Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].CC([O-])(C)C.[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>CC(O)(C)C>[CH3:13][C:12]([O:11][C:1](=[O:10])[CH:2]([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH3:23])[C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])([CH3:15])[CH3:14]
Reactant: CCCCCCCCCCCCCCBr
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCCCCCCCCCCCCCC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 75 °C
Reaction time: 8 h
Yield: 48.5 %

Procedure:
A suspension of di-tert butyl malonate (10.80 g, 50 mmol) and t-BuOK (5.60 g, 50 mmol) was stirred (30 min, 75° C.) in t-BuOH (150 mL, dried over 4A sieves). To this was added a solution of 1-bromotetradecane (13.85 g, 50 mmol) and the reaction stirred at 75° C. overnight. Solvent was removed by rotary evaporation, giving a white semi-solid, which was partitioned between CH2Cl2 (100 mL) and saturated aqueous NaCl (2×300 mL), dried (MgSO4) and evaporated to a colorless oil (15.3 g). Purification by silica gel flash chromatography (100% hexane incremented to hexane:CH2Cl2 (70:30)) gave product (34) as a colorless oil (10.0 g, 48%). High resolution FAB MS:C25H49O4 (M+H); Theor. 413.3630855. Found 413.3627625.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:15].S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N+:3]=1[O-:15]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(C#N)cn1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C#N)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Methylnicotinonitrile (3.68 g, 31.15 mmol) is dissolved in chloroform (60 ml). 3-Chloroperoxybenzoic acid (7.53 g, 32.71 mmol) is added dropwise as a solution in chloroform (60 ml), and the solution is stirred at room temperature overnight. Sodium sulphite (2.92 g, 23.17 mmol) is added, and the resulting mixture is stirred for one hour. The reaction is quenched with saturated sodium bicarbonate solution, and the product is extracted with chloroform (500 ml). The organic phase is washed with brine, dried over magnesium sulphate monohydrate, filtered and concentrated in vacuo. The residue is used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].CC1(C)C(C)(C)OB([C:26]2[CH:27]=[C:28]([S:32]([N:35]3[CH2:40][CH2:39][CH:38]([OH:41])[CH2:37][CH2:36]3)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=2)O1>>[NH2:1][C:2]1[N:16]=[CH:15][C:14]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([S:32]([N:35]3[CH2:40][CH2:39][CH:38]([OH:41])[CH2:37][CH2:36]3)(=[O:34])=[O:33])[CH:27]=2)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Reactant: CC1(C)OB(c2cccc(S(=O)(=O)N3CCC(O)CC3)c2)OC1(C)C
Product: Nc1ncc(-c2cccc(S(=O)(=O)N3CCC(O)CC3)c2)cc1C(=O)Nc1ccncc1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with 1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzenesulfonyl]-piperidin-4-ol gives “A79”; method 1: HPLC/MS: 1.29 min, [M+H]=454;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6](=[O:12])[C:5]2=[O:13].N1C2C(=CC=CC=2)C(=O)C1=O.[F:25][CH:26]([F:36])[CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1I>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6](=[O:12])[C:5]2([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[O:28][CH2:27][CH:26]([F:25])[F:36])[OH:13]
Reactant: FC(F)COc1ccccc1I
Reactant: O=C1Nc2cc(F)c(Cl)cc2C1=O
Agent: O=C1Nc2ccccc2C1=O
Product: O=C1Nc2cc(F)c(Cl)cc2C1(O)c1ccccc1OCC(F)F

Procedure:
The title compound was prepared in analogy to example a.1 using 5-chloro-6-fluoro-isatin as isatin II and 2,2-difluoroethoxyiodobenzene (to form the Grignard reagent).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10](=O)[CH2:11][CH:12](OC)[C:13]([O:15]C)=O)[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].O.[NH2:21][NH2:22].Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13](=[O:15])[NH:21][N:22]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8]
Reactant: NN
Reactant: COC(=O)C(CC(=O)c1cc(Cl)c(C)c(Cl)c1)OC
Agent: Cl
Solvent: O
Solvent: CO
Product: Cc1c(Cl)cc(-c2ccc(=O)[nH]n2)cc1Cl
Yield: 70.6 %

