Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[N+:2]([C:5]1[C:6]([OH:21])=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([OH:20])=[O:19])[CH:13]=2)[CH:8]=[C:9]([F:11])[CH:10]=1)([O-])=O.C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH2:2][C:5]1[C:6]([OH:21])=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([OH:20])=[O:19])[CH:13]=2)[CH:8]=[C:9]([F:11])[CH:10]=1
Reactant: O=C(O)c1cccc(-c2cc(F)cc([N+](=O)[O-])c2O)c1
Agent: [Pd]
Agent: Br
Agent: O=C[O-]
Solvent: CCO
Product: Nc1cc(F)cc(-c2cccc(C(=O)O)c2)c1O
Temperature: 80 °C
Yield: 91.4 %

Procedure:
3′-Nitro-5′-fluoro-2′-hydroxy-biphenyl-3-carboxylic acid hydrobromide 2e (417 mg, 1.5 mmol) was dissolved in 60 mL of ethanol followed by addition of 0.5 g of palladium on carbon and ammonium formate (0.95 g, 1.5 mmol). The reaction mixture was heated to reflux at 80° C. for 20 minutes. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was filtered and the filtrate was concentrated under reduced pressure and dried to obtain the title compound 3′-amino-5′-fluoro-2′-hydroxy-biphenyl-3-carboxylic acid 2f (339 mg, yield 91.5%) as a purple solid.
Reaction SMILES: [C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:8][CH2:9][N:10]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:11](=[O:22])[NH:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+].I[CH:49]([CH3:51])[CH3:50]>CC(C)=O>[CH:49]([O:17][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][CH:21]=[C:13]([NH:12][C:11]([N:10]([CH2:9][CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:22])[CH:14]=1)([CH3:51])[CH3:50]
Reactant: O=C(O)c1cccc(NC(=O)N(CCC(c2ccccc2)c2ccccc2)CCN2CCOCC2)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CC(C)OC(=O)c1cccc(NC(=O)N(CCC(c2ccccc2)c2ccccc2)CCN2CCOCC2)c1
Yield: 99 %

Procedure:
200 mg (0.41 mmol, 1 eq.) of product of Example 45 are dissolved in 2 mL of acetone and 2 mL of dry DMF under argon. 283 mg (2.05 mmol, 5 eq.) of K2CO3 and 328 μL (3.28 mmol, 8 eq.) of 2-iodopropane, the mixture is heated under reflux for 2 hours. The medium is then concentrated and taken up in water and the aqueous phase is extracted with ethyl acetate. The organic phase is washed with water then brine, dried over MgSO4, filtered and concentrated. The oil obtained is freed from DMF by entraining the DMF to the rotary evaporator with ethyl acetate, then dried with a vane pump. The product is obtained in the form of white crystals (m=214 mg, yield=99%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([O:44][CH3:45])[C:41]=1[O:42][CH3:43])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([NH:29][C:30]3[NH:34][C:33]4[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=4[N:31]=3)[CH2:25][CH2:24]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[CH2:9]1)=[O:7].[Cl:46][C:47]1[S:51][C:50]([CH2:52]Cl)=[CH:49][CH:48]=1>>[CH3:45][O:44][C:40]1[CH:39]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:41]=1[O:42][CH3:43])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([NH:29][C:30]3[N:31]([CH2:52][C:50]4[S:51][C:47]([Cl:46])=[CH:48][CH:49]=4)[C:32]4[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=4[N:34]=3)[CH2:25][CH2:24]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5[nH]4)CC3)(c3ccc(F)c(F)c3)C2)cc(OC)c1OC
Reactant: ClCc1ccc(Cl)s1
Product: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5n4Cc4ccc(Cl)s4)CC3)(c3ccc(F)c(F)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 37.2 using 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-(3,4-difluorophenyl) pyrrolidine and 5-chloro-2-(chloromethyl)thiophene to give, after purification on silica gel eluting with 1/2 methanol/ethyl acetate, the title compound: mp; 110-120° C. Rf=0.40 (silica gel, 1/2 methanol/ethyl acetate).
Reaction SMILES: CC(C)(CC)C(=O)[O:4][CH2:5][C:6]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:7]=1[O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:22])[C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1.[OH-].[Na+].Cl>CO>[OH:4][CH2:5][C:6]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:7]=1[O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([C:18](=[O:22])[C:19]([OH:21])=[O:20])=[CH:16][CH:17]=1
Reactant: CCC(C)(C)C(=O)OCc1cccc(C)c1OCCOc1ccc(C(=O)C(=O)O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cccc(CO)c1OCCOc1ccc(C(=O)C(=O)O)cc1
Reaction time: 18 h

