Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([CH2:13][PH:14]([CH2:16][OH:17])=[O:15])([O:10][CH2:11][CH3:12])[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:18])[C:5]([CH2:13][PH:14]([CH2:16][O:17][S:20]([CH3:19])(=[O:22])=[O:21])=[O:15])([O:10][CH2:11][CH3:12])[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)(C[PH](=O)CO)OCC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CC(C)C)(C[PH](=O)COS(C)(=O)=O)OCC
Temperature: -20 °C

Procedure:
2-(Ethoxy)(hydroxymethyl)phosphinoylmethyl-4-methylpentanoic acid ethyl ester (5 g) was dissolved in 20 mL of CH2Cl2 and cooled to -20° C. (in duplicate). Methanesulfonyl chloride (1.5 mL) and triethylamine (3.0 mL) were added to solution dropwise. After 15 minutes the bath was removed and the reaction left at room temperature for 3% hours. Each solution was then washed with 10 mL cold 2% HCl, 10 mL NaHCO3 (sat), 10 mL brine, dried with MgSO4, filtered and evaporated to yield 12.8 g (combined yield) of 2-(ethoxy)(methane-sulfonyloxymethyl)phosphinoylmethyl-4-methylpentanoic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].[Li]CCCC.[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1)([O-:14])=[O:13]>C1COCC1>[CH3:1][C:2]([OH:6])([CH3:3])[C:4]#[C:5][CH:19]([C:18]1[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:22][CH:21]=1)[OH:20]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: C#CC(C)(C)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(O)C#CC(O)c1ccc([N+](=O)[O-])cc1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 64.3 %

Procedure:
To a stirred −78° C. solution of 2-methylbut-3-yn-2-ol (6.1 mL, 63.5 mmol, 1.2 eq) in dry THF (250 mL), n-BuLi (62 mL, 2.3 M in hexane, 142 mmol, 2.7 eq) was added dropwise over 10 minutes under an inert atmosphere. After being stirred for 40 min at −78° C., a solution of 4-nitrobenzaldehyde (8 g, 52.9 mmol, 1 eq) in dry THF (50 mL) was added to the reaction mixture and stirring was continued for an additional 1 h at −78° C. The reaction mixture was then quenched with a saturated NH4Cl solution and extracted with EtOAc (2×200 mL). The combined organic layers were washed with water (200 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by column chromatography (30% ethyl acetate in hexanes) to afford 4-methyl-1-(4-nitrophenyl)pent-2-yne-1,4-diol (8 g, 65%) as a yellow solid.
Reaction SMILES: N[C:2]1[C:6]2=[N:7][CH:8]=[C:9]([Cl:11])[CH:10]=[C:5]2[O:4][C:3]=1C(OCC)=O.Cl.C([O-])(O)=[O:19].[Na+]>>[Cl:11][C:9]1[CH:10]=[C:5]2[O:4][CH2:3][C:2](=[O:19])[C:6]2=[N:7][CH:8]=1
Reactant: CCOC(=O)c1oc2cc(Cl)cnc2c1N
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Product: O=C1COc2cc(Cl)cnc21
Temperature: 25 °C
Yield: 20 %

Procedure:
A solution of ethyl 3-amino-6-chlorofuro[3,2-b]pyridine-2-carboxylate (0.81 g, 3.35 mmol) in hydrochloric acid (5.0 M in water, 50.0 mL, 3.35 mmol) was heated to reflux for 4 h and cooled to RT. The pH was adjusted to 7 with saturated NaHCO3. The aqueous phase was extracted with EtOAc (3×) and the combined organic extracts were dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel eluting with a gradient of 0% to 100% EtOAc in DCM gave 6-chlorofuro[3,2-b]pyridin-3(2H)-one (0.12 g, 0.68 mmol, 20% yield) as a yellow solid. LC/MS (ESI+) m/z=170.0 (M+H). Calculated for C7H4ClNO2 169.0.
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].CN.[Cl:7][C:8]1[N:9]=[CH:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]3[S:21][C:22]4[CH2:28][C:27](=O)[CH2:26][CH:25]([C:30]5[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=5)[C:23]=4[N:24]=3)=[CH:15][C:14]=2[O:37][CH3:38])[CH:12]=1>CO>[Cl:7][C:8]1[N:9]=[CH:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]3[S:21][C:22]4[CH2:28][CH:27]([NH:2][CH3:1])[CH2:26][CH:25]([C:30]5[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=5)[C:23]=4[N:24]=3)=[CH:15][C:14]=2[O:37][CH3:38])[CH:12]=1
Reactant: [BH3-]C#N
Reactant: COc1cc(Nc2nc3c(s2)CC(=O)CC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Agent: CN
Agent: [Na+]
Solvent: CO
Product: CNC1Cc2sc(Nc3ccc(-n4cnc(Cl)c4)c(OC)c3)nc2C(c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 9.7 %

