Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:7][C:6](=[O:8])[C:5](=[C:9]([CH3:11])[CH3:10])[C:4](=[O:12])[O:3]1.[C-:14]#[N:15].[K+]>>[CH3:13][C:2]1([CH3:1])[O:3][C:4](=[O:12])[CH:5]([C:9]([CH3:10])([CH3:11])[C:14]#[N:15])[C:6](=[O:8])[O:7]1
Reactant: CC(C)=C1C(=O)OC(C)(C)OC1=O
Reactant: [C-]#N
Agent: [K+]
Product: CC1(C)OC(=O)C(C(C)(C)C#N)C(=O)O1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 120, Step 2 starting from 2,2-dimethyl-5-(1-methylethylidene)-1,3-dioxane-4,6-dione and potassium cyanide.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1.[C:23]([OH:29])([C:25]([F:28])([F:27])[F:26])=[O:24]>C(Cl)Cl>[Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:3]=1[O:4][CH:5]1[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1.[C:23]([OH:29])([C:25]([F:28])([F:27])[F:26])=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2c(Cl)cccc2Cl)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1cccc(Cl)c1OC1CCNCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
tert-Butyl 4-(2,6-dichlorophenoxy)piperidine-1-carboxylate (5.54 g) was mixed with 50 ml of mixture of TFA and CH2Cl2 (1:1). The mixture was stirred at room temperature for 4 hours. The solvents were removed under vacuum residue was Freeze-dried using CH3CN/water system. The desired 4-(2,6-dichlorophenoxy)piperidine was obtained as TFA salt (white solid) in 100% yield.
Reaction SMILES: [CH2:1]([CH:3]([C:6](=O)[CH3:7])[CH:4]=O)[CH3:2].[Na].[C:10]([CH2:12][C:13]([NH2:15])=[O:14])#[N:11].C([O-])(=O)C.[NH2+]1CCCCC1>O.C(O)(=O)C>[C:10]([C:12]1[C:13](=[O:14])[NH:15][C:1]([CH3:2])=[C:3]([CH2:6][CH3:7])[CH:4]=1)#[N:11]
Reactant: N#CCC(N)=O
Reactant: CCC(C=O)C(C)=O
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Product: CCc1cc(C#N)c(=O)[nH]c1C
Temperature: 25 °C

Procedure:
According to the method described in J.Heterocyclic Chem., 24, 351 (1987), a mixture of 2-ethyl-3-oxobutanal, sodium salt (37.5 g, 0.275 mmol), cyanoacetamide (25.2 g, 0.30 mol), aqueous piperidinium acetate (22 mL) [prepared from glacial acetic acid (4.2 mL), water (10 mL) and piperidine (7.2 mL)] in water (775 ml) was refluxed for four hours. Glacial acetic acid (30 ml) was added cautiously (much foaming) as the product precipitated. Upon cooling to room temperature, the product was collected by filtration, washed with cold water and air dried to yield 22.3 g (50%), m.p. 237°-240° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH3:17])[C:7]1=[O:18].ClCCCCN1C(=O)C2C(=CC=CC=2)N(C)C1=O.[I-:37].[Na+]>C(C(C)=O)C>[I:37][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH3:17])[C:7]1=[O:18]
Reactant: Cn1c(=O)n(CCCCBr)c(=O)c2ccccc21
Reactant: [I-]
Agent: Cn1c(=O)n(CCCCCl)c(=O)c2ccccc21
Agent: [Na+]
Solvent: CCC(C)=O
Product: Cn1c(=O)n(CCCCI)c(=O)c2ccccc21
Yield: 100 %