Procedure:
To a solution of 4-[[2-[2-[(2,2-dimethyl-1-oxobuyloxy)methyl]-6-methylphenoxy]ethyl]oxy]-alpha-oxobenzeneacetic acid [2:1]hydrate (0.032 g) in methanol (10 mL) was added aqueous 1N sodium hydroxide (1.0 mL). After 18 hours at 40° C., the reaction was acidified with 1N hydrochloric acid (2 mL), then concentrated in vacuo to ~2 mL and extracted with dichloromethane. The organic extract was evaporated to provide 0.014 g of 4-[[2-[2-(hydroxymethyl)-6-methylphenoxy]ethyl]oxy]-alpha-oxobenzeneacetic acid as a white solid.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[S:8][C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[N:18]([CH3:27])[S:19]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)(=[O:21])=[O:20])=[N:6][CH2:5]1.[C:28]1(=[O:34])[NH:32][C:31](=[O:33])[CH2:30][CH2:29]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C1(C)C=CC=CC=1>[O:34]=[C:28]1[CH2:29][CH2:30][C:31](=[O:33])[N:32]1[CH2:2][CH2:3][CH:4]1[S:8][C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[N:18]([CH3:27])[S:19]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)(=[O:21])=[O:20])=[N:6][CH2:5]1
Reactant: CN(c1cccc2cc(C3=NCC(CCO)S3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: O=C1CCC(=O)N1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CN(c1cccc2cc(C3=NCC(CCN4C(=O)CCC4=O)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.2 %

Procedure:
A solution (10 mL) of N-{2-[5-(2-hydroxyethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (100 mg), succinimide (29 mg) and triphenylphosphine (93 mg) in tetrahydrofuran was added a 40% toluene solution (0.155 mL) of diethyl azodicarboxylate, and the mixture was stirred at room temperature for 18 hr. A 40% toluene solution (0.155 mL) of diethyl azodicarboxylate was added again to the reaction solution, and the mixture was further stirred at room temperature for 5 days. The reaction solution was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=2:8-10:0), and the obtained colorless oil was crystallized from ethyl acetate-hexane to give the title compound (36 mg, yield: 30%) as colorless prism crystals. MS:503(MH+). melting point 189-191° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:21][CH2:20][C@:9]23[C:10]4[C:11]5[O:19][C@H:8]2[C:7](=[O:22])[CH2:6][CH2:5][C@H:4]3[C@H:3]1[CH2:16][C:15]=4[CH:14]=[CH:13][C:12]=5[O:17][CH3:18].[OH-].[Na+].C(S(O)=O)(N)=N.N#N>C(O)C.CO>[CH3:1][N:2]1[C@@H:3]2[CH2:16][C:15]3[CH:14]=[CH:13][C:12]([O:17][CH3:18])=[C:11]4[O:19][C@H:8]5[C@H:7]([OH:22])[CH2:6][CH2:5][C@@H:4]2[C@:9]5([C:10]=34)[CH2:20][CH2:21]1
Reactant: COc1ccc2c3c1O[C@H]1C(=O)CC[C@H]4[C@@H](C2)N(C)CC[C@]314
Agent: N#N
Agent: N=C(N)S(=O)O
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: COc1ccc2c3c1O[C@H]1[C@H](O)CC[C@H]4[C@@H](C2)N(C)CC[C@@]341