Procedure:
Sodium cyanoborohydride (37 mg, 0.59 mmol) and methylamine (170 μL, 0.34 mmol) were added to a solution of 2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-(4-fluorophenyl)-4,5-dihydrobenzo[d]thiazol-6(7H)-one (50 mg, 0.107 mmol, from example 75) in MeOH (1.1 mL). The mixture was stirred at rt for 4 hours. The crude reaction mixture was purified using preparatory HPLC (Column: Phenomenex Luna C18 30×100 mm, Solvent A=10 mM Ammonium Acetate in 95:5 water/ACN, Solvent B=10 mM Ammonium Acetate in 5:95 water/ACN. Flow rate: 40 ml/mM, 30-95% B, 20 min to afford 5.0 mg (9% yield) of N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(4-fluorophenyl)-N6-methyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine. LC-MS (M+H)+ 484.2.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[N:22]=[C:21]([NH2:23])[CH:20]=[N:19][CH:18]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33].Cl>C(Cl)Cl>[CH:12]1[C:8]2[CH2:9][CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6](=[CH:16][C:17]3[N:22]=[C:21]([NH:23][S:32]([CH3:31])(=[O:34])=[O:33])[CH:20]=[N:19][CH:18]=3)[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: Nc1cncc(C=C2c3ccccc3CCc3ccccc32)n1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cncc(C=C2c3ccccc3CCc3ccccc32)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
Mix 6-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-pyrazin-2-ylamine (35 mg, 0.117 mmol), triethylamine (34 μL, 0.234 mmol), N,N-dimethylaminopyridine (2 mg, 0.018 mmol), and methanesulfonyl chloride (10 μL, 0.123 mmol) in CH2Cl2 (2 mL). Stir at room temperature overnight and add 150 μL triethylamine and 40 μL methanesulfonyl chloride. Stir at room temperature for 6 h and add 1.00N aqueous HCl (1 mL). Load mixture onto a Varian ChemElut CE1005 solid-phase extraction cartridge, then elute, collect, and concentrate 45 mL CH2Cl2. Dissolve crude product in THF (5 mL), add 1.0M tetrabutylammonium fluoride (0.30 mL), and heat to reflux for 1 h. Cool to room temperature and dilute with H2O and brine. Extract into ethyl acetate, dry (MgSO4) and concentrate organics. Chromatograph on silica gel (4 g), eluting with 20%→35% ethyl acetate/hexanes to afford 19 mg (43%) of the title compound as a white solid. MS (ES) 378 (M+H), 376 (M−H); HPLC shows 100% purity.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([S:24]([C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=1)(=[O:26])=[O:25])[CH:18]=[CH:17]2.[N:36]1[CH:41]=[CH:40][C:39]([N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[CH:38][CH:37]=1>CN(C=O)C>[Cl:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([S:24]([C:27]1[CH:28]=[CH:29][C:30]([C:31]([N:45]3[CH2:46][CH2:47][N:42]([C:39]4[CH:40]=[CH:41][N:36]=[CH:37][CH:38]=4)[CH2:43][CH2:44]3)=[O:32])=[CH:34][CH:35]=1)(=[O:26])=[O:25])[CH:18]=[CH:17]2
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: O=C(O)c1ccc(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(c1ccc(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)cc1)N1CCN(c2ccncc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 20.7 %

