Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@H:9]([CH:13]=O)[CH:10]([CH3:12])[CH3:11])=O)(C)(C)C.[OH:15][C@@H:16]([C@H:44]([OH:59])[C@H:45]([OH:58])[C@@H:46]([NH:49][C:50](=[O:57])[C@H:51]([CH2:53][CH:54]([CH3:56])[CH3:55])[NH2:52])[CH2:47][OH:48])[C:17]([NH:19][C@H:20]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:21][C:22]([O:24]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:23])=[O:18].C([BH3-])#N.[Na+]>CO>[NH2:8][C@@H:9]([CH:10]([CH3:12])[CH3:11])[CH2:13][NH:52][C@H:51]([C:50]([NH:49][C@@H:46]([CH2:47][OH:48])[C@@H:45]([OH:58])[C@@H:44]([OH:59])[C@H:16]([OH:15])[C:17]([NH:19][C@H:20]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:21][C:22]([OH:24])=[O:23])=[O:18])=[O:57])[CH2:53][CH:54]([CH3:56])[CH3:55]
Reactant: CC(C)C[C@H](N)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)OC(c1ccccc1)c1ccccc1)c1ccccc1
Reactant: CC(C)[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)C[C@H](NC[C@@H](N)C(C)C)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)O)c1ccccc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 10.3 %

Procedure:
To a solution of N-tert-butoxycarbonyl-L-valinal (240 mg) and diphenylmethyl (S)-3-[(2S,3R,4R,5S)-2,3,4,6-tetrahydroxy-5-(L-leucyl)aminohexanoyl]amino-3-phenylpropionate (278 mg) in methanol (10 ml) was added sodium cyanoborohydride (63 mg) at 0° C. and the mixture was stirred at 0° C. for 2 hours and at room temperature for 18 hours. After concentration under reduced pressure, the residue was subjected to flush silica gel column chromatography, followed by elution with ethyl acetate-methanol(20:1). The effective fractions were combined and concentrated under reduced pressure. To the residue was added 4N hydrogen chloride solution in ethyl acetate (10 ml) and the whole was stirred at room temperature for 1 hour. Removal of the organic solvent gave a residue, which was passed through a column of DIAION HP-20SS (Mitsubishi kasei corporation), followed by elution with water-acetonitrile. The effective fractions were combined and concentrated under reduced pressure. The residue was recrystallized from methanol-diethylether to afford the title compound (25 mg).
Reaction SMILES: C([O:4][CH:5](OC(C)C)[C:6]([CH3:27])([CH3:26])[C:7](=[O:25])[C@H:8]([CH3:24])[C@@H:9]([O:15][C:16]([O:18][CH2:19][C:20]([Cl:23])([Cl:22])[Cl:21])=[O:17])[C@@H:10]([CH3:14])[CH2:11][CH:12]=[CH2:13])(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1COCC1.O>[O:25]=[C:7]([C@H:8]([CH3:24])[C@@H:9]([O:15][C:16]([O:18][CH2:19][C:20]([Cl:21])([Cl:22])[Cl:23])=[O:17])[C@@H:10]([CH3:14])[CH2:11][CH:12]=[CH2:13])[C:6]([CH3:27])([CH3:26])[CH:5]=[O:4]
Reactant: C=CC[C@H](C)[C@H](OC(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C(=O)C(C)(C)C(OC(C)C)OC(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CC[C@H](C)[C@H](OC(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C(=O)C(C)(C)C=O

Procedure:
A mixture of (4R,5S,6S)-1,1-diisopropoxy-5-(2,2,2-trichloroethoxycarbonyloxy)-2,2,4,6-tetramethyl-8-nonen-3-one (4.58 g) and p-toluenesulfonic acid monohydrate (0.45 g) in 100 mL of 3:1 THF/water is heated at reflux for 7 hours. The mixture is cooled and poured into sat. aq. NaHCO3, then extracted with ethyl acetate. The extract is dried over Na2SO4, filtered, and evaporated. The product is purified by chromatography on Sio2 (3% ethyl acetate/hexanes).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:11][CH:10]([CH2:18][OH:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[K+].[CH3:22]I>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:11][CH:10]([CH2:18][O:19][CH3:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CC(CO)Sc2ccccc21
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCC1CN(C(=O)OC(C)(C)C)c2ccccc2S1
Temperature: 25 °C