Procedure:
75 mg. (0.25 mmol.) of 17-methyl-4,5α-epoxy-3-methoxymorphinan-6-one is dissolved in 20 ml. of methanol. The resulting solution is treated with 10 ml. of aqueous sodium hydroxide (150 mg.) containing 95 mg. (0.88 mmol.) formamidinesulfinic acid. The resulting mixture is magnetically stirred for one hour at 80° C. under a current of N2. The reaction mixture is thereafter stripped of ethanol and extracted with chloroform. Upon evaporation of chloroform, a residue of dihydroisocodeine is obtained. The NMR spectrum (CDCl3) of the dihydroisocodeine product is identical with that of the published reference spectrum (see S. Okuda et al., Chem. Pharm. Bull., 12, 104 (1964). The dihydroisocodeine free base is converted to its hydrochloride which has no melting point below 300° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][NH:6][C:7]1[CH:8]=[C:9]([CH:13]=O)[N:10]([CH3:12])[N:11]=1.[F:18][C:19]1[CH:20]=[C:21]2[C:27](I)=[CH:26][N:25]([Si](C(C)C)(C(C)C)C(C)C)[C:22]2=[N:23][CH:24]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][NH:6][C:7]1[CH:8]=[C:9]([CH2:13][C:27]2[C:21]3[C:22](=[N:23][CH:24]=[C:19]([F:18])[CH:20]=3)[NH:25][CH:26]=2)[N:10]([CH3:12])[N:11]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cc(F)cnc21
Reactant: Cn1nc(NCc2cccc(Cl)c2)cc1C=O
Product: Cn1nc(NCc2cccc(Cl)c2)cc1Cc1c[nH]c2ncc(F)cc12

Procedure:
(3-Chloro-benzyl)-[5-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1-methyl-1H-pyrazol-3-yl]-amine P-2006 was prepared in two steps from 5-(3-chloro-benzylamino)-2-methyl-2H-pyrazole-3-carbaldehyde 145 and 5-fluoro-3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine 146 as shown in Scheme 18.
Reaction SMILES: [CH3:1][CH:2]([C:6]([NH:8][CH:9]1[C:15](=[O:16])[N:14]([CH3:17])[C:13]2[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=2[C:11]2[CH:22]=[CH:23][CH:24]=[CH:25][C:10]1=2)=[O:7])[C:3](O)=[O:4].[CH:26]1([CH2:29][NH2:30])[CH2:28][CH2:27]1.[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C.CC#N>CN(C=O)C.C(O)(C(F)(F)F)=O>[CH:26]1([CH2:29][NH:30][C:3](=[O:4])[CH:2]([CH3:1])[C:6]([NH:8][CH:9]2[C:15](=[O:16])[N:14]([CH3:17])[C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=3[C:11]3[CH:22]=[CH:23][CH:24]=[CH:25][C:10]2=3)=[O:7])[CH2:28][CH2:27]1
Reactant: CC(C(=O)O)C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21
Reactant: NCC1CC1
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CC(C(=O)NCC1CC1)C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Methyl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-malonamic acid (20 mg, 0.059 mmol) and cyclopropylmethylamine (5 mg, 0.059 mmol) were placed in a disposable polypropylene tube and dissolved in DMF (2 ml). TPTU (2-(2-pyridon-1-yl)-1,1,3,3-tetramethyl uronium tetrafluoroborate, 19 mg, 0.065 mmol) was added, and the mixture was shaken overnight at r.t. The title compound, MS: m/e=392.2 (M+H+), was isolated from the reaction mixture by automated, preparative HPLC (YMC CombiPrep C18 column 50×20 mm, solvent gradient 5–95% CH3CN in 0.1% TFA(aq) over 6.0 min, λ=230 nm, flow rate 40 ml/min).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]([NH:15][C@@H:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][C:19]=1[Cl:27])[CH3:17])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C)C=O.ClCCl>[CH2:5]([O:12][C:13]([NH:15][C@@H:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([Cl:3])=[O:23])=[CH:20][C:19]=1[Cl:27])[CH3:17])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C[C@@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)O)cc1Cl
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Thionyl chloride (5 ml) and dimethylformamide (1 drop) were added to a solution of (R)-4-(1-benzyloxycarbonylaminoethyl)-3-chlorobenzoic acid (680 mg) in dichloromethane (7 ml), and the mixture was stirred at room temperature for 4 hours. After the reaction, the solvent was evaporated under reduced pressure to give (R)-4-(1-benzyloxycarbonylaminoethyl)-3-chlorobenzoyl chloride as crystals. Then, the crystals were dissolved in dichloromethane (12 ml). The solution was dropwise added to a solution of 4-aminopyridine (187 mg) and diispropylethylamine (267 mg) in dichloromethane (5 ml) at room temperature, and the mixture was stirred for 1 hour. After the reaction, water was added to the reaction mixture. The mixture was extracted with chloroform, washed with water and dried. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=20:1) to give 650 mg of (R)-4-(4-pyridyl)-4-(1-benzyloxycarbonylaminoethyl)-3-chlorobenzamide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][OH:13])=[CH:4][CH:3]=1.[C:14]([Cu])#[N:15]>CN(C=O)C>[C:14]([C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][OH:13])=[CH:4][CH:3]=1)#[N:15]
Reactant: N#C[Cu]
Reactant: OCCOCCc1ccc(Br)cc1
Solvent: CN(C)C=O
Product: N#Cc1ccc(CCOCCO)cc1
Temperature: 145 °C