Procedure:
A mixture of 3.05 g (0.01 mole) of methyl 4-(3,5-dichloro-4-methylphenyl)-2-methoxy-4-oxobutyrate, 0.6 g (0.012 mole) of hydrazine monohydrate and 30 ml of methanol was heated under reflux for 3.5 hours. 1.1 ml of concentrated hydrochloric acid was then added to the mixture, after which it was again heated under reflux for a further 6 hours. At the end of this time, the solvent was distilled off and the residue was washed, in turn, with water and with a small amount of diethyl ether, after which it was dried to give 1.80 g of the desired product. The washings were extracted with ethyl acetate and the extract was dried over anhydrous sodium sulphate, after which the organic solvent was distilled off. The residue was washed in turn with benzene and with diethyl ether, to give a further 0.11 g of the desired product. The total yield of 6-(3,5-dichloro-4-methylphenyl)-3(2H)pyridazinone was 1.91 g (74.9%) and the properties of the product were identical with those of the products of Examples 1(d), 2 and 3.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[CH2:19]1[O:21][CH2:20]1>C1COCC1.CCOCC>[CH:1]1[C:13]2[CH:12]([CH2:19][CH2:20][OH:21])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: C1CO1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.5 %

Procedure:
To a stirred, cooled (-78° C.) solution of 6.00 g (36.1 mmol) of fluorene in 75 mL of THF was added 15.4 mL (36.2 mmol) of 2.35 M n-BuLi in hexanes dropwise. The resulting dark orange mixture was stirred for 1.5 h and 26.0 mL (36.4 mmol) of 1.4 M ethylene oxide in Et2O was added. The resulting bright orange mixture was warmed slowly to room temperature over 3.5 h, quenched with saturated aqueous NH4Cl and concentrated at reduced pressure. The residue was poured into water and extracted twice with Et2O. The combined organic layers were washed with brine and dried over magnesium sulfate. Solvent was removed at reduced pressure and the crude product was chromatographed on 150 g of flash silica gel eluting with 25% EtOAc in hexane to afford 5.05 g (67%) of the desired alcohol as a white solid, mp 98°-99° C.
Reaction SMILES: C([Mg]Cl)(C)C.[CH2:6]([CH:9]([CH2:20][CH:21]=[CH2:22])[CH2:10][O:11][SiH2:12][C:13]1[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=1)[CH:7]=[CH2:8].C(C(CC=C)[CH2:27][O:28][SiH2]C1C=CC([Mg]Cl)=CC=1)C=C.CN(C=O)C.Cl>C1COCC1>[CH2:6]([CH:9]([CH2:20][CH:21]=[CH2:22])[CH2:10][O:11][SiH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH:27]=[O:28])=[CH:15][CH:14]=1)[CH:7]=[CH2:8]
Reactant: C=CCC(CC=C)CO[SiH2]c1ccc([Mg]Cl)cc1
Reactant: C=CCC(CC=C)CO[SiH2]c1ccc(I)cc1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=CCC(CC=C)CO[SiH2]c1ccc(C=O)cc1
Yield: 85 %

Procedure:
Firstly, i-PrMgCl (0.71 mL, 2 M in THF, 1.42 mmol) was added dropwise to a THF solution (2 mL) of 4-(diallylethoxysilyl)iodobenzene (255 mg, 0.71 mmol) obtained in Synthesis example 7 at −30° C. The resultant mixture was stirred under a nitrogen atmosphere at −30° C. for 1.5 hours to obtain a solution containing 4-(diallylethoxysilyl)phenylmagnesium chloride (Grignard solution). Then, DMF (110 μL, 1.42 mmol) was added dropwise to the obtained solution at −30° C., and the resultant mixture was stirred under a nitrogen atmosphere at room temperature for 13 hours to obtain a reaction mixture. Subsequently, an aqueous solution of HCl of 10% by mass was added to the reaction mixture to cease the reaction. After that, an organic layer was separated from the reaction mixture, and an aqueous layer was extracted with ether. The organic layer thus collected was washed with sat. NaHCO3 and sat. NaCl, and dried with MgSO4. The dried organic layer was filtered and concentrated to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (hexane/EtOAc=20/1) to obtain 4-(diallylethoxysilyl)benzaldehyde (158 mg, 85% yield).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([NH:13][C@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:15]2=[O:26])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Cl:27][C:28]1[CH:33]=[N:32][C:31](Cl)=[CH:30][N:29]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:2][C:3]1[C:4]([NH:13][C@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([CH:20]3[CH2:21][CH2:22][N:23]([C:31]4[CH:30]=[N:29][C:28]([Cl:27])=[CH:33][N:32]=4)[CH2:24][CH2:25]3)[C:15]2=[O:26])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Clc1cnc(Cl)cn1
Reactant: O=C1[C@@H](Nc2ncc(C(F)(F)F)cc2Cl)CCCN1C1CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1[C@@H](Nc2ncc(C(F)(F)F)cc2Cl)CCCN1C1CCN(c2cnc(Cl)cn2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 42.2 %

