Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([C:10]([O-:12])=O)=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Li+].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:38][C:39]1[CH:40]=[C:41]([S:45]([NH2:48])(=[O:47])=[O:46])[CH:42]=[CH:43][CH:44]=1>CN(C=O)C.O>[C:1]([C:5]1[S:9][C:8]([C:10]([NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([S:45](=[O:47])(=[O:46])[NH2:48])[CH:40]=2)=[O:12])=[N:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1nnc(C(=O)[O-])s1
Reactant: Nc1cccc(S(N)(=O)=O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1nnc(C(=O)Nc2cccc(S(N)(=O)=O)c2)s1
Reaction time: 4 h
Yield: 31.4 %

Procedure:
A solution of lithium 5-tert-butyl-1,3,4-thiadiazole-2-carboxylate (0.2 g, 1 mmol) and HATU (0.38 g, 1.0 mmol) in DMF (5 mL) was stirred at room temperature for 10 minutes, then 3-amino-benzenesulfonamide (0. 17 g, 1.0 mmol) was added. The reaction was stirred for four hours, diluted with water, and extracted with ethyl acetate. The combined extracts were washed with brine and water, dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel with 0-5% methanol in dichloromethane to give 5-tert-butyl-N-(3-sulfamoylphenyl)-1,3,4-thiadiazole-2-carboxamide (107 mg, 31% yield). LC/MS: m/z 341.1 (M+H)+ at 2.79 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:10][CH2:11][C:12]1[CH2:13][S:14][C@@H:15]2[C@H:22]([NH:23][C:24](=[O:34])/[C:25](/[C:29]3[O:30][CH:31]=[CH:32][CH:33]=3)=[N:26]\[O:27][CH3:28])[C:21](=[O:35])[N:16]2[C:17]=1[C:18]([OH:20])=[O:19])(=[O:9])[NH2:8].[C:36]([O:39][CH:40](Br)[CH3:41])(=[O:38])[CH3:37].Cl>CN(C)C=O.C(OCC)(=O)C>[C:7]([O:10][CH2:11][C:12]1[CH2:13][S:14][C@@H:15]2[C@H:22]([NH:23][C:24](=[O:34])/[C:25](/[C:29]3[O:30][CH:31]=[CH:32][CH:33]=3)=[N:26]\[O:27][CH3:28])[C:21](=[O:35])[N:16]2[C:17]=1[C:18]([O:20][CH:40]([O:39][C:36](=[O:38])[CH3:37])[CH3:41])=[O:19])(=[O:9])[NH2:8]
Reactant: CC(=O)OC(C)Br
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1ccco1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(C)OC(C)=O)=C(COC(N)=O)CS[C@H]12)c1ccco1
Reaction time: 0.42 h

Procedure:
Potassium carbonate (760 mg, 5.5 mmole) was added to a solution of (6R,7R)-3-carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylic acid (4.57 g, 11 mmole) in N,N-dimethylformamide (25 ml) and the mixture was stirred at ca 20° for 25 minutes. 1-Bromoethyl acetate (1.8 g, 11 mmole) in N,N-dimethylformamide (5 ml) was added to the above solution and the reaction mixture was stirred for 40 minutes at ca 20°. The reaction mixture was worked up by pouring it into excess 2 N hydrochloric acid, followed by extraction with ethyl acetate (3 times). The combined organic extracts were washed with 2 N hydrochloric acid and saturated sodium bicarbonate solution, dried (magnesium sulphate) and evaporated in vacuo to yield a foam which was dissolved in ethyl acetate and precipitated from ether.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1/[C:18](=[N:22]/[OH:23])/[C:19]([OH:21])=[O:20].C(Br)(Br)Br>CS(C)=O>[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1/[C:18](=[N:22]/[O:23][CH2:2][C:3](=[O:4])[NH:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)/[C:19]([OH:21])=[O:20]
Reactant: O=C(O)/C(=N\O)c1ccco1
Reactant: O=C(CCl)NOc1ccccc1
Solvent: BrC(Br)Br
Solvent: CS(C)=O
Product: O=C(CO/N=C(\C(=O)O)c1ccco1)NOc1ccccc1
Yield: 50 %