Procedure:
To a solution of 2-[2-(4-bromophenyl)ethoxy]ethanol (10.8 g, 0.044 mol; see step (iii) above in DMF (100 mL), CuCN (7.8 g, 0.088 mol) was added and refluxed at 140 to 150° C. overnight. After removal of DMF by distillation, the reaction was quenched by the addition of water. Inorganic matter was removed by filtration and the aqueous layer was extracted with ethyl acetate (4×100 mL). The combined organic layers were washed with water and brine before being concentrated. The crude product was purified by column chromatography (silica gel: 60-120 mesh, petroleum ether:ethyl acetate (75:25) eluent). This yielded 4.3 g (51%) of the sub-title compound.
Reaction SMILES: [Br-].[CH2:2]([C@H:7]1[CH2:12][CH2:11][C@H:10]([CH2:13][CH2:14][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:9][CH2:8]1)[CH2:3][CH2:4][CH2:5][CH3:6].[C:34]([C:36]1[CH:41]=[CH:40][C:39]([CH:42]2[CH2:47][CH2:46][C:45](=O)[CH2:44][CH2:43]2)=[CH:38][CH:37]=1)#[N:35].O>COC(C)(C)C.O1CCCC1>[CH2:2]([C@H:7]1[CH2:12][CH2:11][C@H:10]([CH2:13][CH:14]=[C:45]2[CH2:46][CH2:47][CH:42]([C:39]3[CH:40]=[CH:41][C:36]([C:34]#[N:35])=[CH:37][CH:38]=3)[CH2:43][CH2:44]2)[CH2:9][CH2:8]1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: N#Cc1ccc(C2CCC(=O)CC2)cc1
Reactant: CCCCC[C@H]1CC[C@H](CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Solvent: COC(C)(C)C
Product: CCCCC[C@H]1CC[C@H](CC=C2CCC(c3ccc(C#N)cc3)CC2)CC1
Reaction time: 0.17 h

Procedure:
A suspension of 10.6 g of 2-(trans-4-pentylcyclohexyl)ethyl-triphenylphosphonium bromide in 100 ml of dry t-butyl methyl ether was treated portionwise under an inert gas atmosphere at 5°-10° C. with 2.2 g of potassium t-butylate and the mixture was stirred for a further 10 minutes. Subsequently, a solution of 3.5 g of 4-(p-cyanophenyl)cyclohexanone in 50 ml of tetrahydrofuran was added dropwise over a period of 30 minutes to the orange suspension. The mixture was stirred at room temperature overnight and then treated with 50 ml of water. The aqueous phase was separated and extracted with diethyl ether. The combined organic phase was washed neutral with water, dried over sodium sulphate and concentrated. The residue was chromatographed on silica gel with hexane/ethyl acetate (vol. 95:5), thereby obtaining 3.8 g of p-[4-[2-(trans-4-pentylcyclohexyl)ethylidene]cyclohexyl]benzonitrile.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9]C(=O)C)(=[O:3])[CH3:2].O.C(OC(OC(=O)C)CCC)(=O)C.O1CCCC1>C(O)(=O)C>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCCOC(C)=O
Agent: CCCC(OC(C)=O)OC(C)=O
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)OCCCCO
Yield: 0.3 %