Procedure:
1.9 g of 4-tert-butoxycarbonyl-2(R,S)-hydroxymethyl-3,4-dihydro-2H1,4-benzothiazine are dissolved in 20 ml of tetrahydrofuran, and 1.5 g of a 20% potassium hydride suspension in oil are added at 0° C. 1.3 ml of methyl iodide are then added dropwise. The mixture is allowed to warm to room temperature and, when the reaction has ended, the mixture is poured onto water. After customary working up, the crude product is purified over 250 g of silica gel by means of FC (methylene chloride as the mobile phase): Rf (D)=0.45.
Reaction SMILES: [CH2:1]([C@H:3]([NH:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:14]=1[OH:29])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>C1COCC1>[CH2:1]([C@H:3]([NH:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:14]=1[O:29][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CC[C@H](NC(=O)c1c(O)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)COc1c(-c2ccccc2)nc2ccccc2c1C(=O)N[C@@H](CC)c1ccccc1
Reaction time: 2.5 h
Yield: 135.4 %

Procedure:
2.0 g (5.2 mmol) of (S)-N-(α-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide (compound of Description 1) were dissolved, under nitrogen atmosphere and magnetic stirring, in 20 ml of THF. 2.0 g (14.5 mmol) of K2CO3, 0.87 ml (7.8 mmol) of ethyl bromoacetate and a small amount of Ki were added and the reaction mixture was left at room temperature under magnetical stirring for 2.5 hours. The precipitate was filtered off and the solution was evaporated in-vacuo to dryness; the residue was dissolved in water and extracted with EtOAc; the organic phase was separated, dried over Na2SO4 and evaporated in-vacuo to dryness to obtain 3.3 g of a dense yellow oil. The oil was purified by flash chromatography on 230-400 mesh silica gel, eluting with a mixture of hexane/EtOAc 70:30 containing 0.5% of 28% NH4OH, and the purified product was triturated with i-Pr2O/i-PrOH to yield 2.1 g of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([NH:13][C:14](=[O:22])OC3C=CC=CC=3)=[CH:11][C:10]([CH3:23])=[N:9]2)=[CH:4][CH:3]=1.[NH2:24][C:25]1[CH:41]=[CH:40][C:28]([O:29][C:30]2[CH:35]=[CH:34][N:33]=[C:32]3[NH:36][C:37](=[O:39])[NH:38][C:31]=23)=[CH:27][CH:26]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([NH:13][C:14]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([O:29][C:30]4[CH:35]=[CH:34][N:33]=[C:32]5[NH:36][C:37](=[O:39])[NH:38][C:31]=45)=[CH:40][CH:41]=3)=[O:22])=[CH:11][C:10]([CH3:23])=[N:9]2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)[nH]c23)cc1
Reactant: Cc1cc(NC(=O)Oc2ccccc2)n(-c2ccc(Cl)cc2)n1
Product: Cc1cc(NC(=O)Nc2ccc(Oc3ccnc4[nH]c(=O)[nH]c34)cc2)n(-c2ccc(Cl)cc2)n1
Yield: 81.4 %

