH2:21][CH2:20]1
Reactant: O=C(N1CCCN(C2CCC2)CC1)N1CC(O)C1
Reactant: Cc1ccc2cc(Br)ccc2n1
Agent: Cc1cnc2c(ccc3c(C)c(C)cnc32)c1C
Product: Cc1ccc2cc(OC3CN(C(=O)N4CCCN(C5CCC5)CC4)C3)ccc2n1

Procedure:
In a similar fashion (Route 21, GP J) except for replacing phenantroline with 3,4,7,8-tetramethylphenantroline, 1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-ol (128 mg, 0.51 mmol) and 6-bromo-2-methylquinoline (224 mg, 1.01 mmol) gave the title compound as brown oil after purification by FCC (52 mg, 25%).
Reaction SMILES: [CH2:1]([CH:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=2)=[CH:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].N.[CH3:20][N:21](C)C=O>>[CH2:1]([CH:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:20]#[N:21])=[CH:14][CH:13]=2)=[CH:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CN(C)C=O
Reactant: CCCCCC1C=CC(c2ccc(Br)cc2)=CC1
Agent: N
Product: CCCCCC1C=CC(c2ccc(C#N)cc2)=CC1

Procedure:
In 15 ml of N,N-dimethylformamide, 4 g of the 1-pentyl-4-(4-bromophenyl)dihydrobenzene, which had been obtained in Example 8, were dissolved, followed by the addition of 1.4 g of cuprous cyanide. The resulting mixture was reacted for 6 hours at reflux temperature. After the completion of the reaction, aqueous ammonia was added to the reaction mixture, followed by the extraction of the reaction mixture with toluene. The extract was washed with aqueous ammonia and then with saturated NaCl. Anhydrous sodium sulfate was thereafter added to dry the extract. The toluene was distilled off under reduced pressure. The reaction product so obtained was recrystallized twice from ethanol, whereby 0.8 g of 1-pentyl-4-(4-cyanophenyl)dihydrobenzene was obtained.
Reaction SMILES: [CH2:1]1[N:6]([CH2:7][CH2:8][C:9]([O:11]CC)=[O:10])[CH2:5][CH2:4][N:3]2[CH2:14][CH2:15][CH2:16][CH2:17][CH:2]12.[OH-].[Na+]>C(O)C>[CH2:1]1[N:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH2:5][CH2:4][N:3]2[CH2:14][CH2:15][CH2:16][CH2:17][CH:2]12
Reactant: CCOC(=O)CCN1CCN2CCCCC2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCN1CCN2CCCCC2C1

Procedure:
A solution of 6.0 g of the compound obtained in Step A in 50 ml of ethanol and 25 ml of a 1M sodium hydroxide solution is heated for 5 hours at 50° C. and then concentrated to dryness in vacuo and dried in the presence of P2O5 to yield the expected compound.
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14]2[N:20]([CH3:32])[C:21](=[O:31])[C:22]([C:24]4[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=4)=[CH:23][C:13]3=2)[S:8][CH:9]=1)=[N+]=[N-]>CO.C(O)(=O)C.[Pd]>[NH2:1][CH2:4][C:5]1[N:6]=[C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14]2[N:20]([CH3:32])[C:21](=[O:31])[C:22]([C:24]4[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=4)=[CH:23][C:13]3=2)[S:8][CH:9]=1
Reactant: Cn1c(=O)c(-c2ccc(Br)cc2)cc2c3cc(-c4nc(CN=[N+]=[N-])cs4)ccc3n(C)c21
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: Cn1c(=O)c(-c2ccc(Br)cc2)cc2c3cc(-c4nc(CN)cs4)ccc3n(C)c21
Reaction time: 48 h

Procedure:
370 mg (0.73 mmol) of compound B 6-(4-azidomethylthiazol-2-yl)-3-(4-bromophenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one are dissolved in 40 ml of methanol and 40 ml of glacial acetic acid. 40 mg of Pd/C are added. The mixture is hydrogenated under 60 psi at 25° C. for 48 hours. The reaction medium is filtered over celite. Washing is carried out with ethanol. The filtrate is evaporated to dryness. The residue is dissolved in a CH2Cl2/MeOH mixture and the product is adsorbed onto silica. Purification is carried out on a silica column, elution being carried out with 97/02/01 CH2Cl2/MeOH/NH4OH and then with 93/05/02 CH2Cl2/MeOH/NH4OH.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1)[CH3:2]>[Cl-].[Cl-].[Cl-].[Ti+3]>[CH2:1]([C:3]1[CH:4]=[C:5]([N:9]2[CH2:10][CH2:11][N:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=3)[CH2:13][CH2:14]2)[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1cccc(N2CCN(Cc3ccc([N+](=O)[O-])cc3)CC2)c1
Agent: [Ti+3]
Agent: [Cl-]
Product: CCc1cccc(N2CCN(Cc3ccc(N)cc3)CC2)c1

Procedure:
In the manner given in Example 1B, 1-(3-ethylphenyl)-4-(p-nitrobenzyl)piperazine is reduced with aqueous titanium trichloride to give 1-(3-ethylphenyl)-4-[(4-aminophenyl)methyl]piperazine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5](=O)[CH2:6][C:7]([C:9]12[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2)=O)[CH3:2].O.[NH2:22][NH2:23]>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[NH:22][N:23]=[C:7]([C:9]23[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]4)[CH2:10]2)[CH2:16]3)[CH:6]=1)=[O:20])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)C12CC3CC(CC(C3)C1)C2
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(C23CC4CC(CC(C4)C2)C3)n[nH]1
Yield: 91.1 %