Procedure:
The tube reactor is charged with 85 grams of silica-magnesia catalyst (70% silica -- 30% magnesia, 3/16 inch × 3/16 inch pills, Davison Chemical) and maintained at 220°-250° C. As in Example 1, 50.0 grams of 1,4-butanediol diacetate and 50 ml. of water are copassed over one hour. The effluent contains, as shown by quantitative glpc analysis, 12.2 grams of the unconverted butanediol diacetate (24% recovery), 15.1 grams of tetrahydrofuran and 24.4 grams of acetic acid (96% and 93% yields, respectively, based on 76% conversion), and 0.1 grams of 4-acetoxybutanol (0.3% yield).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1[C:17]2[CH2:16][CH2:15][C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[CH:12]([CH2:22][C:23]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=O)[C:11]=2[CH:10]=[CH:9][CH:8]=1>O1CCOCC1>[CH:7]1[C:17]2[CH2:16][CH2:15][C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[CH:12]([CH2:22][CH2:23][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CC1c2ccccc2CCc2ccccc21)N1CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Product: c1ccc2c(c1)CCc1ccccc1C2CCN1CCCC1

Procedure:
A mixture of 28.5 g of lithium aluminum hydride and 300 ml of dry dioxane, stirred under argon, is treated dropwise over a period of 1.25 hours with a solution of 230 g of 1-[(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)acetyl]-pyrrolidine in 700 ml of dry dioxane, whereby the mixture is heated to boiling under reflux. 10 minutes after completion of the addition, the mixture is cooled to about 10°-15° and excess lithium aluminum hydride is destroyed by the cautious addition of 200 ml of ethyl acetate, the temperature rising to about 40°. The mixture is subsequently cooled to about 10° and hydrolyzed by the slow dropwise addition of about 250 ml of water while cooling well. The mixture is suction filtered while back-washing with about 200 ml of chloroform and the filtrate is evaporated in vacuo. The residual brown oil is taken up in 1 l of ether and extracted successively with 300 ml of 2 N hydrochloric acid, 150 ml of 2N hydrochloric acid and twice with 100 ml of water each time. The acid-aqueous phase is made basic with about 100 ml of 28 percent sodium hydroxide while cooling with ice and extracted successively with 500 ml of hexane and twice with 300 ml of hexane each time. The organic extracts are washed twice with 250 ml of saturated sodium chloride solution each time and twice with 250 ml of distilled water each time, dried over magnesium aluminum in the presence of a spatula tip of active carbon and evaporated in vacuo. After drying the residue at 40° in a high vacuum, there is obtained 1-[2-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)ethyl]pyrrolidine as a light yellow oil which crystallizes slowly; m.p. 51°-53°. By distillation of the crude base under argon over a Hickmann head at 163°-165°/0.09 Torr there is obtained pure material of melting point 53.5°-54°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:33]=[CH:32][CH:31]=[CH:30][C:24]=1[CH:25]=[CH:26][C:27](Cl)=[O:28]>>[Cl:22][C:23]1[CH:33]=[CH:32][CH:31]=[CH:30][C:24]=1/[CH:25]=[CH:26]/[C:27]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)=[O:28]
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: O=C(Cl)C=Cc1ccccc1Cl
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C(=O)/C=C/c3ccccc3Cl)CC1)O2

Procedure:
Compound 61 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 2-chlorocinnamoyl chloride and conditions outlined in procedure N. M.p.=110-115° C.; 300 MHz 1H NMR (DMSO) δ 8.0-7.75 (m, 5H), 7.6-7.4 (m, 3H), 7.4-7.25 (m, 1H), 7.2-7.1 (m, 1H), 4.5-4.35 (m, 1H), 3.45-3.05 (m, 5H), 2.25-1.7 (m, 4H); LCMS: 466 [M+H].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.[C:11]1([C:17]2[CH:22]=[C:21](Cl)[CH:20]=[CH:19][N:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.O>[C:11]1([C:17]2[CH:22]=[C:21]([C:4]3[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][CH:5]=3)[CH:20]=[CH:19][N:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1ccccc1B(O)O
Reactant: Clc1ccnc(-c2ccccc2)c1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc(-c2ccnc(-c3ccccc3)c2)c1
Yield: 77.3 %