Procedure:
Method F was used with phenyl 1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-yl-carbamate (41 mg, 0.12 mmol) and 7-(4-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one (20 mg, 0.08 mmol). The solid residue obtained after evaporation of the solvents was washed only with Et2O to afford the title compound (31 mg, 79%) as a pale pink solid. 1H-NMR (6, ppm, DMSO-d6): 2.19 (s, 3H, CH3), 6.28 (s, 1H, HPyz,4), 6.31 (d, 1H, HPy,5, J=5.8 Hz), 7.10 (d, 2H, Harom,Ph,3+5, J=8.9 Hz), 7.47 (d, 2H, Harom,Ph,2+6, J=8.9 Hz), 7.57 (m, 4H, Harom,4—Cl—Ph), 7.74 (d, 1H, HPy,6, J=5.8 Hz), 8.47 (bs, 1H, NHurea), 9.05 (bs, 1H, NHurea), 11.19 (bs, 1H, NHPy3), 11.37 (bs, 1H, NHPy2). 13C-NMR (6, ppm, DMSO-d6): 13.7, 99.3, 105.1, 112.8, 119.8, 120.5, 125.7, 129.2, 131.5, 136.3, 137.2, 137.5, 141.2, 145.8, 146.8, 148.2, 148.5, 151.6, 154.1. LC-MS (m/z): 476 (M+H, 100). HRMS (EI): m/z [M+H]+ calcd. for C23H19N7O3Cl: 476.1238; found: 476.1213.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[C:21]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[CH:28]([CH3:32])[NH:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=[C:18]([O:33][CH3:34])[N:17]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:27]3[CH2:26][CH2:25][C:24]4[C:29](=[CH:30][CH:31]=[C:22]([C:21]5[C:16]([O:15][CH3:14])=[N:17][C:18]([O:33][CH3:34])=[CH:19][CH:20]=5)[CH:23]=4)[CH:28]3[CH3:32])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: COc1ccc(-c2ccc3c(c2)CCNC3C)c(OC)n1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: COc1ccc(-c2ccc3c(c2)CCN(C(=O)c2cc4ncc(Cl)cn4n2)C3C)c(OC)n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-(2,6-Dimethoxy-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=2)([OH:17])[CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1.[H][H]>C(O)(=O)C.[Pt]=O>[CH3:25][O:24][C:20]1[CH:19]=[C:18]([C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)([OH:17])[CH2:10][CH:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)[CH:23]=[CH:22][CH:21]=1
Reactant: COc1cccc(C(O)(Cc2ccncc2)c2cccc(OC)c2)c1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CC(=O)O
Product: COc1cccc(C(O)(CC2CCNCC2)c2cccc(OC)c2)c1

Procedure:
A solution of alpha,alpha-bis(3-methoxyphenyl)-4-pyridine-ethanol (63 g) in acetic acid (400 ml) was hydrogenated over platinum oxide (2 g; 100 p.s.i.; 50°). The reaction was stopped after the uptake of the theoretical amount of hydrogen (0.564 mol), then it was filtered to remove the catalyst and the solvent was evaporated under reduced pressure. After the residue was taken up in water (400 ml) and toluene (200 ml), the mixture was heated to reflux and then made basic with 10N sodium hydroxide. The mixture was cooled to 5°, and the resulting solid was collected by filtration, then was washed in turn with water, toluene, toluene-hexane (1:1) and hexane to give, after drying, 62.5 g of alpha,alpha-bis(3-methoxyphenyl)-4-piperidineethanol, mp 111°-113°.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[C:37]3[C:41](=[CH:42][CH:43]=2)[NH:40][N:39]=[CH:38]3)O1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([C:35]2[CH:36]=[C:37]3[C:41](=[CH:42][CH:43]=2)[NH:40][N:39]=[CH:38]3)[CH:3]=1)=[O:15]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: CC1(C)OB(c2ccc3[nH]ncc3c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc4[nH]ncc4c3)nc3c2cnn3C(C)C)c(=O)[nH]1
Yield: 48.1 %