Procedure:
This compound was prepared as described in Preparation 4 from phenyl chloroacetohydroxamate and Z-2-(fur-2-yl)-2-hydroxyiminoacetic acid. νmax (CHBr3) 3350 (NH), 3700-2100 (bonded OH), 1754, 1725 (--CO2H), 1705, 1680 cm-1 (--CONH--), τ(DMSO d6) 2.05, 3.11, 3.29 (furyl), 5.3 (--OCH2CO--), 2.4-3.1 (phenyl). Yield 50%.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C@@H:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])[CH2:13][CH2:12]2)=[C:7]2[C:3]=1[C:4](=[O:37])[N:5]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)[C:6]2=[O:25].C([O-])(=O)C.[Na+].[CH3:43][S:44]([CH:47]=[CH2:48])(=[O:46])=[O:45]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.CC(N(C)C)=O>[CH3:36][O:35][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[O:33][CH3:34])[CH2:26][N:5]1[C:4](=[O:37])[C:3]2[C:7](=[C:8]([N:11]3[CH2:12][CH2:13][N:14]([C@@H:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH3:18])[CH2:15][CH2:16]3)[CH:9]=[CH:10][C:2]=2[CH:48]=[CH:47][S:44]([CH3:43])(=[O:46])=[O:45])[C:6]1=[O:25]
Reactant: COc1ccc(CN2C(=O)c3c(Cl)ccc(N4CCN([C@H](C)c5ccccc5)CC4)c3C2=O)cc1OC
Reactant: C=CS(C)(=O)=O
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(CN2C(=O)c3c(C=CS(C)(=O)=O)ccc(N4CCN([C@H](C)c5ccccc5)CC4)c3C2=O)cc1OC
Temperature: 150 °C
Yield: 19.4 %

Procedure:
A 10 mL sealed tube was charged with Compound 10 (100.0 mg, 0.19 mmol), sodium acetate (22.0 mg, 0.27 mmol), bis(tri-t-butylphosphine)palladium (0) (13.0 mg, 0.03 mmol), methyl vinylsulfone (0.02 ml, 0.23 mmol), and dimethylacetamide (1.0 mL). The tube was charge with argon and sealed. The mixture was heated at 150° C. for 24 h. The mixture was cooled to room temperature and purified via flash chromatography (230-400 mesh silica gel 60, gradient 90:10-50:50 hexanes:ethyl acetate) to give 21.7 mg (19%) of Compound 62 as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.44 (d, J=15.6, 1 H), 7.48-7.53 (m, 5 H), 7.01-7.08 (m, 3 H), 6.70-6.90 (m, 3 H), 4.64 (s, 2 H), 4.42 (q, J=6.9 Hz, 1 H), 3.94 (s, 3 H), 3.86 (s, 3 H), 3.33-3.80 (m, 8 H), 3.07 (s, 3 H), and 1.86 (d, J=6.7 Hz, 3 H); MS (ES+) 590 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH:3]=[CH:4][C:5]#[N:6].C(N(CC)CC)C.[F:15][C:16]1[C:24]([F:25])=[C:23]([F:26])[C:22]([F:27])=[CH:21][C:17]=1[C:18](Cl)=[O:19]>O1CCOCC1>[CH3:1][N:2]([CH3:7])[CH:3]=[C:4]([C:18](=[O:19])[C:17]1[CH:21]=[C:22]([F:27])[C:23]([F:26])=[C:24]([F:25])[C:16]=1[F:15])[C:5]#[N:6]
Reactant: CN(C)C=CC#N
Reactant: O=C(Cl)c1cc(F)c(F)c(F)c1F
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CN(C)C=C(C#N)C(=O)c1cc(F)c(F)c(F)c1F

Procedure:
First 9.7 g of 3-dimethylaminoacrylonitrile are added dropwise, then 10.5 g of triethylamine are added to a solution of 21.25 g of 2,3,4,5-tetrafluorobenzoyl chloride in 75 ml of anhydrous dioxane, while cooling in ice and stirring at about 10°-15° C. The mixture is heated to boiling under reflux for 4 hours, the solvent is removed by distillation in vacuo, and the residue is taken up in methylene chloride/water. The phases are separated, and the aqueous solution is again extracted with methylene chloride. The combined organic phases are washed with water, dried with sodium sulphate, and the methylene chloride is removed in vacuo. After recrystallization of the crystalline residue from ethanol, 23.5 g of 3-dimethylamino-2-(2,3,4,5-tetrafluorobenzoyl)acrylonitrile of melting point 149°-151° C. are obtained.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[CH3:12][O:13][C:14](=[O:18])[C@@H:15]([CH3:17])[NH2:16].C(N(CC)CC)C>CO>[CH3:12][O:13][C:14](=[O:18])[C@@H:15]([CH3:17])[NH:16][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)[C@@H](C)N
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)[C@@H](C)Nc1ncccc1[N+](=O)[O-]
Yield: 5.9 %

