Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:10]3[CH2:12][CH:13]([CH3:16])[CH2:14][CH2:15][C:9]=3[C:8]([CH3:18])([CH3:17])[O:7][C:6]=2[CH:5]=[C:4]([CH:19]([CH:21]([CH3:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH3:20])[CH:3]=1.[BrH:28].[O:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][CH2:37][C:38](O)=[O:39])[CH2:31][CH2:30]1.C1(N=C=NC2CCCCC2)CCCCC1.C(Cl)Cl>CCOCC.CO.C(Cl)(Cl)Cl>[BrH:28].[CH3:27][CH:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:19]([C:4]1[CH:3]=[C:2]([O:1][C:38](=[O:39])[CH2:37][CH2:36][CH2:35][N:32]2[CH2:31][CH2:30][O:29][CH2:34][CH2:33]2)[C:11]2[C:10]3[CH2:12][CH:13]([CH3:16])[CH2:14][CH2:15][C:9]=3[C:8]([CH3:17])([CH3:18])[O:7][C:6]=2[CH:5]=1)[CH3:20]
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CC(C)CC1
Reactant: O=C(O)CCCN1CCOCC1
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCCCCC(C)C(C)c1cc(OC(=O)CCCN2CCOCC2)c2c(c1)OC(C)(C)C1=C2CC(C)CC1

Procedure:
4.12 g. (11.15 mmole) of 1-Hydroxy-3-(3-methyl-2-octyl)-6,6,9-trimethyl-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran was combined with 2.84 g. (11.15 mmole) of γ-morpholinobutyric acid hydrobromide and 2.48 g. (12.0 mmole) of dicyclohexylcarbodiimide in 250 ml. of methylene chloride and stirred at room temperature for 16 hours. The by-product of dicyclohexylurea was removed by filtration and the filtrate was evaporated to give a golden, viscous residue. The material was dissolved in ether and the solid which appeared was removed by filtration. Recrystallization from benzene/ether gave 2.8 g. (41%) of product as colorless crystals, m.p. 120°-122°. The compound showed an Rf 0.7 in 10 % MeOH/CHCl3 ; the infrared and nmr spectra are consistent with the proposed structure.
Reaction SMILES: [OH:1][CH2:2][SnH2:3][C:4]1[C:17]2[C:8](=[N:9][CH:10]=[C:11]3[C:16]=2[CH:15]=[CH:14][CH:13]=[CH:12]3)[CH:7]=[CH:6][CH:5]=1.[CH:18]1C2C(=NC=C3C=2C=CC=C3)C=CC=1>>[CH3:18][N:9]1[CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17]2[C:4]([SnH2:3][CH2:2][OH:1])=[CH:5][CH:6]=[CH:7][C:8]1=2
Reactant: OC[SnH2]c1cccc2ncc3ccccc3c12
Reactant: c1ccc2c(c1)cnc1ccccc12
Product: CN1Cc2ccccc2-c2c([SnH2]CO)cccc21

Procedure:
Employing the procedure described in Example 2, but substituting the hydroxymethylphenanthridinyl stannane 35 prepared as described in Example 30 for the stannane 2, provides the N-methyl hydroxymethylphenanthridinyl stannane 36.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C@@H:8]([CH:28]=O)[CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[Br-].[N+:32]([C:35]1[CH:60]=[CH:59][CH:58]=[CH:57][C:36]=1[CH2:37][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O-:34])=[O:33].[PH4+].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>COCCOC.C(Cl)Cl>[C:1]([O:5][C:6](=[O:30])[NH:7][C@@H:8](/[CH:28]=[CH:37]/[C:36]1[CH:57]=[CH:58][CH:59]=[CH:60][C:35]=1[N+:32]([O-:34])=[O:33])[CH2:9][O:10][Si:11]([C:24]([CH3:25])([CH3:26])[CH3:27])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: O=[N+]([O-])c1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](C=O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: ClCCl
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N[C@@H](/C=C/c1ccccc1[N+](=O)[O-])CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.1 %