Procedure:
Preparation C13, Step 2: 4-Adamantan-1-yl-2,4-dioxo-butyric acid ethyl ester 7.80 g, 28 mmol, 1 eq.), hydrazine hydrate (1.36 mL, 28 mmol, 1 eq.) and ethanol (20 mL) were refluxed until reaction was complete by LCMS. Stripped off the ethanol, and extracted (3×) with ethyl acetate (50 mL). The organic layers were combined, dried and stripped to give 7.00 g of 5-adamantan-1-yl-2H-pyrazole-3-carboxylic acid ethyl ester as a yellow solid. MS found: (M+H)+=275.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14]OS(C)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Cn2ccnc2)CC1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A solution of the title compound from Step B (1.0 g, 3.408 mmoles) in DMF (15 mL) was added to a stirred solution of NaH (0.27 g, 6.817 mmoles) and imidazole (0.464 g, 6.817 mmoles) in DMF (15 mL) under nitrogen atmosphere. The mixture was stirred at 60° C. for 16 h. DMF was evaporated in vacuo. The resulting crude product was extracted with CH2Cl2 and the extract was successively washed with water and brine, and the CH2Cl2 was evaporated to leave the title residue which was chromatographed on silica gel using 3% (10% conc NH4OH in methanol)-CH2Cl2 as eluant to give the title compound (0.823 g). FABMS (M+1)=266.2, δH (CDCl3) 0.8-1.0 (m, 2H), 1.2 (s, 9H), 1.2-1.4 (m, 1H), 1.65 (m, 1H), 2.4 (dt, 2H), 3.6 (d, 2H), 4.8 (d, 2H), 6.7 (s, 1H), 6.8 (s, 1H), 7.2 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.N1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[N+:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:4]([N:1]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:5]=1[C:6]#[N:7])([O-:14])=[O:13]
Reactant: C1CCNC1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: N#Cc1c(N2CCCC2)cccc1[N+](=O)[O-]

Procedure:
Prepared as in Example 90c from 2,6-dinitrobenzonitrile and pyrrolidin to give 2-nitro-6-(pyrrolidin-1-yl)benzonitrile which was used in the next step without any further purification. 1H NMR (400 MHz, DMSO-d6) δ 1.97-1.94 (m, 4H), 3.60-3.57 (m, 4H), 7.22 (d, J=8.0 Hz, 1H), 7.41 (d, J=6.8 Hz, 1H), 7.58 (t, J=8.0 Hz, 1H). MS 218 (MH+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=4)=[C:15](Br)[C:16]3=[O:19])=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[F:57][C:58]1[CH:59]=[C:60](B(O)O)[CH:61]=[CH:62][C:63]=1[F:64]>>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=4)=[C:15]([C:61]4[CH:60]=[CH:59][C:58]([F:57])=[C:63]([F:64])[CH:62]=4)[C:16]3=[O:19])=[CH:12][CH:11]=2)[CH2:3][CH2:2]1
Reactant: O=C1C(Br)=C(c2ccc(C(F)(F)F)cc2)c2ccc(OCCN3CCOCC3)cc21
Reactant: OB(O)c1ccc(F)c(F)c1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: O=C1C(c2ccc(F)c(F)c2)=C(c2ccc(C(F)(F)F)cc2)c2ccc(OCCN3CCOCC3)cc21
Yield: 31 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 6-(2-morpholinoethoxy)-2-bromo-3-(4-(trifluoromethyl)phenyl)-1H-inden-1-one obtained in Step 6 of Example 32 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, 3,4-difluorophenylboronic acid instead of 3-pyridinylboronic acid, and being purified by prep HPLC (CH3CN/H2O=7:3) to obtain the title compound (31%).
Reaction SMILES: C(OC[N:10]1[C:15]2[CH:16]=[C:17]([N:20]3[C:24](=[O:25])[CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]3)[CH:18]=[CH:19][C:14]=2[O:13][CH2:12][C:11]1=[O:34])C1C=CC=CC=1.C([O-])=O.[NH4+].CO>[Pd].O1CCCC1>[O:25]=[C:24]1[N:20]([C:17]2[CH:18]=[CH:19][C:14]3[O:13][CH2:12][C:11](=[O:34])[NH:10][C:15]=3[CH:16]=2)[CH2:21][C@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:23]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC(=O)N(c2ccc3c(c2)N(COCc2ccccc2)C(=O)CO3)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CC(=O)N(c2ccc3c(c2)NC(=O)CO3)C1
Temperature: 100 °C
Yield: 92.6 %

Procedure:
To a mixture of tert-butyl [(3R)-1-{4-[(benzyloxy)methyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl}-5-oxopyrrolidin-3-yl]carbamate (15.0 g, 32.1 mmol), ammonium formate (6.93 g, 110 mmol), methanol (250 ml) and tetrahydrofuran (93 ml) was added 10% Palladium on carbon (50% wet, 15.0 g) and the mixture was heated under reflux for 1 hour on an oil bath at 100° C. Ammonium formate (7.00 g, 111 mmol) was added and the mixture was further heated under reflux for 1 hour. Subsequently the catalyst was removed by filtration and the residue was washed thoroughly with a mixed solvent of chloroform-methanol (1:1). The filtrate and washings were combined to remove the solvent under reduced pressure and the residue was suspended in water from which the insoluble material was removed by filtration. The residue was washed with water and dried with heating under reduced pressure. 10.33 g (93%) of the title compound was obtained in the form of a white solid.