Procedure:
A suspension of 2-chloro-3-nitropyridine (37.76 g, 0.239 mole), (R)-alanine methyl ester hydrochloride (50 g, 0.358 mole) and triethylamine (60.3 g, 0.597 mole) in methanol (370 ml) was refluxed overnight under nitrogen. The solvents were removed under reduced pressure and the resulting solid was triturated in ethyl acetate (300 ml), filtered, and rinsed with additional ethyl acetate. The filtrate and washings were combined and washed once with water. The aqueous wash was extracted with ethyl acetate and the combined organic layers were washed several times with water, dried over sodium sulfate, filtered and evaporated under reduced pressure to give an oil weighing 45.6 g (85%). Elution of a portion of the oil with 1:6 tetrahydrofuran/hexane through a silica gel column gave 3.2 g of product after evaporation of solvent. Drying of a portion of the solid under high vacuum at room temperature gave 0.98 g of title compound, mp 39°-40° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:10]2[C:24]([O:26]CC)=[O:25])=[CH:5][CH:4]=1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC.Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:10]2[C:24]([OH:26])=[O:25])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccccc2C1c1ccc(OC)cc1
Agent: CC[SiH](CC)CC
Agent: Cl
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc(C2c3ccccc3C(c3ccccc3)C2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
Ethyl (RS)-1-(4-Methoxyphenyl)-3-phenylindene-2-carboxylate. To a solution of ethyl (1RS) [1-hydroxy-1-(4-methoxyphenyl)]-3-phenylindene-2-carboxylate (4.65 g, 12.0 mmol) in CH2Cl2 (40 ml) at 0° C. under an argon atmosphere was added triethylsilane (2.34 ml, 14.6 mmol), followed by boron trifluoride etherate (8.8 ml, 71 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 10 min, at which time was added slowly 3M HCl (50 ml). The mixture was extracted with EtOAc (150 ml). The organic extract was washed successively with H2O, aqueous NaHCO3, H2O and saturated aqueous NaCl and dried. The solvent was removed in vacuo, and the residue was purified by flash chromatography on silica gel, eluting with 10% EtOAc/ hexanes to provide the title compound (4.2 g, 95%) as a mixture of Δ1 and Δ2 double bond isomers.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[C:9]2[N:4]([C:5](=[S:11])[NH:6][CH2:7][CH2:8]2)[N:3]=1.I[CH3:13]>[OH-].[Na+]>[CH3:1][C:2]1[N:10]=[C:9]2[N:4]([C:5]([S:11][CH3:13])=[N:6][CH2:7][CH2:8]2)[N:3]=1
Reactant: CI
Reactant: Cc1nc2n(n1)C(=S)NCC2
Agent: [Na+]
Agent: [OH-]
Product: CSC1=NCCc2nc(C)nn21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 505 mg (3 mmol) of 2-methyl-7,8-dihydro[1,2,4]triazolo[1,5-c]pyrimidine-5(6H)-thione in 12 mL of 50% sodium hydroxide (aqueous) was treated with 0.187 mL (426 mg, 3.3 mmol) of iodomethane. The mixture was stirred vigorously at room temperature in a stoppered flask. After 2 h, the mixture was partitioned between 25 mL of dichloromethane and 12 mL of water (CAUTION: exotherm upon addition of water). The organic phase was separated, and the aqueous phase was re-extracted with an additional 5 mL of dichloromethane. The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated to dryness. The residue was flash chromatographed on silica gel (99:1 dichloromethane:methanol) to yield the title compound as white crystals, mp 75.5-76.5° C. LC-MS 183 (M+1).
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[CH:9]=[C:8]([NH:12][NH2:13])[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:6]1=[O:23])[CH2:2][CH2:3][CH3:4].[CH3:24][N:25]=[C:26]=S.C(O)C>CN(C=O)C>[CH2:1]([N:5]1[C:10](=[O:11])[C:9]2[C:24]([NH:25][CH3:26])=[N:13][NH:12][C:8]=2[N:7]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[C:6]1=[O:23])[CH2:2][CH2:3][CH3:4]
Reactant: CN=C=S
Reactant: CCCCn1c(=O)cc(NN)n(Cc2ccc(OC)cc2)c1=O
Solvent: CN(C)C=O
Solvent: CCO
Product: CCCCn1c(=O)c2c(NC)n[nH]c2n(Cc2ccc(OC)cc2)c1=O
Yield: 53 %