Procedure:
1,1′-Carbonyldiimidazole (0.15 g) was added to a stirred solution of 4-(6-chloronaphth-2-ylsulphonyl)benzoic acid (0.29 g) in DMF (10 ml) which had been cooled to 0° C. and the mixture was stirred at 0° C. for 30 minutes. N-(4-Pyridyl)piperazine (0.164 g) was added, the cooling bath was removed and the mixture was stirred at ambient temperature for 16 hours. The solvent was removed by evaporation and the residue was partitioned between ethyl acetate and water. The ethyl acetate extract was washed with water and with brine, dried (MgSO4) and evaporated. The residue was triturated under diethyl ether to give 1-[4-(6-chloronaphth-2-ylsulphonyl)benzoyl]-4-(4-pyridyl)piperazine (0.085 g), m.p. 267-269° C.;
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[Cu][C:26]#[N:27]>N1C=CC=CC=1.CN1CCCC1=O>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:26]#[N:27])=[CH:20][CH:19]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: N#C[Cu]
Reactant: CCC[C@H]1CC[C@H](c2ccc(CCc3ccc(Br)cc3)cc2)CC1
Solvent: c1ccncc1
Solvent: CN1CCCC1=O
Product: CCC[C@H]1CC[C@H](c2ccc(CCc3ccc(C#N)cc3)cc2)CC1

Procedure:
Analogously to Example 4(b), 1-[4-(trans-4-n-propylcyclohexyl)-phenyl]-2-(4-bromophenyl)-ethane is reacted with copper(I) cyanide in pyridine/N-methylpyrrolidone to give 1-[4-(trans-4-n-propylcyclohexyl)-phenyl]-2-(4-cyanophenyl)-ethane; m.p. 36°.
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][NH:21][CH2:22][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:7][C:6]([OH:23])=[C:5]([CH3:24])[CH:4]=1.Cl.[CH3:26][N:27]([CH3:34])[CH2:28]/[CH:29]=[CH:30]/[C:31](O)=[O:32]>>[CH3:26][N:27]([CH3:34])[CH2:28]/[CH:29]=[CH:30]/[C:31]([N:21]1[CH2:20][CH2:19][C:18]2[C:11]3[C:10]([NH:9][C:8]4[C:3]([F:2])=[CH:4][C:5]([CH3:24])=[C:6]([OH:23])[CH:7]=4)=[N:15][CH:14]=[N:13][C:12]=3[S:16][C:17]=2[CH2:22]1)=[O:32]
Reactant: Cc1cc(F)c(Nc2ncnc3sc4c(c23)CCNC4)cc1O
Reactant: CN(C)C/C=C/C(=O)O
Agent: Cl
Product: Cc1cc(F)c(Nc2ncnc3sc4c(c23)CCN(C(=O)/C=C/CN(C)C)C4)cc1O

Procedure:
The compound was synthesized in analogy to Example 122 from 4-fluoro-2-methyl-5-(5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-ylamino)phenol hydrochloride from Example 72A (100 mg, 0.27 mmol) and (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride from Example 1A (63 mg, 0.38 mmol) to yield 29 mg (24%).
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)=[CH:13][CH:12]=1)[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[Cl:25][C:26]1[C:27]([Cl:41])=[CH:28][C:29]2[O:34][CH2:33][C:32](=[O:35])[N:31]([CH2:36][C:37]([OH:39])=O)[C:30]=2[CH:40]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[Cl:25][C:26]1[C:27]([Cl:41])=[CH:28][C:29]2[O:34][CH2:33][C:32](=[O:35])[N:31]([CH2:36][C:37]([N:2]([CH3:1])[C@H:3]([C:11]3[CH:12]=[CH:13][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=4)=[CH:15][CH:16]=3)[CH2:4][N:5]3[CH2:10][CH2:9][O:8][CH2:7][CH2:6]3)=[O:39])[C:30]=2[CH:40]=1
Reactant: O=C(O)CN1C(=O)COc2cc(Cl)c(Cl)cc21
Reactant: CN[C@@H](CN1CCOCC1)c1ccc(-c2cccc(OC)c2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cccc(-c2ccc([C@H](CN3CCOCC3)N(C)C(=O)CN3C(=O)COc4cc(Cl)c(Cl)cc43)cc2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 46.2 %