Procedure:
A solution of the title A compounds, 3-(4-bromobutyl)-1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazoline and 3-(4-chlorobutyl)-1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazoline (1:1 mixture; 2.35 g, 8.13 mmol) in 30 mL of methyl ethyl ketone is treated with sodium iodide (2.64 g, 17.62 mmol) at RT. The reaction is heated at reflux for 16 h, then cooled and the solvent is evaporated under reduced pressure. The residue is partitioned between 200 mL of ethyl acetate and 5 mL of water. The organic solution is washed with 10 mL of 1% aqueous sodium sulfite and 10 mL of brine, dried over anhydrous MgSO4, and concentrated to give 3.10 g (100%) of 3-(4-iodobutyl)-1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazoline as a white solid: m.p. 105-107° C.; NMR (CDCl3) 1.75-1.95 (m, 4H), 3.22 (t, 2H, J=6.8), 3.59 (s, 3H), 4.11 (t, 2H, J=7.1), 7.17-7.28 (m, 2H), 7.67 (dt, 1H, J=1.6, 7.9), 8.21 (dd, 1H, J=1.5, 7.9); IR 1702, 1658; ESI-MS 359 (M++1).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[N:8]=[CH:9][N:10]3[C:19]4[C:14](=[C:15](C(F)(F)F)[CH:16]=[CH:17][CH:18]=4)[C:13](=[O:24])[N:12]([CH3:25])[C:11]=23)[N:3]=1.CN1C(=O)C2[C:30](=[CH:31]C=CC=2C(F)(F)F)NC1=O.CC1ON=C(C[N+]#[C-])N=1>>[CH:1]1([C:2]2[O:6][N:5]=[C:4]([C:7]3[N:8]=[CH:9][N:10]4[C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[C:13](=[O:24])[N:12]([CH3:25])[C:11]=34)[N:3]=2)[CH2:31][CH2:30]1
Reactant: Cn1c(=O)[nH]c2cccc(C(F)(F)F)c2c1=O
Reactant: Cc1nc(-c2ncn3c4cccc(C(F)(F)F)c4c(=O)n(C)c23)no1
Agent: [C-]#[N+]Cc1noc(C)n1
Product: Cn1c(=O)c2ccccc2n2cnc(-c3noc(C4CC4)n3)c12

Procedure:
3-(5-methyl-1,2,4-oxadiazol-3-yl)-4,5-dihydro-4-methyl-5-oxo-6-trifluoromethyl-imidazo(1,5-a)quinazoline, M.p. 251.5°-251.9° C., by reaction between 3-methyl-5-trifluoromethyl 1,2,3,4-tetrahydro-2,4-dioxo-quinazoline and 5-methyl-3-isocyanomethyl-1,2,4-oxadiazole.
Reaction SMILES: C(O)C.[Cl-].[NH4+].[N+:6]([C:9]1[CH:26]=[CH:25][C:12]([CH:13]=[C:14]2[CH:19]3[C:20]([CH3:22])([CH3:21])[C:16]([CH3:23])([CH2:17][CH2:18]3)[C:15]2=[O:24])=[CH:11][CH:10]=1)([O-])=O>[Zn].O>[NH2:6][C:9]1[CH:10]=[CH:11][C:12]([CH:13]=[C:14]2[CH:19]3[C:20]([CH3:22])([CH3:21])[C:16]([CH3:23])([CH2:17][CH2:18]3)[C:15]2=[O:24])=[CH:25][CH:26]=1
Reactant: CC12CCC(C(=Cc3ccc([N+](=O)[O-])cc3)C1=O)C2(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: CC12CCC(C(=Cc3ccc(N)cc3)C1=O)C2(C)C
Yield: 99 %

Procedure:
A mixture of fine zinc powder (60 g), ethanol (250 ml), ammonium chloride (2 g) and water (20 ml) is heated to the reflux temperature and the paranitrobenzylidenecamphor (20 g, 0.07 mol) is added in portions with stirring. The mixture is allowed to reflux for half an hour, the zinc is filtered and the mixture is rinsed with alcohol. The filtrate is poured in ice (500 g). The precipitate obtained is filtered, washed with water and dried under vacuum. A quantitative yield of para-aminobenzylidenecamphor (17.7 g) is obtained. It is recrystallised in ethanol to give the expected derivative:
Reaction SMILES: [NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1.[OH-].[Na+].OO.CC(O)=[O:38]>CCO.CS(C)=O>[NH2:1][C@H:2]1[C:7]([F:8])([F:9])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=3)=[CH:22][CH:21]=2)[C:14]([C:17]([NH2:18])=[O:38])=[N:15][CH:16]=1
Reactant: N#Cc1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1ccc(-c2ccncc2)cc1
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: NC(=O)c1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1ccc(-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-chloropyrazine-2-carbonitrile (74 mg, 0.257 mmol), 4-(pyridin-4-yl)aniline (60 mg, 0.352 mmol), K2CO3 (100 mg, 0.724 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (15 mg, 0.066 mmol) in dioxane (4 mL) was degassed with Ar, then was stirred at 110 C for 20 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to give 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(4-(pyridin-4-yl)phenylamino)pyrazine-2-carbonitrile (41 mg). The compound 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(4-(pyridin-4-yl)phenylamino)pyrazine-2-carbonitrile (41 mg, 0.097 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (30%, 1.0 mL) were added. The mixture was stirred at room temperature for 15 min. HOAc (0.1 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (32 mg). MS 440.3 (M+H); UV 201.7, 242.5, 278.7 nm; t 0.384 min.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10]([C:13]1[CH:18]=[N:17][N:16]2[CH:19]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:21]=[C:15]2[C:14]=1Cl)(=[O:12])[NH2:11].[CH3:28][C@:29]1([NH2:37])[CH2:33][CH2:32][C@@H:31]([NH2:34])[C:30]1([CH3:36])[CH3:35]>CN(C)C=O>[NH2:37][C@@:29]1([CH3:28])[CH2:33][CH2:32][C@@H:31]([NH:34][C:14]2[C:15]3[N:16]([CH:19]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:21]=3)[N:17]=[CH:18][C:13]=2[C:10](=[O:12])[NH2:11])[C:30]1([CH3:36])[CH3:35]
Reactant: CC1(C)[C@H](N)CC[C@]1(C)N
Reactant: CCOC(=O)c1cc2c(Cl)c(C(N)=O)cnn2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(N[C@@H]3CC[C@](C)(N)C3(C)C)c(C(N)=O)cnn2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 44.8 %