Procedure:
A flask was charged with (S)-3-(3-chloro-5-(trifluoromethyl)pyridin-2-ylamino)-1,4′-bipiperidin-2-one hydrochloride (0.075 g, 0.18 mmol), 2,5-dichloropyrazine (0.030 g, 0.20 mmol), Hunig's base (0.095 mL, 0.54 mmol), and DMF (3 mL). The reaction was stirred at 100° C. overnight. The organic solvents were removed under reduced pressure. The residue was purified using silica gel column chromatography with 50-100% ethyl acetate in hexanes to provide (S)-3-(3-chloro-5-(trifluoromethyl)pyridin-2-ylamino)-1′-(5-chloropyrazin-2-yl)-[1,4′-bipiperidin]-2-one (0.037 g, 0.076 mmol, 42% yield) as yellow solid. Mass spectrum (apci) m/z=489.2 (M+H).
Reaction SMILES: [CH2:1]([N:3]([CH3:17])[S:4]([C:7]1[CH:8]=[N:9][C:10]([Sn](C)(C)C)=[CH:11][CH:12]=1)(=[O:6])=[O:5])[CH3:2].[NH2:18][C:19]1[C:24]([C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[C:31](=[O:35])[NH:30][CH2:29][CH2:28]3)=[CH:23][C:22](Br)=[CH:21][N:20]=1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:18][C:19]1[N:20]=[CH:21][C:22]([C:10]2[CH:11]=[CH:12][C:7]([S:4]([N:3]([CH2:1][CH3:2])[CH3:17])(=[O:6])=[O:5])=[CH:8][N:9]=2)=[CH:23][C:24]=1[C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[C:31](=[O:35])[NH:30][CH2:29][CH2:28]2
Reactant: CCN(C)S(=O)(=O)c1ccc([Sn](C)(C)C)nc1
Reactant: Nc1ncc(Br)cc1-c1ccc2c(c1)CCNC2=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCN(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3ccc4c(c3)CCNC4=O)c2)nc1
Temperature: 90 °C
Yield: 51 %

Procedure:
A mixture of N-ethyl-N-methyl-6-(trimethylstannyl)pyridine-3-sulfonamide (225 mg, 0.6 mmol) and 6-(2-amino-5-bromopyridin-3-yl)-3,4-dihydroisoquinolin-1(2H)-one (190 mg, 0.6 mmol) and Pd(PPh3)4 (34 mg, 0.03 mmol) in dioxane (3 mL) was degassed and heated to 90° C. At completion, the reaction was cooled to room temperature and concentrated. The residue was purified by flash chromatography over silica gel to provide 6′-amino-N-ethyl-N-methyl-5′-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-[2,3′-bipyridine]-5-sulfonamide as a yellow solid (134 mg, 50% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.88 (dd, J=17.9, 2.1 Hz, 2H), 8.17-8.22 (m, 1H), 8.10-8.16 (m, 2H), 7.94 (d, J=7.8 Hz, 2H), 7.43-7.51 (m, 2H), 3.41 (s, 2H), 3.30 (s, 3H), 2.97 (t, J=6.4 Hz, 2H), 0.86 (t, J=7.3 Hz, 3H); MS (EI) m/z=438.5 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:18])[CH:14]=3)[C:9]2=[O:19])[CH:5]=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[NH:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1.O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:19])[N:8]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:29]3[CH:30]=[N:26][NH:27][CH:28]=3)[CH:3]=1)[CH2:17][CH2:16]2
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: O=C1c2ccc(Cl)cc2CCN1c1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C1c2ccc(Cl)cc2CCN1c1cncc(-c2cn[nH]c2)c1
Yield: 27.7 %

