Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][CH2:5][C:6]1[N:7]=[C:8]([CH:11]([CH3:13])[CH3:12])[S:9][CH:10]=1.[O:14]([C:21]([NH:23][C@H:24]([C:28]([OH:30])=[O:29])[CH:25]([CH3:27])[CH3:26])=O)C1C=CC=CC=1.O>C1COCC1>[CH3:3][N:4]([C:21]([NH:23][C@H:24]([C:28]([OH:30])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:14])[CH2:5][C:6]1[N:7]=[C:8]([CH:11]([CH3:13])[CH3:12])[S:9][CH:10]=1
Reactant: CC(C)[C@H](NC(=O)Oc1ccccc1)C(=O)O
Reactant: CNCc1csc(C(C)C)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)cs1
Temperature: 50 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
To a stirred slurry of 95% NaH (560 mg, 23.2 mmol) at -10° C. in 20 mL of THF was slowly added N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amine (3.76 g, 22.1 mmol) keeping the temperature not more than 0° C. THF (5 mL) was added as a rinse. A solution of N-phenoxycarbonyl-L-Valine (5.0 g, 21.1 mmol) dissolved in 20 mL of THF was added slowly keeping the temperature not more than 0° C. THF (5 mL) was added as a rinse. After 4 hours, water (100 mL) was added, and the THF was removed under reduced pressure. The pH was adjusted to 9 with concentrated HCl, and the phenol by-product was removed with methyl tert-butyl ether washes (3×60 mL). The aqueous phase was stirred with 70 mL of toluene and adjusted to pH 3 with 4 N HCl. The aqueous phase was separated and extracted twice more with toluene (2×70 mL). The combined toluene extracts were concentrated under reduced pressure, and the residue was redissolved in toluene and heptane (50 mLs of a 1:1 v/v solution), warmed to 50° C. and allowed to cool to ambient temperature. The product was collected by filtration, washed with heptane and dried under vacuum to afford the title compound as a white powder in 83% yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:9]=[C:10]=[S:11])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:12][NH2:13]>C1C=CC=CC=1.C(O)C>[Cl:1][C:2]1[C:3]([NH:9][C:10]([NH:13][CH3:12])=[S:11])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: S=C=Nc1ncc(Cl)cc1Cl
Reactant: CN
Solvent: CCO
Solvent: c1ccccc1
Product: CNC(=S)Nc1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 3,5 dichloro-2-pyridylisothiocyanate (5.13 g.) in benzene (20 ml.) was added to a solution of methylamine in ethanol (5 ml., 33%) and the mixture was stirred for 18 hours at ambient temperature. Petroleum ether (60°-80° C., 30 ml.) was added and the resulting precipitate was filtered off and recrystallised from benzene-light petroleum to give colourless microcrystals of 1-(3,5-dichloro-2-pyridyl)-3-methyl-2-thiourea (4.18 g.) m.pt. 105°-109° C.
Reaction SMILES: Cl[CH:2]([N:7]=[C:8](Cl)[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[C:3]([F:6])([F:5])[F:4].[C:17](#[N:20])[CH:18]=[CH2:19].N12CCCN=C1CCCCC2>CN(C)C=O>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]2[NH:7][C:2]([C:3]([F:6])([F:5])[F:4])=[CH:19][C:18]=2[C:17]#[N:20])=[CH:10][CH:11]=1
Reactant: FC(F)(F)C(Cl)N=C(Cl)c1ccc(Cl)cc1
Reactant: C=CC#N
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1cc(C(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 38.8 %

Procedure:
A solution of N-[1-chloro-(2,2,2-trifluoroethyl)]-4-chlorobenzimidoyl chloride (5.80 g, 0.02 mol) and acrylonitrile (1.33 g, 0.025 mol) in N,N-dimethylformamide (15 mL) is treated with 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU, 8.53 g, 0.056 mol) over 1 hour while maintaining the temperature at 45°-50° C. The reaction mixture is then stirred at 50° C. for 4 hours, quenched with dilute HCl, and extracted with ethyl acetate. The organic extract is concentrated in vacuo to obtain a residue. Flash chromatography of the residue on silica gel, packed and eluted with 20% ethyl acetate in heptane, and crystallization from heptane and small amount of ethyl acetate gives the title product as a white crystalline solid (2.1 g, 38.9% yield): mp 239-240° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH:18][CH:19]4[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]4)[C:16]=3[N:17]=2)=[CH:4][C:3]=1[NH:32][S:33]([C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=1[F:43])(=[O:35])=[O:34].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:32][S:33]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=2[F:43])(=[O:34])=[O:35])=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH:18][CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[C:16]=3[N:17]=2)=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncnc3ccc(-c4cnc(Cl)c(NS(=O)(=O)c5ccc(F)cc5F)c4)nc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1cc(-c2ccc3ncnc(NC4CCNCC4)c3n2)cnc1Cl)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.3 %