Procedure:
A solution of tert-butyl[(2R)-1-{[tert-butyl(diphenyl)silyl]oxy}-3-oxopropan-2-yl]carbamate (3, 3.12 g, 7.3 mmol) in DME (30 ml) was treated with solid (2-nitrobenzyl)(triphenyl)phosphonium bromide(3.76 g, 7.86 mmol) (or any other suitable phosphonium salt), the mixture stirred at room temperature under N2 atmosphere for 30 min and then the reaction flask was charged with a solid mixture of potassium carbonate (1.78 g, 12.86 mmol) and 18-crown-6 (219 mg, 0.83 mmol). The purple mixture was further stirred at the same temperature for 14 h; diluted with DCM, washed with saturated NaHCO3, dried over MgSO4, filtered and concentrated Purified through a chromatographic cartridge of silicagel (50 g) eluted with 10% to 35% EtOAc in hexane to get 1.52 g (38% yield) of title compound as light yellow oil. MS: m/z=569.2 (MNa+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10]2[N:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:11]=2[C:12]([OH:14])=O)[CH2:7]1.Cl.[NH2:27][C:28]1([C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)[CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][CH:6]1[CH2:7][N:8]([C:10]2[N:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][C:11]=2[C:12]([NH:27][C:28]2([C:31]3[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=3)[CH2:30][CH2:29]2)=[O:14])[CH2:9]1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Reactant: O=C(O)c1cc(C(F)(F)F)cnc1N1CC(Oc2cccc(Cl)c2)C1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(C(F)(F)F)cnc3N3CC(Oc4cccc(Cl)c4)C3)CC2)cc1
Yield: 11.2 %

Procedure:
The title compound (D175) (14 mg) was prepared according to the experimental procedure described in Description 144 starting from 2-(3-(3-chlorophenoxy)azetidin-1-yl)-5-(trifluoromethyl)nicotinic acid (D124) (85 mg, 0.228 mmol) and methyl 4-(1-aminocyclopropyl)benzoate (D7) (51.92 mg, 0.228 mmol).
Reaction SMILES: Cl[CH2:2][O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[NH:11]1[CH:15]=[CH:14][CH:13]=[N:12]1>CN(C=O)C>[CH2:4]([O:3][CH2:2][N:11]1[CH:15]=[CH:14][CH:13]=[N:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: ClCOCc1ccccc1
Reactant: c1cn[nH]c1
Solvent: CN(C)C=O
Product: c1ccc(COCn2cccn2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Chloromethoxymethyl-benzene (purity ˜60%, 2.0 mL, 14 mmol) was added dropwise to a stirred solution of 1H-pyrazole (1.93 g, 28.4 mmol) in DMF (10 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for an additional 1.5 h. The reaction was then quenched by the addition of concentrated aqueous NH3 (1 mL). The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography on silica gel (elution with DCM/MeOH 1:20) to give the title compound. MS (m/z): 189.0 [M+H+].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH3:20])[C:14]([F:16])([F:15])[C:13]([CH3:18])([CH3:17])[O:12][CH2:11][C:10](=[O:19])[NH:9]2)[CH:7]=1.[NH2:22][C:23]1[CH:24]=[CH:25][C:26]([Cl:29])=[N:27][CH:28]=1>>[Cl:29][C:26]1[N:27]=[CH:28][C:23]([NH:22][C:2]2[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]3([CH3:20])[C:14]([F:16])([F:15])[C:13]([CH3:18])([CH3:17])[O:12][CH2:11][C:10](=[O:19])[NH:9]3)[CH:7]=2)=[CH:24][CH:25]=1
Reactant: CC1(C)OCC(=O)N[C@](C)(c2cc(Br)ccc2F)C1(F)F
Reactant: Nc1ccc(Cl)nc1
Product: CC1(C)OCC(=O)N[C@](C)(c2cc(Nc3ccc(Cl)nc3)ccc2F)C1(F)F
Yield: 32.7 %

Procedure:
Prepared in an analogous manner as described for intermediate A9A or A13A from (R)-5-(5-bromo-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-1,4-oxazepan-3-one (intermediate A16B) (200 mg, 546 μmol) and commercially available 5-amino-2-chloropyridine [CAS no 5350-93-6] (140 mg, 1.09 mmol). The (R)-5-(5-(6-chloropyridin-3-ylamino)-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-1,4-oxazepan-3-one (74 mg, 32.7%) was obtained as a light brown foam. MS (ISP): m/z=414.2 [(M+H)+] and 416.2 [(M+2+H)+].
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]([OH:25])[CH2:20][O:21][CH2:22][CH2:23]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)CCC.O1CCOCC1>[OH:25][CH2:19][CH2:20][O:21][CH2:22][CH2:23][N:10]1[CH2:9][CH2:8][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:12][CH2:11]1
Reactant: OCCOCCCl
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Solvent: C1COCCO1
Product: OCCOCCN1CCC(c2ccccc2)(c2ccccc2)CC1