Procedure:
N,N-Diisopropylethylamine (7.18 mL, 41.1 mmol) was added to a mixture of ethyl 3-carbamoyl-4-chloropyrrolo[1,2-b]pyridazine-6-carboxylate (3.67 g, 13.71 mmol, from Preparation 4), (1S,3R)-1,2,2-trimethylcyclopentane-1,3-diamine (2.93 g, 20.57 mmol, prepared according to conditions described in Tetrahedron Asymmetry 2001, 12, 1579 and Eur. J. Inorg. Chem. 2006, 839) and N,N-dimethylformamide (50 mL). The mixture was stirred in a 90° C. oil bath for 1 h, quenched with saturated sodium bicarbonate (250 mL) and extracted with ethyl acetate (4×200 mL). The combined extracts were dried (MgSO4), filtered, concentrated and pumped under vacuum. The solid residue was treated with ethyl acetate (60 mL) and sonicated for 10 min. Vacuum filtration gave the first batch of the title compound (2.292 g). The filtrate was concentrated to dryness. The solid residue was treated with dichloromethane (5 mL), ethyl acetate (4 mL) and hexanes (16 mL). The mixture was sonicated for 15 min and filtered. The solid was washed with 20% ethyl acetate in hexanes to give second batch of the title compound (2.146 g). The combined amount of the title compound was 4.438 g (87% yield). 1H NMR (500 MHz, methanol-d4) δ ppm 8.19 (1 H, s), 8.00 (1 H, d, J=1.66 Hz), 7.33 (1 H, d, J=1.66 Hz), 4.47 (1 H, t, J=8.18 Hz), 4.35 (2 H, q, J=7.03 Hz), 2.21-2.49 (1 H, m), 1.77-1.93 (2 H, m), 1.63-1.75 (1 H, m), 1.38 (3 H, t, J=7.21 Hz), 1.21 (3 H, s), 1.07 (3 H, s), 0.96 (3 H, s); MS (ES+) m/z: 374.2 (M+H); HPLC retention time: 2.975 min (analytical HPLC Method F).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=2)[C:35]([NH2:37])=[O:36])O1.C([O-])([O-])=O.[Na+].[Na+]>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>[CH3:23][O:22][C:14]1[CH:13]=[C:12]([NH:11][C:4]2[C:5]3[N:10]=[CH:9][S:8][C:6]=3[N:7]=[C:2]([C:32]3[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=3)[C:35]([NH2:37])=[O:36])[N:3]=2)[CH:17]=[C:16]([O:18][CH3:19])[C:15]=1[O:20][CH3:21]
Reactant: CC1(C)OB(c2cccc(C(N)=O)c2)OC1(C)C
Reactant: COc1cc(Nc2nc(Cl)nc3scnc23)cc(OC)c1OC
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(Nc2nc(-c3cccc(C(N)=O)c3)nc3scnc23)cc(OC)c1OC
Temperature: 97 °C
Reaction time: 16 h
Yield: 28.9 %