Procedure:
To a solution of tert-butyl 4-(6-(6-chloro-5-(2,4-difluorophenylsulfonamido)pyridin-3-yl)pyrido[3,2-d]pyrimidin-4-ylamino)piperidine-1-carboxylate (1.28 g, 2.03 mmol) in DCM (20 mL) was added TFA (3.10 mL, 40.5 mmol) at 0° C. The reaction mixture was stirred for 4 h at room temperature and removed the solvent in vacuo. DCM was poured into the residue, and neutralized with aq. Na2HCO3. The resulting solid was filtered and washed with MeOH and EtOAc to give N-(2-chloro-5-(4-(piperidin-4-ylamino)pyrido[3,2-d]pyrimidin-6-yl)pyridine-3-yl)-2,4-difluorobenzenesulfonamide (954 mg, 89%) as a pale yellow solid. 1H-NMR (DMSO-d6, Varian 400 MHz) δ 1.84-2.00 (2H, m), 2.12-2.24 (2H, m), 3.04-3.18 (2H, m), 3.32-3.46 (2H, m), 4.38-4.52 (1H, m), 7.07 (1H, dt, J=2.0, 8.4 Hz), 7.22 (1H, dt, J=2.4, 10.0 Hz), 7.83-7.92 (1H, m), 8.04 (1H, d, J=8.0 Hz), 8.11 (1H, d, J=8.8 Hz), 8.19 (1H, d, J=8.8 Hz), 8.26 (1H, d, J=2.4 Hz), 8.43 (2H, brs), 8.52 (1H, s), 8.59 (1H, d, J=2.4 Hz). m/z=532.2 [M+1]+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[O:13][N:12]=[C:11]([C:14]([F:17])([F:16])[F:15])[N:10]=1)(C)(C)C.[ClH:19]>C(OCC)(=O)C.O1CCOCC1>[ClH:19].[F:17][C:14]([F:15])([F:16])[C:11]1[N:10]=[C:9]([CH2:8][NH2:7])[O:13][N:12]=1
Reactant: CC(C)(C)OC(=O)NCc1nc(C(F)(F)F)no1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: NCc1nc(C(F)(F)F)no1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 0.29 g (3-trifluoromethyl-[1,2,4]oxadiazol-5-ylmethyl)-carbamic acid tert-butyl ester in 3 ml ethyl acetate was added 1.5 ml of a 4M solution of hydrochloric acid in dioxane and the mixture was stirred at ambient temperature for 18 h. The resulting clear solution was evaporated and the residue was triturated under ethyl acetate. The solid was collected by filtration and dried to constant weight under high vacuum to yield 0.145 g of the title compound as white crystals, 169.2 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8](Br)[CH2:9][CH2:10][CH3:11]>>[CH2:8]([N:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCBr
Reactant: C1CCCNCC1
Product: CCCCN1CCCCCC1

Procedure:
The first N-substitution of azepane was carried out using butyl bromide as an N-alkylating agent to form 1-butylazepane. An equimolar amount of butyl bromide was added dropwise to a solution of azepane in methanol keeping the temperature at 2° C. by an ice-water bath. The mixture was hydrolyzed with potassium carbonate, extracted with ether, and dried over Na2SO4. The solution was fractionally distilled at reduced pressure and the fraction with by 195° C. was collected. 1H-NMR (300 MHz, CDCl3) δ 0.90 (t, 3H), 1.28 (sextet, 2H), 1.42 (m, 2H), 1.60 (broad m, 8H), 2.42 (m, 2H), 2.60 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])[N:5]2[CH:22]=1.[CH:23](=O)[CH2:24][CH2:25][CH3:26].N1CCCCC1>C(O)C>[CH:23](=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:6]2[N:5]3[CH:22]=[C:2]([CH3:1])[N:3]=[C:4]3[CH:9]=[CH:8][CH:7]=2)[C:19]1=[O:20])[CH2:24][CH2:25][CH3:26]
Reactant: CCCC=O
Reactant: Cc1cn2c(SCCCCN3C(=O)CSC3=O)cccc2n1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCCC=C1SC(=O)N(CCCCSc2cccc3nc(C)cn23)C1=O