Procedure:
A solution of 3-butyl-6-hydrazino-1-(4-methoxybenzyl)-uracil (2.0 g, 6.3 mM) and methyl isothiocyanate (1.36 ml, 20 mM) in DMF (20 ml) was stirred at 120° C. for 20 hours. To the solution was added ethanol (20 ml) and the mixture was cooled to give crude crystals. Recrystallization from DMF/ethanol gave colorless crystals (1.2 g, 53%), m.p. 292°-294° C.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH2:13][NH:12][CH2:11][CH2:10]2.CO>ClCCl>[CH2:13]1[C:14]2[C:9](=[CH:8][C:7]([OH:6])=[CH:16][CH:15]=2)[CH2:10][CH2:11][NH:12]1
Reactant: COc1ccc2c(c1)CCNC2
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: Oc1ccc2c(c1)CCNC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of boron tribromide (1.2 mL, 12.5 mmol) in dichloromethane (12.5 mL) was added dropwise to a −78° C. solution of 6-methoxytetrahydroisoquinoline (1.0 g, 5.0 mol, prepared as described in Org. Synth 1988, 67, 60) in dichloromethane (38 mL) The mixture was stirred for 1 hour, warmed to 0° C., stirred for 1 hour, warmed to room temperature, and stirred for 1 hour. The mixture was cooled to −78° C., treated dropwise with methanol (20 mL), warmed to room temperature, stirred for 1 hour, and concentrated to provide the desired product.
Reaction SMILES: [CH:1]1([CH2:6][N:7]([CH2:33][CH3:34])[C:8]2[N:13]=[C:12]3[N:14]([CH3:18])[N:15]=[C:16]([CH3:17])[C:11]3=[CH:10][C:9]=2[CH2:19][N:20]([CH2:23][C:24]2[CH:29]=[C:28]([F:30])[C:27]([F:31])=[C:26]([F:32])[CH:25]=2)[C:21]#[N:22])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[NH4+].[N-:37]=[N+:38]=[N-:39].[Na+]>CN(C=O)C>[CH:1]1([CH2:6][N:7]([CH2:33][CH3:34])[C:8]2[N:13]=[C:12]3[N:14]([CH3:18])[N:15]=[C:16]([CH3:17])[C:11]3=[CH:10][C:9]=2[CH2:19][N:20]([CH2:23][C:24]2[CH:29]=[C:28]([F:30])[C:27]([F:31])=[C:26]([F:32])[CH:25]=2)[C:21]2[NH:39][N:38]=[N:37][N:22]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [N-]=[N+]=[N-]
Reactant: CCN(CC1CCCC1)c1nc2c(cc1CN(C#N)Cc1cc(F)c(F)c(F)c1)c(C)nn2C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC1CCCC1)c1nc2c(cc1CN(Cc1cc(F)c(F)c(F)c1)c1nnn[nH]1)c(C)nn2C
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a stirred suspension of [6-(cyclopentylmethyl-ethyl-amino)-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-ylmethyl-(3,4,5-trifluoro-benzyl)-cyanamide (0.280 g, 0.590 mmol) and ammonium chloride (0.160 g, 2.95 mmol) in dry DMF (10 mL) was added sodium azide (0.195 g, 2.95 mmol) and the reaction mixture was heated at 100° C. overnight. After the reaction mixture was cooled to RT, ice water was added, and this mixture was stirred for 30 min, and then extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate and evaporated to yield the product as oil (yield: 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:63]([CH:70]1[CH2:74][CH2:73][CH2:72][NH:71]1)[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:71]1[CH2:72][CH2:73][CH2:74][CH:70]1[CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: c1ccc(CC2CCCN2)cc1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(Nc1ncnc2cc(C(=O)N3CCCC3Cc3ccccc3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 2-benzyl-pyrrolidine in DMSO at ambient temperature.
Reaction SMILES: Cl.[CH3:2][S:3]([N:6]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:8]2([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:7]1)(=[O:5])=[O:4].[OH-].[Na+].[CH2:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH:23]1[NH:31][C:32](=O)[O:33]C1C=CC=CC=1.O>CS(C)=O>[CH2:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:22][CH:23]1[NH:31][C:32]([N:11]1[CH2:10][CH2:9][C:8]2([C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:6]([S:3]([CH3:2])(=[O:4])=[O:5])[CH2:7]2)[CH2:13][CH2:12]1)=[O:33]
Reactant: CS(=O)(=O)N1CC2(CCNCC2)c2ccccc21
Reactant: O=C(NC1Cc2ccccc2C1)Oc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CS(=O)(=O)N1CC2(CCN(C(=O)NC3Cc4ccccc4C3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
1-Methanesulfonylspiro[indoline-3,4′-piperidine]hydrochloride (60 mg) and 10M aqueous sodium hydroxide (33 μL) were added to a solution of phenyl N-(2-indanyl)carbamate (50 mg) in dimethyl sulfoxide (2 mL), and the mixture was stirred at room temperature for one hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was washed with ethyl acetate to give the title compound (65 mg) as a colorless crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH:34]([CH3:36])[CH3:35])([C:30](OC)=O)[CH2:12][CH2:13][CH2:14][CH:15]2[CH2:24][C:23]3[C:18](=[CH:19][C:20]([O:27][CH3:28])=[C:21]([O:25][CH3:26])[CH:22]=3)[CH2:17][N:16]2[CH3:29])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1(C)C(C)=CC=CC=1.[Al]([NH2:48])(C)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH:34]([CH3:35])[CH3:36])([C:30]#[N:48])[CH2:12][CH2:13][CH2:14][CH:15]2[CH2:24][C:23]3[C:18](=[CH:19][C:20]([O:27][CH3:28])=[C:21]([O:25][CH3:26])[CH:22]=3)[CH2:17][N:16]2[CH3:29])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)C(CCCC1Cc2cc(OC)c(OC)cc2CN1C)(c1ccc(OC)c(OC)c1)C(C)C
Reactant: C[Al](C)N
Solvent: ClCCl
Solvent: Cc1ccccc1C
Product: COc1ccc(C(C#N)(CCCC2Cc3cc(OC)c(OC)cc3CN2C)C(C)C)cc1OC