Procedure:
To a stirred solution of 5-chloro-N-(3,4,5-trimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine (337 mg, 0.95 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (190 mg, 1.15 mmol) and Na2CO3 (347 mg, 3.27 mmol) in 2 mL of water and 50 mL of dioxane was added Pd(PPh3)4 (100 mg, 0.086 mmol) in one portion at room temperature under nitrogen. Then the mixture was stirred at 97° C. for 16 hours under nitrogen. The solvent was evaporated at 40° C. at reduced pressure and the residue was purified by silica gel chromatography (silica gel 200-300 mesh, eluting with a mixture of petroleum ether and ethyl acetate (1:2)) to give a crude product. It was purified by preparative HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 ml/inj, flow rate: 20 ml/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 20% acetonitrile/80% water (0.1% TFA V/V) initially, and then proceed to 45% acetonitrile/55% water (0.1% TFA V/V) in a linear fashion after just 9 min.) to give 3-(7-(3,4,5-trimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzamide (120 mg, 27.4%) as a solid. 1H NMR (300 MHz, DMSO): δ 10.10 (s, 1H), 9.43 (s, 1H), 8.93 (s, 1H), 8.58 (d, 1H, J=8.1 Hz), 8.03-8.00 (m, 2H), 7.65-7.60 (m, 3H), 7.50 (brs, 1H), 3.87 (s, 3H), 3.71 (s, 3H), 3.30 (s, 3H). LC-MS: 438 [M+H]+, tR=1.43 min. HPLC: 99.77% at 214 nm, 99.84% at 254 nm, tR=5.68 min.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([C:16]([O:18]C)=O)[CH:9]=[C:10]([CH:15]=2)[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:20]([O:23][CH3:24])(=[O:22])[CH3:21].C[O-].[Na+].Cl>CN(C)C=O.O>[CH3:14][O:13][C:11]([C:10]1[CH:9]=[C:8]([C:16](=[O:18])[CH2:21][C:20]([O:23][CH3:24])=[O:22])[CH:7]=[C:6]([N:1]2[CH:2]=[CH:3][CH:4]=[CH:5]2)[CH:15]=1)=[O:12]
Reactant: COC(C)=O
Reactant: COC(=O)c1cc(C(=O)OC)cc(-n2cccc2)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CC(=O)c1cc(C(=O)OC)cc(-n2cccc2)c1
Temperature: 55 °C
Yield: 8.9 %