Procedure:
To a solution of 0.67 g (2.0 mmol) of 3-[4-(2-methylimidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 0.18 ml (2.0 mmol) of n-butyraldehyde in 10 ml of ethanol, 0.02 ml (0.2 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1/4) to yield 0.794 g (quant, light yellow oily substance) of the desired product.
Reaction SMILES: [F:1][C:2]1[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:14])=[N:12][CH:13]=[C:8]2[C:7]([C:15]2[N:16]=[N:17][C:18]([C:22]([CH3:28])([CH3:27])[C:23]([O:25]C)=O)=[C:19](O)[N:20]=2)=[N:6]1.P(Cl)(Cl)(Cl)=O.[NH3:39]>C(#N)C>[F:1][C:2]1[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:14])=[N:12][CH:13]=[C:8]2[C:7]([C:15]2[N:16]=[N:17][C:18]3[C:22]([CH3:28])([CH3:27])[C:23](=[O:25])[NH:39][C:19]=3[N:20]=2)=[N:6]1
Reactant: COC(=O)C(C)(C)c1nnc(-c2nn(Cc3cccc(F)c3F)c3nc(C)ncc23)nc1O
Reactant: N
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: Cc1ncc2c(-c3nnc4c(n3)NC(=O)C4(C)C)nn(Cc3cccc(F)c3F)c2n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
160 mg (purity 89%, 0.313 mmol) of methyl 2-{3-[1-(2,3-difluorobenzyl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-5-hydroxy-1,2,4-triazin-6-yl}-2-methylpropanoate were admixed with 4 ml (42.913 mmol) of phosphoryl chloride and the mixture was stirred at RT for 2.5 h. The reaction solution was diluted with 20 ml of dry acetonitrile and gradually added dropwise while cooling with ice to 40 ml of a 25% aqueous ammonia solution, and the mixture was stirred at RT for 1 h. The reaction mixture was concentrated on a rotary evaporator and the precipitate was filtered off. The residue was stirred with hot ethanol/water and filtered with suction, and the solids were dried under high vacuum. 70 mg of the target compound were obtained (52% of theory).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[Cl:23][C:24]1[CH:44]=[CH:43][C:27]2[C:28](=[O:42])[C:29]3[C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[N:35][NH:34][C:30]=3[C:31](=O)[NH:32][C:26]=2[CH:25]=1>C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:44]=[CH:43][C:27]2[C:28](=[O:42])[C:29]3[C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[N:35][NH:34][C:30]=3[C:31](=[S:10])[NH:32][C:26]=2[CH:25]=1
Reactant: CCOC(=O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1n[nH]c2c(=S)[nH]c3cc(Cl)ccc3c(=O)c12
Yield: 82 %

Procedure:
To a suspension of Lawesson's Reagent [(2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide) (0.32 g. 0.80 mmol) in dry toluene (15 mL) at room temperature was added 7-chloro-3-(ethoxycarbonyl)pyrazolo-[3,4-c][1]benzazepine-4,10(1H,9H)-dione (0.51 g, 1.59 mmol) in one portion. The resulting slurry was heated to reflux for 1.5 hours. The reaction mixture was filtered to remove insoluble material. The filtrate was concentrated via rotary evaporator to give a green oil which was purified by flash chromatography using chloroform:methanol (9:1) as the eluent. The yellow-green solid recovered was recrystallized from methanol to give the title compound (0.44 g, 82%, mp 248.0-252.6° C.).
Reaction SMILES: O(C)[Na].CO.Br.[C:7]([N:10]1[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]1=[O:17])(=[NH:9])[NH2:8].[CH3:18][N:19]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=1)[C:20](=[O:28])[C:21]([C:26]#[N:27])=[CH:22]OCC>CO>[C:26]([C:21]([C:20](=[O:28])[N:19]([CH3:18])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=1)=[CH:22][NH:9][C:7](=[NH:8])[N:10]1[CH2:14][C:13]([CH3:15])([CH3:16])[NH:12][C:11]1=[O:17])#[N:27]
Reactant: CC1(C)CN(C(=N)N)C(=O)N1
Reactant: CCOC=C(C#N)C(=O)N(C)c1cccc(C(F)(F)F)c1
Agent: Br
Agent: CO[Na]
Solvent: CO
Product: CN(C(=O)C(C#N)=CNC(=N)N1CC(C)(C)NC1=O)c1cccc(C(F)(F)F)c1
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 77.7 %