Procedure:
(1R)—N-Methyl-1-[3′-(methyloxy)-4-biphenylyl]-2-(4-morpholinyl)ethanamine (3.3 g, 10 mmol) was dissolved in 100 mL of DMF at room temperature with magnetic stirring. The resulting solution was treated with (6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetic acid (4.3 g, 12 mmol, with 23 wt % LiCl) followed by triethylamine (2.8 mL, 20 mmol) and BOP (5.3 g, 12 mmol). The reaction mixture was maintained at room temperature for 16 h. The reaction mixture was filtered and the filtrate was added slowly to of H2O (300 mL) with vigorous stirring. The precipitate which formed was collected by filtration and further purified by silica gel chromatography (120 g Redisep column, silica, 40 um, 60 Å, 80 mL/min, A: MeOH (with 10% NEt3), B: CH2Cl2, A: 1% for 20 min, 2% for 20 min, 5% for 10 min; detection at 254 nm). The combined fractions were concentrated, and the resulting residue was triturated with MeOH. The white solid was collected by filtration to give the title compound (2.7 g, 46%). MS (ES) m/e 585 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[CH:10][O:9][C:8]=2[C:18]([NH:20][NH2:21])=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:25][CH2:26][CH3:27])(=O)C>>[C:14]([C:13]1[CH:12]=[C:11]([CH:7]=[CH:27][C:26]=1[OH:25])[C:10]([NH:21][NH:20][C:18]([C:8]1[O:9][CH:10]=[C:11]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:19])=[O:9])#[N:15]
Reactant: NNC(=O)c1occ(-c2ccncc2)c1-c1ccccc1
Reactant: CCOC(C)=O
Product: N#Cc1cc(C(=O)NNC(=O)c2occ(-c3ccncc3)c2-c2ccccc2)ccc1O
Reaction time: 8 h

Procedure:
A mixture of 3-phenyl-4-(4-pyridyl)-2-furancarboxylic acid hydrazide (compound of Reference Example 11, 0.28 g) and the compound of Reference Example 63 (0.33 g in ethyl acetate (10 ml) was heated at reflux while stirring overnight. The thus-precipitated crystals were collected by filtration and recrystallized from ethyl acetate, thereby giving 0.02 g of the desired compound. Melting point: 179-181° C.
Reaction SMILES: CN(C=O)C.[NH:6]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:7]([C:15]([OH:17])=O)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.ClC(OCC(C)C)=O.[CH2:33]([NH2:37])[CH:34]([CH3:36])[CH3:35]>C(N(CC)CC)C>[NH:6]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:7]([C:15]([NH:37][CH2:33][CH:34]([CH3:36])[CH3:35])=[O:17])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)CN
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
In a DMF solution containing a mixed anhydride prepared from 2.0 g oi Boc-Phe-OH, 1.15 ml of triethylamine and 1.08 ml of isobutyl chloroformate, 1.50 ml of isobutylamine was added under ice cooling and the resultant mixture was stirred for 14 hr. The reaction mixture was treated similarly to that in Example 51 (Process 1) to give 1.91 g of the title compound.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[N:11]=1.Cl[C:18]([O:20][CH3:21])=[O:19].O>O1CCCC1>[F:9][C:10]1[C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:13]=[C:12]([F:16])[N:11]=1
Reactant: COC(=O)Cl
Reactant: Fc1cccc(F)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(F)nc1F
Reaction time: 3 h
Yield: 43.2 %

Procedure:
To a stirred solution of 91 ml (0.182 mol) of 2.0 molar lithium diisopropylamide (in hexanes) in 200 mL dry tetrahydrofuran cooled to -70° under nitrogen was added dropwise a solution of 20.0 g of 2,6-difluoropyridine (0.174 mol) in 75 mL dry tetrahydrofuran such that the temperature was maintained below -60°. The solution was stirred at -70° fo 3 hours and was then added via a cannula to a solution 21.7 g (0.230 mol) of methyl chloroformate in 100 mL dry tetrahydrofuran cooled to -70° under nitrogen. After stirring another hour at -70°, the mixture was poured into water and extracted with ether. The combined organic layers were washed with brine, dried over magnesium sulfate, and evaporated to a semisolid which was purified by flash chromatography to afford 13.0 g (43%) orange oil: NMR (CDCl3, 200 MHz) 3.95 (3H, s), 6.9 (1H, m), 8.5 (1H, m); IR (neat) 1745, 1730, 1610, 1415, 1290 cm-1.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][C:47](=O)[CH:46]([O:51][CH2:52][CH:53]=[CH2:54])[CH2:45]2)[CH:7]([CH3:56])[CH:6]([OH:57])[CH2:5][C:4]1=[O:58])[CH3:2].[CH2:59]([NH2:66])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1.C([BH3-])#N.[Na+]>C(O)(C)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:55])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH:66][CH2:59][C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)[CH:46]([O:51][CH2:52][CH:53]=[CH2:54])[CH2:45]2)[CH:7]([CH3:56])[CH:6]([OH:57])[CH2:5][C:4]1=[O:58])[CH3:2]
Reactant: NCc1ccccc1
Reactant: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CCC1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(C)O
Product: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CCC1NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(3"-allyloxy-4"-oxocyclohexyl]-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone in dry isopropyl alcohol (3 ml) is added benzyl amine (86.5 mg). The mixture is stirred at r.t. for 30 minutes, and then cooled to -78° C. To this solution is added a solution of sodium cyanoborohydride (6.7 mg) in isopropyl alcohol (0.5 ml). The reaction is stirred at -78° C. and poured into ice water. Extraction with ethyl acetate, followed by purification gives the title compound as a mixture of epimers at C-4".
Reaction SMILES: [C:1]([C:3](=[CH:12]OCC)[C:4]([NH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])#[N:2].[CH3:16][C:17]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:18]=1[NH2:19].CCCCCC>C(O)C>[C:1]([C:3](=[CH:12][NH:19][C:18]1[C:20]([CH3:24])=[CH:21][CH:22]=[CH:23][C:17]=1[CH3:16])[C:4]([NH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])#[N:2]
Reactant: Cc1cccc(C)c1N
Reactant: CCOC=C(C#N)C(=O)NC(=O)OCC
Solvent: CCCCCC
Solvent: CCO
Product: CCOC(=O)NC(=O)C(C#N)=CNc1c(C)cccc1C