Procedure:
To a 5-mL microwave vial were added 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (70 mg, 0.187 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (59.4 mg, 0.243 mmol), DMSO (1.5 mL) and sodium carbonate (0.281 mL, 0.562 mmol), and the mixture was degassed with nitrogen for 10 min. Next was added bis(triphenylphosphine)palladium(II) chloride (10.51 mg, 0.015 mmol). The contents were sealed and irradiated (microwave) at 140° C. overnight. The mixture was filtered and the residue was washed with DMSO. The crude product in DMSO was purified using reverse-phase HPLC. The TFA salt of the product was neutralized using saturated NaHCO3, filtered, washed with water and dried under high vacuum to give 41 mg (48%) of product. LCMS E-S (M+H)=456.0 1H NMR (400 MHz, DMSO-d6) δ ppm 1.56 (d, J=6.8 Hz, 6H), 2.14 (s, 3H), 2.23 (s, 3H), 4.38-4.53 (m, 2H), 5.27-5.49 (m, 1H), 5.91 (s, 1H), 7.59-7.75 (m, 1H), 8.24 (s, 2H), 8.37 (s, 2H), 8.69 (s, 1H), 8.95-9.09 (m, 1H), 11.49-11.67 (m, 1H), 13.21-13.35 (m, 1H).
Reaction SMILES: OS(O)(=O)=O.[NH2:6][C:7]1[C:15]([Cl:16])=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[Cl:17].[CH3:18]O>>[NH2:6][C:7]1[C:8]([Cl:17])=[CH:9][C:10]([C:11]([O:13][CH3:18])=[O:12])=[CH:14][C:15]=1[Cl:16]
Reactant: CO
Reactant: Nc1c(Cl)cc(C(=O)O)cc1Cl
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Cl)c(N)c(Cl)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
conc. H2SO4 (2.5 mL, 97.04 mmol) was added drop wise to a stirred solution of 4-amino-3,5-dichlorobenzoic acid (10.0 g, 48.54 mmol) in MeOH (150 mL) at 0° C. and the reaction mixture was then stirred at 80° C. for 8 h. The volatiles were evaporated; ice-water was added to the residue and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to afford the title compound as a white solid (7.5 g, 70%): 1H NMR (300 MHz, DMSO-d6) δ 8.05 (s, 2H), 3.96 (s, 3H); ESIMS m/z 282 ([M]+); IR (KBr): 1733, 762, 514 cm−1.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)[N:3]=1.[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[CH:16]1([CH2:15][NH:14][C:4]2[N:5]=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[C:7]([C:8]#[N:9])=[C:2]([N:28]3[CH2:29][CH2:30][N:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:26][CH2:27]3)[N:3]=2)[CH2:18][CH2:17]1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: N#Cc1c(Cl)nc(NCC2CC2)nc1NCCO
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(NCCO)nc(NCC2CC2)nc1N1CCN(c2ccccc2)CC1

Procedure:
In analogy to the procedure described in example 47b, 4-chloro-2-(cyclopropylmethyl-amino)-6-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with 1-phenyl-piperazine in dioxane in the presence of N-ethyl-diisopropylamine at 100° C. to yield 2-(cyclopropylmethyl-amino)-4-(2-hydroxy-ethylamino)-6-(4-phenyl-piperazin-1-yl)-pyrimidine-5-carbonitrile as an amorphous, white solid; MS: [M+H]+=394.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[N:12]=2)=[CH:4][CH:3]=1.[OH-].[K+].C(Cl)(=O)C(Cl)=O.[CH2:30](O)[CH2:31][CH2:32][CH3:33]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)=[C:11]([CH2:13][C:14]([O:16][CH2:30][CH2:31][CH2:32][CH3:33])=[O:15])[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1nc(-c2ccc(F)cc2)oc1-c1ccsc1
Reactant: CCCCO
Agent: O=C(Cl)C(=O)Cl
Agent: [K+]
Agent: [OH-]
Product: CCCCOC(=O)Cc1nc(-c2ccc(F)cc2)oc1-c1ccsc1
Yield: 42.2 %

Procedure:
2 g of 2-[2-(4-fluorophenyl)-5-(3-thienyl)-4-oxazolyl]acetic acid, 0.5 g of potassium hydroxide, 4.2 g of oxalyl chloride and 20 ml of n-butanol are treated in the same manner as described in Example 17. One g of n-butyl 2-[2-(4-fluorophenyl)-5-(3-thienyl)-4-oxazolyl]acetate is thereby obtained. Yield: 42.2%
Reaction SMILES: O=[C:2]1[C:6]2[NH:7][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:9][C:5]=2[CH2:4][CH2:3]1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([F:25])[CH:24]=1)[CH2:19][Mg]Cl>>[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([F:25])[CH:24]=1)[CH2:19][CH:2]1[C:6]2[NH:7][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:9][C:5]=2[CH2:4][CH2:3]1
Reactant: Fc1cc(Cl)cc(C[Mg]Cl)c1
Reactant: CCOC(=O)c1cc2c([nH]1)C(=O)CC2
Product: CCOC(=O)c1cc2c([nH]1)C(Cc1cc(F)cc(Cl)c1)CC2
Yield: 11 %