Procedure:
3.60 g (=3.67 ml, 20 mmol) of 30% strength NaOCH3 /CH3OH solution were added to a solution of 4.74 g (20 mmol) of 1-amidino-4,4-dimethyl-2-oxoimidazolidine hydrobromide in 47 ml of methanol at room temperature, and the mixture was stirred at 45° C. for 30 min. The solution was then cooled to 20° C. and, at 20° C., 5.97 g (20 mmol) of 2-cyano-3-ethoxyacrylic acid N-methyl-N-(3-trifluoromethylphenyl)amide were added and the mixture was stirred at 20° C. for 20 min, at room temperature for 1.5 hours and while cooling in an icebath for 30 min. The solid which had separated out was filtered off with suction, washed with ether and worked up further as described in Example 1. Likewise, the residue from the filtrate (mother liquor) was further worked up as described in Example 1 and dried. 6.35 g (=77.7% yield) of, according to TLC (CH2Cl2 /C2H5 OH=10:1), virtually pure compound IV were obtained.
Reaction SMILES: [NH2:1][C:2]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]C)=O)=[S:3].O.[NH2:13][NH2:14]>CO>[NH:13]([C:8](=[O:10])[CH2:7][CH2:6][CH2:5][NH:4][C:2]([NH2:1])=[S:3])[NH2:14]
Reactant: NN
Reactant: COC(=O)CCCNC(N)=S
Solvent: CO
Solvent: O
Product: NNC(=O)CCCNC(N)=S
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.9 %

Procedure:
Methyl 4-[(aminocarbothioyl)amino]butanoate (176.24 mg; 1.00 mmol; 1.00 eq.) (prepared from methyl 3-aminobutanoate, hydrochloride salt (Fluka), following procedure D) is dissolved in MeOH (10.00 ml). Hydrazine hydrate (2.97 ml; 48.89 mmol; 48.89 eq.) is added. The reaction mixture is stirred 5 hours under reflux and overnight at RT. Solvents are evaporated. The resulting oil is dissolved in MeOH and EtOH is added. A white product precipitates. It is filtrated and washed with EtOH, affording N-(4-hydrazino-4-oxobutyl)thiourea (128.5 mg; 72.91%). HPLC, Rt: 6.50 min (purity: 86.9%).
Reaction SMILES: [OH:1][C:2]([CH:10]=[C:11]=[CH2:12])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5].N1C=CN=C1.CN(C)C=O.Cl[Si:24]([CH3:27])([CH3:26])[CH3:25]>O>[CH:10]([C:2]([O:1][Si:24]([CH3:27])([CH3:26])[CH3:25])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5])=[C:11]=[CH2:12]
Reactant: C#CCC(O)(C=C=C)CCCC
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: C#CCC(C=C=C)(CCCC)O[Si](C)(C)C
Reaction time: 70 h