Procedure:
To α-cyano-β-ethoxy-N-ethoxycarbonylacrylamide (1.2 g), dissolved in about 5 ml of boiling ethanol, is added 0.6 g of 2,6-dimethylaniline. The reaction is refluxed for several hours and then hexane is added. On cooling, the reaction is filtered, and washed with ethanol and ether to give α-cyano-β-(2,6-dimethylanilino)-N-ethoxycarbonylacrylamide, m.p. 138°-140°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[CH2:34][C:35](O)=[O:36].CCN=C=NCCCN(C)C>>[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[CH2:34][C:35]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1)=[O:36]
Reactant: O=C(O)Cc1ccc(Cl)cc1Cl
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Agent: CCN=C=NCCCN(C)C
Product: NC(=O)c1ccc2[nH]nc(-c3cccc(NC(=O)Cc4ccc(Cl)cc4Cl)c3)c2c1
Yield: 3.3 %

Procedure:
Following Example 290, the reaction of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (200 mg, 0.56 mmol) with 2,4-dichlorophenylacetic acid (0.15 g, 0.71 mmol) and EDCI (0.17 g, 0.89 mmol) furnished 8 mg (3% yield) of the title compound. 1H NMR (DMSOd6) δ 13.4 (br s, 1H), 10.4 (s, 1H), 8.6 (s, 1H), 8.2 (s, 1H), 8.1 (br s, 1H), 7.9 (dd, 1H), 7.75 (m, 2H), 7.64–7.58 (m, 2H), 7.52–7.4 (m, 2H), 7.35 (s, 1H), 3.9 (s, 2H); ES-MS (m/z) 439 [M]+.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1>C1COCC1>[C:1]1([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1ccc2ccccc2n1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: c1ccc(-c2ccc3ccccc3n2)cc1
Reaction time: 0.83 h
Yield: 70.6 %

Procedure:
A solution of phenylmagnesium bromide (1M in THF, 4.2 mL, 4.2 mmol) is added to a solution of 2-chloro-quinoline (300 mg, 1.83 mmol)) and Fe(acac)3 (32 mg, 0.09 mmol) in THF (10 mL) at −30° C. After stirring for 50 min at that temperature, the reaction is quenched with brine, the aqueous layer is extracted with Et2O, the combined organic phases are dried over Na2SO4 and evaporated, and the residue is purified by flash chromatography (hexane/ethyl acetate, 15:1). After eluting a first fraction containing biphenyl (44 mg), one obtains 2-phenyl-quinoline as a colorless solid (265 mg, 71%). 1H NMR (300 MHz, CD2Cl2) δ8.22–8.25 (m, 3H), 8.16 (d, 1H), 7.92 (d, 1H), 7.86 (d, 1H), 7.75 (m, 1H), 7.46–7.57 (m, 4H); 13C NMR (75 MHz, CD2Cl2) δ 157.3, 148.7, 139.9, 137.0, 130.0, 129.7, 129.1, 127.8, 127.7, 127.6, 127.3, 126.8, 119.1.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([OH:12])[CH:6]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:8]=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.CCOCC>C(Cl)Cl>[OH:12][C:5]1[CH:4]=[C:3]([CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:6]=1)[CH:2]=[O:1]
Reactant: CC(C)c1cc(O)cc(CO)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)c1cc(O)cc(C=O)c1
Reaction time: 4.5 h