Procedure:
The title compound was synthesized in two steps. Ethyl 6-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.40 g, 2.23 mmol) was reacted with 3-chloro-5-fluorobenzylmagnesium chloride (0.25 M in diethyl ether, 23.0 mL, 5.6 mmol) according to General Procedure 3 to give the exocyclic olefin-containing compound (Z)-ethyl 6-(3-chloro-5-fluorobenzylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate, followed by hydrogenation according to General Procedure 6 (with Pt2O), and was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-20% EtOAc/heptane affording the product as brown solid: 0.055 g (11% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([CH:8]=O)[C:5](=[O:10])[CH2:4][CH2:3]1.C(Cl)(=O)C([Cl:15])=O.[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:15][CH:8]=[C:6]1[CH2:7][C:2]([CH3:11])([CH3:1])[CH2:3][CH2:4][C:5]1=[O:10]
Reactant: CC1(C)CCC(=O)C(C=O)C1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC1(C)CCC(=O)C(=CCl)C1
Reaction time: 0.06 h
Yield: 87.5 %

Procedure:
To a solution of 5,5-dimethyl-2-oxo-cyclohexanecarbaldehyde (51 g, 331 mmol) in chloroform (250 mL), oxalyl chloride (40 mL, 465 mmol) is rapidly added. After stirring for 3-4 min ice followed by 2 N aq. NaOH (100 mL) is added. The organic phase is separated and the aq. phase is extracted once more with chloroform. The combined organic extracts are washed with water and dried over Na2SO4. The solvent is removed in vacuo to give 2-chloromethylene-4,4-dimethyl-cyclohexanone (50 g) as a brown oil; LC-MS: tR=0.96 min.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]([CH:14]([CH2:17][CH:18]2[O:22][CH2:21][CH2:20][O:19]2)[CH2:15][OH:16])[CH:10]=[CH:11][C:12]=1[Cl:13].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:16][CH2:15][CH:14]([C:9]1[CH:10]=[CH:11][C:12]([Cl:13])=[C:7]([Cl:6])[CH:8]=1)[CH2:17][CH:18]1[O:19][CH2:20][CH2:21][O:22]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCC(CC1OCCO1)c1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC(CC1OCCO1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Yield: 101.4 %

Procedure:
Methanesulphonyl chloride (5.5 g) was added over 10 minutes to an ice-cooled solution of 2-(3,4-dichlorophenyl)-3-(1,3-dioxolan-2-yl)propan-1-ol (12 g) (see Preparation 15) and triethylamine (5.7 g) in dichloromethane (100 ml). The mixture was stirred for 30 minutes before further addition of dichloromethane (50 ml). The solution was then washed sequentially with water (3×50 ml) and brine (50 ml) before drying over anhydrous sodium sulphate. Removal of the solvent under reduced pressure gave 1-methanesulphonyloxy-2-(3,4-dichlorophenyl)-3-(1,3-dioxolan-2-yl)propane as a yellow oil (15.6 g) which solidified upon standing.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH2:13])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1>O1CCCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](=[S:23])[NH2:13]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)c1ccc2ccccc2c1
Solvent: C1CCOC1
Product: NC(=S)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 83 %