Procedure:
To a stirred, ice-cold solution of 10.85 g. (66.1 mmol.) of 4-hydroxy-4-propadienyl-1-octyne and 13.2 g. (194 mmol.) of imidazole in 50 ml. of dimethylformamide at 0° C. is added 9.5 ml. of chlorotrimethylsilane. The solution is kept at 0° C. for 70 hours and diluted with petroleum ether. The resulting mixture is shaken with water at 0° C. The organic layer is washed with water and brine, dried over magnesium sulfate and concentrated to give the title compound as a liquid.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[Li+].[OH-].N1C=CC=C(CC([N:21]2[CH2:28][S:27][CH2:26][C@@H:22]2[C:23]([OH:25])=[O:24])=O)C=1.[CH2:29]([O:36][C:37]1[CH:48]=[CH:47][C:40]([CH2:41][C@@H:42]([C:44]([OH:46])=[O:45])[NH2:43])=[CH:39][CH:38]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:1]([N:21]2[CH2:28][S:27][CH2:26][C@@H:22]2[C:23]([OH:25])=[O:24])=[O:9])[CH:3]=1.[CH2:29]([O:36][C:37]1[CH:38]=[CH:39][C:40]([CH2:41][C@@H:42]([C:44]([OH:46])=[O:45])[NH2:43])=[CH:47][CH:48]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(O)[C@H]1CSCN1C(=O)Cc1cccnc1
Reactant: O=C(O)c1cccnc1
Agent: N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)[C@H]1CSCN1C(=O)c1cccnc1

Procedure:
Intermediate 18 was coupled to nicotinic acid in a similar manner to that described for Intermediate 19, and subsequently hydrolysed with aqueous LiOH, as described for the compound of Example 7, to afford the title compound. δH (DMSO-d6) 8.78-8.55 (2 H, br m), 8.38 (1 H, br d J 7.8 Hz), 8.21-7.25 (7 H, m), 7.11 (2 H, d, J 8.5 Hz), 6.85 (2 H, br d, J 8.0 Hz), 5.02 (2H, s), 5.03-4.3 (4 H, m), 3.40-3.22 (1 H, br m), 3.03 (1 H, dd, J 13.8, 4.6 Hz) and 2.90-2.75 (2 H, m); m/z (ESI), 492 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([O:15][CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([Cl:14])[CH:8]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].O.Br[CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:32][CH:31]=1>CC#N>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([O:15][CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:26][CH2:27][CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)=[C:9]([Cl:14])[CH:8]=1)[CH3:2]
Reactant: BrCCCOc1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)C(Cc1ccc(O)c(Cl)c1)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C(Cc1ccc(OCCCOc2ccc(-c3ccccc3)cc2)c(Cl)c1)OC
Temperature: 85 °C
Reaction time: 5 h
Yield: 48 %

Procedure:
3-(3 Chloro-4-hydroxy-phenyl)-2-methoxy-propionic acid ethyl ester (0.020 g, 0.077 mmol) was dissolved in CH3CN (3 mL) and 4-(3-bromo-propoxy)-biphenyl (Example 132, Step D), (0.025 g 0.085 mmol) and K2CO3 (0.032 g, 0.23 mmol) were added. The mixture was heated to 85° C. and stirred for 5 hours. After cooling, water (2 mL) was added. The mixture was extracted in EtOAc (3×10 mL), washed with H2O (2×5 mL) and brine (2×5 mL). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (silica gel, hexanes/ethyl acetate 9:1) to produce 3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3-chloro-phenyl}-2-methoxy-propionic acid ethyl ester (0.017 mg, 48%). 1H-NMR (200.15 MHz, CDCl3): δ 7.57–7.24 (m, 9H), 7.02–6.89 (m, 3H), 4.28–4.12 (m, 5H), 3.89 (dd, 1H, J=7.24, 5.62), 3.62 (t, 1H, J=6.44), 3.36 (s, 3H), 2.93 (dd, 2H, J=6.31, 2.42), 2.32 (qn, 2H, J=5.10), 1.25 (t, 3H, J=7.2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[C:10]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:14])[C:11]([CH3:13])=O>>[CH2:16]([O:15][C:10](=[O:14])[C@H:11]([CH3:13])[NH:5][C:4]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)C(=O)OCc1ccccc1
Reactant: Nc1ccc(Cl)c(Cl)c1
Product: C[C@H](Nc1ccc(Cl)c(Cl)c1)C(=O)OCc1ccccc1