Procedure:
2-methylphenyl boronic acid (6.3 g, 46.40 mmol), 2-phenyl-4-chloropyridine (8.0 g, 42.18 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (692 mg, 1.68 mmol), and potassium phosphate tribasic (29.10 g, 126.54 mmol) 250 mL of toluene and 25 mL of water were placed in a 500 mL round-bottom flask. Nitrogen was bubbled directly into the mixture for 30 min after which tris(dibenzylideneacetone)dipalladium(0) (386 mg, 0.421 mmol) was added. Nitrogen was then bubbled for another 15 minutes then the reaction mixture was heated to reflux for 16 h under nitrogen. The mixture was cooled and the organic layer was separated from the aqueous layer. The organic layer was washed with a saturated brine solution, dried over magnesium sulfate, filtered, and the solvent removed under vacuum to give an off-white solid as the crude. The crude was purified by column chromatography using silica gel as the stationary phase and 2% ethyl acetate in hexanes as the mobile phase. 8.0 g of desired product was obtained after purification (77.4% yield).
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.[N:13]1[C:22]2[C:17](=[CH:18][C:19]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.CI>C1COCC1>[N:13]1[C:22]2[C:17](=[CH:18][C:19]([CH:23]([CH3:1])[C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)Cc1ccc2ncccc2c1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)c1ccc2ncccc2c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
THF (5 ml) was taken in a RBF, diisopropyl amine (0.19 ml, 1.29 mmol) was added and cooled to −78° C. under nitrogen atmosphere. Then n-BuLi (0.8 ml, 1.29 mmol) was added and stirred at same temperature for 30 mins. At this stage methyl 2-(quinolin-6-yl)acetate (0.2 g, 0.99 mmol) was added and stirred at −78° C. for 30 mins. Then methyl iodide (0.17 g, 1.2 mmol) was added and stirred at −78° C. for 30 mins and then slowly brought to rt. At rt the reaction mixture was allowed to stir overnight. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer dried on anhydrous Na2SO4 and EtOAc removed using a rotary evaporator to obtain the crude product, which was purified by column chromatography on 60-120 mesh silica gel and EA and Petether (25:75) as eluent. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.89-8.86 (m, 1H), 8.13 (d, J 7.8, 1H), 8.07 (d, J 8.7, 1H), 7.76-7.64 (m, 2H), 7.42-7.37 (m, 1H), 3.92 (q, J 7.2, 1H), 3.68 (s, 3H), 1.60 (d, J 7.2, 3H).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4](I)[N:3]=1.C([Mg]Cl)(C)C.C1(C)C(S([C:25]#[N:26])(=O)=O)=CC=CC=1>ClCCl>[Br:1][C:2]1[N:3]=[C:4]([C:25]#[N:26])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: Cc1ccccc1S(=O)(=O)C#N
Reactant: COc1ccc(I)nc1Br
Agent: CC(C)[Mg]Cl
Solvent: ClCCl
Product: COc1ccc(C#N)nc1Br
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-bromo-6-iodo-3-methoxypryidine (5-1, 2.1 g, 6.69 mmol, 1.0 equiv) in dichloromethane (17 mL) was added isopropylmagnesium chloride (2.00M, 4.35 mL, 8.70 mmol, 1.3 equiv) slowly at 0° C. and the reaction mixture was stirred for 45 minutes. The reaction mixture was then cooled to −78° C. and a solution of toluenesulfonyl cyanide (1.8 g, 10.03 mmol, 1.5 equiv) in dichloromethane (5 mL) was added slowly. The reaction mixture was allowed to warm to ambient temperature over 4 hours. To quench, 2N HCl was added until neutral pH was obtained. The reaction mixture was partitioned between water and dichloromethane and the aqueous phase was extracted with dichloromethane (3×50 mL). The combined organic layer was dried over MgSO4, concentrated and the residue was purified by normal phase column chromatography (10-50% EtOAc in hexanes) to afford the product as a tan solid. ESI+ MS [M+H]+ C7H6BrN2O: 212.9 found, 213.0 required.