Procedure:
2-(5-Bromo-pyridin-3-yl)-6-chloro-3,4-dihydro-2H-isoquinolin-1-one (example 7) (34 mg, 0.1 mmol), Pd(PPh3)4 (5.8 mg, 0.005 mmol), K2CO3 (27.6 mg, 0.2 mmol) and 1H-pyrazole-4-boronic acid pinacol ester (29.1 mg, 0.15 mmol) were dissolved in dioxane (1 mL). The resulting reaction mixture was subject to microwave reaction at 150° C. for 45 min before it was poured into H2O (25 mL) and extracted with EtOAc (2×25 mL). The combined organic layers were washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was then purified by prep-HPLC to give title compound (9 mg, 28%) as a white solid. MS: 325.1 (M+H+).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[F:14][C:15]1[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:16]=1[C:17]#[N:18]>>[F:14][C:15]1[CH:22]=[C:21]([O:23][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=2[C:10]([F:13])([F:12])[F:11])[CH:20]=[CH:19][C:16]=1[C:17]#[N:18]
Reactant: O=Cc1ccc(F)c(C(F)(F)F)c1
Reactant: N#Cc1ccc(O)cc1F
Product: N#Cc1ccc(Oc2ccc(C=O)cc2C(F)(F)F)cc1F

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 4-fluoro-3-(trifluoromethyl)benzaldehyde and 2-fluoro-4-hydroxybenzonitrile.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:19][C:20]([OH:25])([CH2:23][CH3:24])[C:21]#[CH:22]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(N(CC)CC)C.[I-]>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:22]#[C:21][C:20]([OH:25])([CH3:19])[CH2:23][CH3:24])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(I)cc1
Reactant: C#CC(C)(O)CC
Agent: Cl[Pd]Cl
Agent: [I-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(C)(O)C#Cc1ccc(C(CC2CCCC2)C(=O)OC)cc1
Temperature: 70 °C
Yield: 102.5 %

Procedure:
A solution of 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid methyl ester (716 mg, 2.0 mmol) and triethylamine (2 mL, 0.01 mmol) in N,N-dimethylformamide (2 mL) was treated with 3-methyl-1-pentyn-3-ol (0.56 mL, 5.0 mmol). The resulting reaction mixture was degassed with argon and then treated with cooper iodide (10 mg, 0.05 mmol) and bis(triphenylphosphine)palladium (II) chloride (15 mg, 0.02 mmol). The reaction was then heated at 70° C. for 24 h. At this time, the reaction was cooled to 25° C. and concentrated in vacuo. The residue was diluted with ethyl acetate (40 mL) and a half-saturated aqueous sodium chloride solution (1×20 mL). The aqueous layer was back extracted with ethyl acetate (1×40 mL). The combined organic extracts were washed with a half-saturated aqueous sodium chloride solution (1×20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40 ethyl acetate/hexanes) afforded 3-cyclopentyl-2-[4-(3-hydroxy-3-methyl-pent-1-ynyl)-phenyl]-propionic acid methyl ester (673 mg, 98%) as an orange oil: EI-HRMS m/e calcd for C21H28O3 (M+) 328.2038, found 328.2040.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[S:12][C:11]([C:13]([O:15][CH3:16])=[O:14])=[C:10]([CH3:17])[CH:9]=2)[CH2:4][C@H:3]1[O:18][CH3:19].[Cl:20][C:21]1[N:22]=[C:23]([C:28](O)=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>>[Cl:20][C:21]1[N:22]=[C:23]([C:28]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[S:12][C:11]([C:13]([O:15][CH3:16])=[O:14])=[C:10]([CH3:17])[CH:9]=3)[CH2:4][C@H:3]2[O:18][CH3:19])=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27]
Reactant: COC(=O)c1sc(N2CC[C@H](N)[C@H](OC)C2)cc1C
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3cc(C)c(C(=O)OC)s3)C[C@H]2OC)nc1Cl
Yield: 84.4 %