Procedure:
To a solution of the above amide (10.0 g, 58 mmol) in dry tetrahydrofuran (250 ml) was added [2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphenate-2,4-disulfide] (Lawesson's reagent) (16.5 g, 41 mmol) and the resulting mixture was stirred at room temperature for 48 h. The volatiles were evaporated in vacuo and the residue was dissolved in ethyl acetate (100 ml) and filtered through silicagel (100 ml) using ethyl acetate as eluent. The solvent was evaporated in vacuo and to the residue was added a mixture of ethyl acetate (25 ml) and heptane (25 ml). The precipitate was filtered off and washed with heptane (40 ml), dried in vacuo at 50° C. which afforded 9.0 g (83%) of naphthalene-2-carbothioic acid amide as a solid.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([CH3:18])[CH2:16][CH3:17])=[CH:10][CH:9]=1)[CH2:5][OH:6].Cl[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH3:3][CH:4]([O:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH:15]([CH3:18])[CH2:16][CH3:17])=[CH:12][CH:13]=1)[CH2:5][O:6][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: CCC(C)Oc1ccc(OC(C)CO)cc1
Reactant: Clc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCC(C)Oc1ccc(OC(C)COc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of sodium hydride (0.08 g) in 5 ml of tetrahydrofuran (THF) and 2 ml of hexamethylphosphoramide (HMPA), cooled in an ice bath, is added, dropwise, 2-methyl-2-[4-(1-methylpropoxy)phenoxy]ethanol (0.63 g). The mixture is stirred at RT for 2 hours, after which a solution of 2-chloropyridine (0.38 g) in 5 ml of THF is added and the mixture is stirred at 60° for 3 hours. The THF is then removed by rotoevaporation and the residue is purified by column chromatography on silica gel to give the product, 2-{2-methyl-2-[4-(1-methylpropoxy)phenoxy]ethoxy}pyridine, MS m/e 302 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:25]([F:26])=[CH:24][CH:23]=[C:22]([F:27])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](C3C=CN=C(Cl)C=3)=[CH:14][C:6]1=2.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[C:38]([N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)[CH:39]=[CH:40][CH:41]=2)O1>>[Cl:1][C:2]1[C:25]([F:26])=[CH:24][CH:23]=[C:22]([F:27])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([N:42]4[CH2:43][CH2:44][O:45][CH2:46][CH2:47]4)[CH:37]=3)=[CH:14][C:6]1=2
Reactant: CC1(C)OB(c2cccc(N3CCOCC3)c2)OC1(C)C
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(-c4ccnc(Cl)c4)cc32)c1Cl
Product: Fc1ccc(F)c(CN2CCNc3ncc(-c4cccc(N5CCOCC5)c4)cc32)c1Cl

Procedure:
1-(2-Chloro-3,6-difluorobenzyl)-7-(2-chloropyridin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (100 mg) was coupled to 4-[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-morpholine as in General Procedure 4B to give the title compound as a yellow solid. LCMS: m/z=457.05 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.21 (4H, t, J=4.8 Hz), 3.29 (2H, t, J=4.7 Hz), 3.52 (2H, t, J=4.2 Hz), 3.89 (4H, t, J=4.8 Hz), 4.52 (2H, s), 5.09 (1H, bs), 6.84 (1H, dd, J=8.0, 1.9 Hz), 7.00 (3H, m), 7.10 (2H, m), 7.29 (1H, m), 7.72 (1H, d, J=1.8 Hz).
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([O:15]C)=[O:14])[S:2]1.CO.[OH-].[Na+]>O1CCCC1>[S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([OH:15])=[O:14])[S:2]1
Reactant: COC(=O)C(=O)NCCCCCC1CCSS1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C(=O)NCCCCCC1CCSS1
Yield: 73.3 %

Procedure:
The reaction was effected as described in Example 49, but using 92 mg of methyl N-[5-(1,2-dithiolan-3-yl)pentyl]oxcalamidate (prepared as described in Example 65), 4 ml of methanol, 1 ml of tetrahydrofuran and 0.6 ml of a 1N aqueous solution of sodium hydroxide. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the residue. The resulting mixture was neutralized by the addition of 2N aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure. The residue was dissolved in dioxane, after which it was lyophilised, to give 64 mg of the title compound as a pale yellow amorphous substrate, melting at 75 to 79° C.