Procedure:
To a stirring solution of 3-(hydroxymethyl)-5-isopropylphenol in 10 mL of CH2Cl2 was added 1.23 g (5.69 mmol) of PCC. The mixture was stirred for 4.5 h, Et2O was added, and the mixture was stored in a refrigerator. The solvent was concentrated, and the crude product was purified by flash silica gel chromatography (15% EtOAc/hexanes) to provide 218 mg of 3-hydroxy-5-isopropylbenzaldehyde as a pale yellow solid.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.Br[C:10]1[CH:11]=[C:12]2[C:25]3[C:15]([CH2:16][C@@H:17]4[C@@H:22]([C:23]=3[CH:24]=1)[CH2:21][C@H:20]([NH:26][C:27](=[O:33])[N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[CH2:19][N:18]4[CH3:34])=[CH:14][N:13]2[Si](C(C)(C)C)(C)C>>[Cl:1][C:24]1[C:23]2=[C:25]3[C:12]([NH:13][CH:14]=[C:15]3[CH2:16][C@@H:17]3[C@@H:22]2[CH2:21][C@H:20]([NH:26][C:27](=[O:33])[N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[CH2:19][N:18]3[CH3:34])=[CH:11][CH:10]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(Br)cc4c3c(cn4[Si](C)(C)C(C)(C)C)C[C@H]2N(C)C1
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3c(Cl)ccc4[nH]cc(c34)C[C@H]2N(C)C1

Procedure:
With N-chlorosuccinimide and 3-(13-bromo-1-tert-butyldimethylsilyl-6-methyl-8α-ergolinyl)-1 1-diethylurea:
Reaction SMILES: [Al].[O:2]=[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](O[Si](CC)(CC)CC)([C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:4]1>O>[F:14][C:13]([F:15])([F:16])[C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([OH:2])=[CH:4][CH:5]=1
Reactant: CC[Si](CC)(CC)OC1(C(F)(F)F)C=CC(=O)c2ccccc21
Agent: [Al]
Solvent: O
Product: Oc1ccc(C(F)(F)F)c2ccccc12
Temperature: 70 °C
Yield: 89.6 %

Procedure:
A strip of aluminum foil weighing 278 mg (10 mmol) was amalgamated by immersion in a solution of 2% mercuric chloride in water for 15 seconds, washed with absolute ethanol followed by diethyl ether, cut into small pieces, and added to a solution of 353 mg (1.0 mmol) of 1,4-dihydro-1-oxo-4-triethylsiloxy-4-trifluoromethylnaphthalene in 10 mL of 10% water - 90% tetrahydrofuran. The resulting mixture was heated at 70° C. for 1.5 hours, allowed to cool to room temperature, and filtered. The filter cake was washed with diethyl ether. Concentration of the combined filtrates gave a residue which was poured into 25 mL of water. The aqueous mixture was extracted with three 10 mL portions of dichloromethane. Combination, drying (MgSO4), and concentration of the organic layers gave a residue which was purified by PTLC (one 2 mm silica gel plate eluted with dichloromethane), affording 190 mg (90% yield) of 4-trifluoromethyl-1-naphthol as a white solid. An analytical sample was obtained by recrystallization from dichloromethane-hexane: mp 132°-133° C.; 1H NMR (CDCl3) δ 5.50 (broad s, 1H), 6.79 (d, 1H, J=8 Hz), 7.50-7.80 (m, 3H), 8.10-8.45 (m, 2H); 19F NMR (CDCl3, relative to CFCl3) -59.5 ppm (s); IR (KBr) 3327, 1580, 1385, 1355, 1327, 1260, 1251, 1241, 1195, 1178, 1146, 1120, 1111, 1101, 1056, 767, cm-1 ; mass spectrum (70 eV) m/z (relative intensity) 212 (100, M+), 133 (32), 115 (100). Anal. Calcd. for C11H7F3O: C, 62.27; H, 3.33. Found: C, 61.82; H, 3.50.