Procedure:
The same operation as in Example (221c) was performed using methyl cis(±)-5-(4-amino-3-methoxypiperidin-1-yl)-3-methylthiophene-2-carboxylate obtained in Example (245c) (50 mg, 0.18 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (46 mg, 0.26 mmol), WSC hydrochloride (101 mg, 0.53 mmol), 1-hydroxybenzotriazole (26 mg, 0.19 mmol) and N-methylmorpholine (0.04 mL, 0.35 mmol), to obtain 67 mg of the title compound as a white solid (86%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=O)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C[Si]([N-:18][Si](C)(C)C)(C)C.[Li+].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:12][NH2:18])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=Cc1cc(Cl)cc2ccccc12
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: NCc1cc(Cl)cc2ccccc12
Temperature: -40 °C
Reaction time: 1.5 h

Procedure:
The 3-chloro-1-naphthalenecarbaldehyde (2 g) dissolved in dry THF (12 mL) was added dropwise to lithium bis(trimethylsilyl)amide 1M in THF (11.5 mL) previously cooled at −40° C. The resulting yellow mixture was stirred from −40° C. to −20° C. over 1.5 h; then it was cooled down at −50° C. and lithium aluminium hydride 1M in Et2O (10.6 mL) was added; the mixture was stirred at −40° C. for 2 h then it was quenched with HCl 2N (10 mL) and allowed to reach room temperature. The reaction mixture was diluted with further aqueous HCl 2N solution (20 mL) and extracted with CH/Et2O 1/1 (50 mL). The acidic aqueous phase was basified at 0° C. with NaOH pellets until pH=14, then it was extracted with diethyl ether (2×150 mL). The organic phase was dried and concentrated in vacuo to give the title compound (1.78 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[OH:18].[C:19]([C:21]1[CH:22]=[C:23]([S:28]([NH:31][C:32]2[S:36][N:35]=[CH:34][N:33]=2)(=[O:30])=[O:29])[CH:24]=[CH:25][C:26]=1F)#[N:20].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:19]([C:21]1[CH:22]=[C:23]([S:28]([NH:31][C:32]2[S:36][N:35]=[CH:34][N:33]=2)(=[O:30])=[O:29])[CH:24]=[CH:25][C:26]=1[O:18][C:9]1[CH:10]=[CH:11][C:12]([C:14]([F:15])([F:17])[F:16])=[CH:13][C:8]=1[C:7]1[CH:6]=[CH:5][N:4]=[N:3][C:2]=1[CH3:1])#[N:20]
Reactant: Cc1nnccc1-c1cc(C(F)(F)F)ccc1O
Reactant: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1nnccc1-c1cc(C(F)(F)F)ccc1Oc1ccc(S(=O)(=O)Nc2ncns2)cc1C#N
Temperature: 90 °C
Yield: 66 %

Procedure:
2-(3-Methylpyridazin-4-yl)-4-(trifluoromethyl)phenol (Preparation 44, 100 mg, 0.38 mmol) and 3-cyano-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (Preparation 39, 108 mg, 0.38 mmol) were dissolved in dimethylsulfoxide (2 mL). Potassium carbonate (157 mg, 1.14 mmol) was added and the reaction mixture was heated to 90° C. for 4 hours. The reaction mixture was cooled and the crude material purified by reverse phase column chromatography (ISCO™ Companion, C18 silica, 5% to 60% acetonitrile in water gradient elution) to afford the title compound as an off-white solid (130 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:17][CH2:18][O:19][CH2:20][CH2:21]Br.C(N(CC)CC)C>CN(C)C=O>[O:19]1[CH2:20][CH2:21][N:14]([C@H:11]2[CH2:10][CH2:9][C@H:8]([NH:7][C:6](=[O:15])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:13][CH2:12]2)[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Reactant: BrCCOCCBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N2CCOCC2)CC1
Temperature: 25 °C