Procedure:
Alternatively, one may convert the ester group of compound 11.1 directly to the cyano group by treatment with 2 equivalents of dimethylaluminum amide (S. Weinreb, et al., Tetrahedron Lett., 4907 (1979), incorporated herein by reference). This reaction is performed in a suitable aprotic hydrocarbon solvent, preferably a high-boiling solvent such as xylene. Two equivalents of Me2AlNH2 in CH2Cl2 is added to a solution of the ester of formula 11.1 in the appropriate solvent and heated at 80°-170° C., preferably in refluxing xylene, for about 30 minutes to about 20 hours. The reaction is followed by TLC. For example, 3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-(carbomethoxy)butyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline (11.1) is heated in refluxing xylene with Me2AlNH2 for about 15 hours to yield 3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline (1).
Reaction SMILES: [CH3:1][CH:2]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:3]([NH:5][CH2:6][C:7]1([CH3:19])[CH2:11][CH2:10][N:9](CC2C=CC=CC=2)[CH2:8]1)=[O:4].[H][H]>CO.[Pd]>[CH3:1][CH:2]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:3]([NH:5][CH2:6][C:7]1([CH3:19])[CH2:11][CH2:10][NH:9][CH2:8]1)=[O:4]
Reactant: [H][H]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)NCC1(C)CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(NC(=O)OC(C)(C)C)C(=O)NCC1(C)CCNC1
Yield: 96.7 %