Procedure:
Following General Procedure AA above and using 3,4-dichloroaniline (Aldrich) and benzyl pyruvate (prepared by following General Procedure AO above using benzyl alcohol in place of iso-butanol), the title compound was prepared as an oil. The reaction was monitored by tlc on silica gel (Rf=0.4 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Br:12])=[CH:4][CH:3]=1.[Mg].II.[C:16](=[O:18])=[O:17].Cl>C1COCC1.O>[Br:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([C:16]([OH:18])=[O:17])=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)c2ccccc12
Reactant: O=C=O
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Br)c2ccccc12
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A solution of 1,4-dibromonaphthalene (100 g) in THF (500 ml) is added to magnesium (8.49 g) and iodine (trace) in THF (200 ml) over about 2 h and heated at 65-75° C. for up to 7 h (typically 3-4 h) to prepare a solution of the Grignard reagent. The solution is cooled to 0-10° C. and carbon dioxide gas is passed through the solution for 10-16 h. Water (100 ml) is added slowly, and after stirring for about 30 min at 0-10° C., is acidified (typically to pH 2-3) with hydrochloric acid. The THF layer is separated off, and concentrated. The residue is added to aqueous sodium carbonate (20%, 500 ml) and washed with toluene (2×200 ml). The aqueous solution is treated with hydrochloric acid (typically to pH 2-3). The product is filtered off, washed with water, and dried under vacuum at about 90-100° C. for about 12 h (dry weight 60 g).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>>[CH2:36]([O:35][C:33](=[O:34])[NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)[CH3:37]
Reactant: CCOC(=O)Cl
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c[nH]c23)c1
Product: CCOC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4cc(C)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-5-methyl-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A170) and ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: C1(CNCC2C=C(C3C=C4C(=C(C(N)=O)C=3)NC=C4C3CCN(S(CC)(=O)=O)CC3)C=NC=2)CC1.[CH3:36][C:37]1([CH3:52])[C:41]([CH3:43])([CH3:42])[O:40][B:39]([C:44]2[CH:45]=[C:46]([CH:50]=O)[CH:47]=[N:48][CH:49]=2)[O:38]1.[CH3:53][C:54]([CH3:58])([CH3:57])[CH2:55][NH2:56].[BH3-]C#N.[Na+]>>[CH3:53][C:54]([CH3:58])([CH3:57])[CH2:55][NH:56][CH2:50][C:46]1[CH:47]=[N:48][CH:49]=[C:44]([B:39]2[O:38][C:37]([CH3:52])([CH3:36])[C:41]([CH3:43])([CH3:42])[O:40]2)[CH:45]=1
Reactant: CC1(C)OB(c2cncc(C=O)c2)OC1(C)C
Reactant: CC(C)(C)CN
Agent: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cncc(CNCC5CC5)c4)cc23)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(C)(C)CNCc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Yield: 63.7 %

Procedure:
Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), (2,2-dimethylpropyl)amine (0.015 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol) were reacted to give 25 mg of crude (2,2-dimethylpropyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine. The crude (2,2-dimethylpropyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(II) (4.4 mg, 0.00723 mmol) to give 12.7 mg of the title compound (34%).
Reaction SMILES: [CH2:1]([C:7]12[S:14][CH2:13][C:10]([CH2:15][CH2:16][CH3:17])([CH2:11][S:12]1)[CH2:9][O:8]2)[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].C([O-])(=[O:20])C.[Na+].ClC1C=CC=C(C(OO)=O)C=1.O>C(#N)C>[CH2:1]([C:7]12[S:12][CH2:11][C:10]([CH2:15][CH2:16][CH3:17])([CH2:13][S:14]1=[O:20])[CH2:9][O:8]2)[CH2:2][CH2:3][CH2:4][C:5]#[CH:6]
Reactant: CC(=O)[O-]
Reactant: C#CCCCCC12OCC(CCC)(CS1)CS2
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: C#CCCCCC12OCC(CCC)(CS1)CS2=O

Procedure:
A mixture of 1-(hex-5-ynyl)-4-n-propyl-2-oxa-6,7-dithiabicyclo-[2.2.2]octane (0.75 g., 1 equivalent), anhydrous sodium acetate (2.0 g.) and 3-chloroperbenzoic acid (85%, 1.12 g. 2.5 equivalents) was stirred at 20° in dry acetonitrile (50 ml.) for 18 hours. Water was added and the mixture was extracted with ethyl acetate. The extracts were washed with sodium hydrogen carbonate solution, water and dried over anhydrous magnesium sulphate. The solvent was removed in vacuo. After purification by chromatography on silica (eluting with ethyl acetate), 1-(hex-5-ynyl)-4-n-propyl-2-oxa-6,7-dithiabicyclo[2.2.2]octane-6-oxide was obtained as a colourless solid (0.35 g.).