Procedure:
A solution of tert-butyl-4-aminocyclohexylcarbamate (20.32 g, 95 mmol), bis(2-bromoethyl)ether (14.30 ml, 114 mmol) and triethylamine (33.0 ml, 237 mmol) in N,N-dimethylformamide (200 ml) was stirred for 16 hours at 70° C. The reaction mixture was cooled down to room temperature, concentrated and the product was extracted with ethyl acetate. The organic layer was washed with sodium carbonate solution (15% aq.), dried and concentrated. The product was used in next step without purification.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7])=[O:2].S(Cl)([Cl:14])=O.CN(C)C=O>C1(C)C=CC=CC=1>[CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([Cl:14])=[O:7])=[O:2]
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=Cc1cccc(C(=O)Cl)c1
Reaction time: 2 h

Procedure:
A mixture of 3-formylbenzoic acid (84 grams (g), 0.558 moles), thionyl chloride (80.5 g, 0.71 moles), and dimethylformamide (3 milliliters (ml)), in toluene (500 ml) was slowly warmed to 70° C. and stirred at that temperature for 2 hours. The toluene was eliminated in the rotavap to yield 97.7 g of 3-formylbenzoyl used in the next step as such.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([CH2:22][OH:23])[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].[CH:24](O)(C)C>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[CH:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([CH2:22][OH:23])[CH:14]=[CH:13][CH:12]=3)=[O:5])([CH3:24])[CH3:2]
Reactant: CC(C)O
Reactant: CCOC(=O)c1ncc2[nH]c3cccc(CO)c3c2c1COC
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: COCc1c(C(=O)OC(C)C)ncc2[nH]c3cccc(CO)c3c12

Procedure:
5-Hydroxymethyl-4-methoxymethyl-beta-carboline-3-carboxylic acid ethyl ester (7.27 g) is refluxed in isopropanol (1000 ml) with titanium tetraisopropylate (7.1 ml) for 5 hours. The solution is evaporated, the residue is dissolved in ethyl acetate. The complete solution is reached by addition of 1N hydrochloric acid. Then it is made alkaline by addition of 1N sodium hydroxide solution. A precipitate resulting thereby is suctioned off. The filtrate is evaporated and yields a residue of 6.0 g of the title compound.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:6][CH:5]([C:7]([OH:9])=O)[CH2:4]1)[CH3:2].[CH3:10][Li]>CCOCC>[C:7]([CH:5]1[CH2:4][CH:3]([CH2:1][CH3:2])[CH2:6]1)(=[O:9])[CH3:10]
Reactant: CCC1CC(C(=O)O)C1
Reactant: [Li]C
Solvent: CCOCC
Product: CCC1CC(C(C)=O)C1
Reaction time: 3 h

Procedure:
A solution of 6.61 g of 3-ethylcyclobutane-1-carboxylic acid, in 52 ml of distilled ether was stirred under argon at 0°. Methyllithium (85.0 ml of a 1.53 M solution in ether) was added dropwise over a 30 minute period. The reaction mixture was stirred for three hours at 25°, then quenched with 7.3 water-methanol. The layers were separated, and the aqueous layer extracted with ether. The combined organic layers were washed with brine, dried, filtered and the solvents evaporated in vacuo. The resultant oil was distilled (aspirator vacuum) to afford 5.5 g of 1-acetyl-3-ethylcyclobutane, as a clear oil (bp 64°-67°). The material had the following spectral characteristics: nmr (CDCl3) δ 0.80 and 0.82 (3H total, pair of t, each J=7.0 Hz), 1.10 and 1.12 (ca. 1.5H total, pair of s, side product 1-[2-hydroxy-prop-2-yl]-3-ethylcyclobutane), 1.0-2.4 (7 H, m), 2.07 and 2.09 (3H total, pair of s) and 2.7-3.5 ppm (1H, m); ir (CHCl3) 935, 1175, 1370, 1460, 1705, 2870, 2930 and 2970 cm-1, also small 3200-3600 broad and 3600 cm-1 for the side product noted above.