Procedure:
A solution of 23.1 g (61.6 mmol) of [1-methyl-2-[[(3-methyl-1-(phenylmethyl)-3-pyrrolidinyl)methyl]-amino]-2-oxoethyl]carbamic acid, 1,1-dimethylethyl ester in 400 ml of methanol was treated with 3.0 g of 20% palladium on carbon and shaken in a hydrogen atmosphere at temperatures of 22°-26° and pressures of 48.7-53.4 psi for 2.5 hours. The catalyst was removed by filtering through celite and the filtrate was evaporated in vacuo to give 17.0 g of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:15]3[N:14]=2)=[CH:6][C:5]([F:27])=[CH:4][N:3]=1.[CH2:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:29]#[CH:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NC(C)C)(C)C>CN(C=O)C.[Cu]I>[C:34]([O:33][C:32]([NH:31][CH2:28][C:29]#[C:30][C:2]1[C:7]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:15]3[N:14]=2)=[CH:6][C:5]([F:27])=[CH:4][N:3]=1)=[O:38])([CH3:37])([CH3:36])[CH3:35]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cnc3Cl)nc12
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cnc3C#CCNC(=O)OC(C)(C)C)nc12
Temperature: 95 °C

Procedure:
(R)-ethyl 5-(2-(2-chloro-5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (Example 12, Step C; 153 mg, 0.392 mmol) in DMF (2 mL) was added tert-butyl prop-2-ynylcarbamate (122 mg, 0.785 mmol), copper(I) iodide (11 mg, 0.0578 mmol), triphenylphosphine (82.4 mg, 0.314 mmol), di-triphenylphosphine palladium(II) chloride (116 mg, 0.165 mmol), and diisopropylamine (99.3 mg, 0.981 mmol). The reaction mixture was sealed and heated to 95° C. for 8 hours, then cooled to ambient temperature and concentrated under reduced pressure The residue was purified by silica column chromatography, eluting with 33% EtOAc/Hexanes to afford the final product mixed with Ph3P (160 mg, 80.2% yield). MS (apci) m/z=508.9 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[C:5]1[C:10]([NH2:11])=[CH:9][CH:8]=[C:7]([C:12]2[CH2:16][CH2:15][CH2:14][C:13]=2[C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=2[O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=1)[CH3:2].[C:33](Cl)(=[O:35])[CH3:34]>>[CH2:1]([O:3][C:4](=[O:32])[C:5]1[C:10]([NH:11][C:33](=[O:35])[CH3:34])=[CH:9][CH:8]=[C:7]([C:12]2[CH2:16][CH2:15][CH2:14][C:13]=2[C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=2[O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(C2=C(c3cc(C)ccc3OCc3ccccc3)CCC2)ccc1N
Reactant: CC(=O)Cl
Product: CCOC(=O)c1cc(C2=C(c3cc(C)ccc3OCc3ccccc3)CCC2)ccc1NC(C)=O

Procedure:
Prepared by general procedure E but using 3-{2-[5-methyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-6-aminobenzoic acid ethyl ester and acetyl chloride.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH:11]=[O:12].[CH:18]1(Br)[CH2:22][CH2:21][CH2:20][CH2:19]1>CN(C=O)C>[CH:18]1([O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[CH:11]=[O:12])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COc1ccc(C=O)cc1O
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.4 %

Procedure:
Cs2CO3 (214 g, 0.66 mol) was added to a mixture of 3-hydroxy-4-methoxybenzaldehyde (100 g, 0.66 mol) and cyclopentyl bromide (98 g, 0.66 mol) in anhydrous DMF (500 ml). The reaction mixture was stirred at RT for 16 h then treated with a further portion of cyclopentyl bromide (98 g, 0.66 mol) and Cs2CO3 (214 g, 0.66 mol). After a further 6 h at RT, the mixture was filtered and concentrated in vacuo. The residue was dissolved in CH2Cl2 (300 ml) and washed with NaOH solution (10%; 2×150 ml). The organic layer was dried (MgSO4), concentrated in vacuo, and distilled (150° C., 10-2 mbar) to afford the title compound (130 g) as a viscous colourless oil. δH (CDCl3) 1.5-2.0 (8H, br m, CH2)4), 3.87 (3H, s, OMe), 4.80 (1H, br m, OCHCH2), 6.90 (1H, d, J 8.7 Hz, ArH ortho to OMe), 7.30-7.45 (2H, m, 2×ArH meta to OMe), and 9.77 (1H, s, ArCHO).