Procedure:
A mixture of dimethyl 5-(pyrrol-1-yl)isophthalate (3.0 g), methyl acetate (0.86 g) and sodium methoxide (0.81 g) in N,N-dimethylformamide (21 ml) was heated at 55° C. for 3 hours. After being cooled to room temperature, the reaction mixture was poured into water (100 ml) and the whole was adjusted to pH 3 with 10% hydrochloric acid. The resulting precipitate was collected and washed with water. This crude product was purified by column chromatography on silica gel (150 ml) with benzene-ethyl acetate (30:1) as an eluent. The fractions containing the object product were collected and evaporated in vacuo. The residue was recrystallized from methanol to afford methyl 3-[3-methoxycarbonyl-5-(pyrrol-1-yl)phenyl]-3-oxopropionate (0.31 g).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.O[C:11]([CH3:34])([CH3:33])[CH2:12][CH:13]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C:27]2=[O:32])[CH2:14]1.O>ClCCl>[F:7][C:11]([CH3:34])([CH3:33])[CH2:12][CH:13]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C:27]2=[O:32])[CH2:14]1
Reactant: CC(C)(O)CC1CCN(CCc2ccccc2N2CCCCC2=O)C1
Reactant: CCN(CC)S(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CC(C)(F)CC1CCN(CCc2ccccc2N2CCCCC2=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
Diethylaminosulfur trifluoride (31 μl, 0.235 mmol, 1.5 eq) is added to 1-(2-{2-[3-(2-hydroxy-2-methyl propyl)pyrrolidin-1-yl]ethyl}phenyl)piperidin-2-one a13-2 (54 mg, 0.157 mmol, 1 eq) in dichloromethane (5 ml) dropwise and the reaction mixture stirred at room temperature overnight. The reaction mixture is poured into water and stirring is pursued for 1 hour. After phase separation, the aqueous phase is further extracted with dichloromethane (3 times). The combined organic phases are washed with brine (1 time), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue is purified by basic reverse phase chromatography (gradient: acetonitrile/H2O/ammonium formiate from 5% to 40% of acetonitrile in 8 minutes) to afford 6 mg of 1-(2-{2-[3-(2-fluoro-2-methylpropyl)pyrrolidin-1-yl]ethyl}phenyl)piperidin-2-one 85 as a yellow oil.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH:6]([O:9][C:10]2[C:21]3[C:20]4[C@@H:19]([CH2:22][C:23]([NH2:25])=[O:24])[CH2:18][CH2:17][C:16]=4[S:15][C:14]=3[N:13]=[CH:12][N:11]=2)[CH2:5][CH2:4]1.Cl[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][N:2]([CH2:27][C:28](=[O:29])[N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)[CH:3]1[CH2:8][CH2:7][CH:6]([O:9][C:10]2[C:21]3[C:20]4[C@@H:19]([CH2:22][C:23]([NH2:25])=[O:24])[CH2:18][CH2:17][C:16]=4[S:15][C:14]=3[N:13]=[CH:12][N:11]=2)[CH2:5][CH2:4]1
Reactant: CNC1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(N)=O)CC4)CC1
Reactant: O=C(CCl)N1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(CC(=O)N1CCCC1)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(N)=O)CC4)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
A solution of 2-[(3R)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]acetamide (90 mg, 0.25 mmol, 1.00 equiv) in 8 mL of DMF was added 2-chloro-1-(pyrrolidin-1-yl)ethan-1-one (55 mg, 0.37 mmol, 1.50 equiv) and potassium carbonate (69 mg, 0.50 mmol, 2.00 equiv) and the resulting solution was stirred overnight at room temperature. The reaction was quenched with water and extracted with DCM. The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (80 mg) was purified by preparative HPLC under the following conditions (SHIMADZU): column: SunFire Prep C18, 19*150 mm 5 um; mobile phase: water with 0.05% NH4HCO3 and CH3CN (6.0% CH3CN up to 50.0% in 16 min); flow rate: 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the desired 2-[(3R)-12-[(4-[methyl[2-oxo-2-(pyrrolidin-1-yl)ethyl]amino]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]acetamide (50 mg) as a white solid. LCMS (ES): m/z 472 [M+H]+. 1H NMR (300 MHz, CD3OD): δ 8.43 (1H, s), 5.25-5.20 (1H, m), 3.85-3.69 (1H, m), 3.52 (2H, t), 3.42 (2H, t), 3.37 (2H, s), 3.15-2.85 (2H, m), 2.73-2.58 (2H, m), 2.29-2.18 (7H, m), 1.96-1.79 (6H, m), 1.67-1.47 (4H, m).
Reaction SMILES: I/[CH:2]=[C:3]1\[CH2:4][CH2:5][C:6](=[O:8])[O:7]\1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30]>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:28][Si:29]([CH3:31])([CH3:30])[C:32]#[C:33]/[CH:2]=[C:3]1\[CH2:4][CH2:5][C:6](=[O:8])[O:7]\1
Reactant: C#C[Si](C)(C)C
Reactant: O=C1CC/C(=C\I)O1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#C/C=C1\CCC(=O)O1

Procedure:
To a solution of 5(E)-iodomethylidenetetrahydro-2-furanone (820 mg), palladium (II) acetate (40 mg) and triphenylphosphine (80 mg) in 5 ml of triethylamine under argon was added 42 ml of trimethylsilylacetylene. The solution was refluxed for 4 hours and then partitioned between 150 ml of methylene chloride and 50 ml of water. The methylene chloride layer, dried over magnesium sulphate, was evaporated to an oil. This oil was purified by column chromatography on silica gel (10% ethyl acetate:petrolium ether, IR: 2130, 1820, 1762 cm-1.
Reaction SMILES: [SH:1][C:2]1[N:3]([CH3:15])[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:14]=1.[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([S:1][C:2]1[N:3]([CH3:15])[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:14]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cn1c(S)nc2cnc3ccccc3c21
Reactant: ClCc1ccccc1
Product: Cn1c(SCc2ccccc2)nc2cnc3ccccc3c21

Procedure:
Using the method of Example 162, 2-mercapto-1-methyl-1H-imidazo[4,5-c]quinoline (from Example 165 below) was reacted with benzyl chloride to provide 2-benzylthio-1-methyl-1H-imidazo[4,5-c]quinoline. Recrystallization first from isopropanol then from ethanol provided solid product, m.p. 160°-163° C. Analysis: Calculated for C18H15N3S: %C, 70.8; %H, 5.0; %N, 13.8. Found: %C, 70.3; %H, 4.7; %N, 13.7.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=1>CN(C)C=O>[F:21][C:19]1[CH:20]=[C:15]([CH:16]=[C:17]([F:22])[CH:18]=1)[CH2:14][N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[CH:8]=[CH:9]1
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: Fc1cc(F)cc(CBr)c1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2ccn(Cc3cc(F)cc(F)c3)c2c1
Reaction time: 0.5 h
Yield: 123.6 %

Procedure:
—Sodium hydride (50% dispersion in oil, 4.8 g, 100 mmol) was added to a solution of 6-nitroindole (15.0 g, 92.6 mmol) in dry dimethylformamide (750 ml). After 30 min. stirring, 1-bromomethyl-3,5-difluoro-benzene (19.5 g, 94 mmol) was added. Stirring was continued for 1 h and the reaction mixture was quenched with water. The product was extracted into ethyl acetate; the combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was stirred with heptane to produce a white solid which was collected by filtration to give 1-(3,5-difluoro-benzyl)-6-nitro-1H-indole (33 g). The product was used in the following step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.[OH:25][CH2:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[CH2:23]([S:20]([N:17]1[CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:31]4[CH:30]=[CH:29][CH:28]=[C:27]([CH2:26][OH:25])[CH:32]=4)[CH:3]=3)[NH:7][N:6]=2)[CH2:15][CH2:16]1)(=[O:22])=[O:21])[CH3:24]
Reactant: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: OCc1cccc(B(O)O)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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4cccc(CO)c4)cc23)CC1
Yield: 67.7 %

Procedure:
Following the general procedure of Example 65, a mixture of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indazole-7-carboxamide (Intermediate 13) (180 mg, 0.4337 mmols), [3-(hydroxymethyl)phenyl]boronic acid (264 mg, 1.74 mmols), cesium carbonate (282 mg, 0.868 mmol), and Pd(PPh3)4 (22 mg, 0.021 mmol) in dioxane/water (2 mL/0.7 mL) was reacted. The reaction mixture was concentrated, redissolved in methylene chloride and filtered. The filtrate was concentrated and the residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (130 mg, 68%)
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[C:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[S:5][CH:6]=1.[NH2:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24]>CN(C=O)C>[Br:1][C:2]1[C:3]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:13])=[CH:14][CH:15]=2)[S:5][CH:6]=1
Reactant: COC(=O)Cc1c(Br)csc1-c1ccc(C(=O)O)cc1
Reactant: CCC(N)CC
Solvent: CN(C)C=O
Product: CCC(CC)NC(=O)c1ccc(-c2scc(Br)c2CC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.8 %

Procedure:
4-(4-Bromo-3-methoxycarbonylmethyl-thiophen-2-yl)-benzoic acid (0.303 g, 0.85 mmol) was dissolved in DMF (2 mL) and carbonyldiimidizole (0.172 g, 1.06 mmol) was added. The solution was stirred at RT for thirty minutes and 3-aminopentane (0.222 g, 2.55 mmol) was added. Stirring was continued for 3 h and the solvent was removed. The mixture was partitioned between EtOAc and H2O. The EtOAc was dried (MgSO4) and the solvent was removed to yield methyl [4-bromo-2-(4-{[(1-ethylpropyl)amino]carbonyl}phenyl)thien-3-yl]acetate (0.248 g) as a white solid. mp 97-98° C.; 1H NMR (500 MHz, DMSO-d6) δ: 0.87 (t, 6H, J=7.3 Hz), 1.49 (m, 2H), 1.54 (m, 2H), 3.65 (s, 3H), 3.71 (s, 2H), 3.80 (m, 1H), 7.51 (d, 1H, J=8.5 Hz), 7.85 (s, 1H), 7.95 (d, 2H, J=8.5 Hz), 8.12 (d, 1H, J=8.7 Hz). MS (ES) m/z 424.0 ([M+H]+). MS (ES) m/z 456.0 ([M+CH3OH+H]+). MS (ES) m/z 847.0 ([2M+H]+). Anal. Calcd for C19H22BrNO3S: C, 53.78; H, 5.23; N, 3.30. Found: C, 53.65; H, 4.77; N, 3.52.