Procedure:
82 g of 4,4-diphenylpiperidine, 50 g of diethylene glycol monochlorohydrin, 250 g of finely powdered potassium carbonate and 1 g of potassium iodide are heated at the boiling point under reflux, with vigorous stirring, in 1.2 l of a 1:1 mixture of dioxane and 1-butanol for 50 h. After cooling, the mixture is filtered and the filtrate is concentrated. The oily residue is taken up in ethyl acetate and the solution is filtered again. After the filtrate has been concentrated to constant weight (high vacuum), the title compound is obtained as a waxy viscous residue. Yield: 106 g. The hydrochloride is obtained with ethereal hydrochloric acid and is recrystallized from 2-propanol. M.p.: 120°-121° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][C:12]1=[O:20].N1CCCCC1>C(O)C>[Br:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:11][C:12]1=[O:20]
Reactant: Cc1c(Br)cccc1C=O
Reactant: O=C1Cc2ccccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(Br)cccc1C=C1C(=O)Nc2ccccc21
Temperature: 82.5 °C
Reaction time: 15.25 h
Yield: 29.9 %

Procedure:
Step 2 A solution of 3-bromo-2-methylbenzaldehyde (200 mg, 1.01 mmol) and indolin-2-one (134 mg, 1.01 mmol) in ethanol (10 mL) was treated with piperidine (0.099 mL, 1.01 mmol) and heated at 80-85° C. After 15.25 h, the solution was cooled to rt and concentrated. The residue was purified by column chromatography (eluting with a gradient from 80:20 to 30:70 hexane-ethyl acetate) to provide 3-(3-bromo-2-methylbenzylidene)indolin-2-one as a bright yellow solid (94.9 mg, 30%). 1H NMR (400 MHz, chloroform-d) δ 7.89 (1H, br. s.), 7.85 (1H, s), 7.64 (1H, d, J=7.9 Hz), 7.47 (1H, d, J=7.7 Hz), 7.20 (1H, td, J=7.7, 1.1 Hz), 7.07-7.16 (2H, m), 6.87 (1H, d, J=7.9 Hz), 6.81 (1H, td, J=7.6, 1.0 Hz), 2.43 (3H, s). Mass spectrum m/z 314, 316 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.Cl[C:11]1[S:12][CH:13]=[C:14]([Cl:16])[N:15]=1.C(O)C.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.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:16][C:14]1[N:15]=[C:11]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[S:12][CH:13]=1
Reactant: Clc1csc(Cl)n1
Reactant: OB(O)c1cccnc1
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: Cc1ccccc1
Solvent: CCO
Product: Clc1csc(-c2cccnc2)n1
Temperature: 95 °C
Yield: 78 %

Procedure:
To a suspension of pyridin-3-ylboronic acid (3.87 g, 31.5 mmol) in toluene (120 mL) was added 2,4-dichlorothiazole (4.62 g, 30 mmol) followed by ethanol (60 mL) and a 2.0 M solution of K2CO3 (30.0 mL, 60.0 mmol). The solution was degassed by applying vacuum and then purging with nitrogen (3 times). To the reaction mixture was added tetrakis(triphenylphosphine)palladium (0) (1.733 g, 1.500 mmol) and the flask was heated at 95° C. under nitrogen for 16 hours. The aqueous layer was removed and the organic layer was concentrated. The crude product was purified via silica gel chromatography (0-100% ethyl acetate/hexanes) to afford the title compound as a brown solid (4.6 g, 74%): mp 84-86° C.; IR (KBr) 3092 cm−1; 1H NMR (400 MHz, CDCl3) δ 9.16-9.13 (m, 1H), 8.69 (dd, J=4.8, 1.6 Hz, 1H), 8.23 (ddd, J=8.0, 2.2, 1.7 Hz, 1H), 7.40 (ddd, J=8.0, 4.8, 0.8 Hz, 1H), 7.16 (s, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:37])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][C:35]=2[CH3:36])[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:14][C:12]1[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]2[NH:19][C:20](=[O:37])[CH2:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[CH:31]=[N:32][CH:33]=[CH:34][C:35]=4[CH3:36])[CH:25]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1ccncc1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)c(C)cc2NC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccncc1-c1cccc(C2=Nc3cc(C)c(C(F)(F)F)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from (5-methyl-2-{3-[3-(4-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M213) (291 mg, 0.552 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (182 mg, 81%).
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2C(=NN(CC)N=2)N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:42])([F:41])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].I[CH2:44][C:45]1([CH3:49])[CH2:48][O:47][CH2:46]1>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:41])([F:42])[CH2:37]2)[C:30]2[C:31](=[N:33][N:34]([CH2:44][C:45]3([CH3:49])[CH2:48][O:47][CH2:46]3)[N:35]=2)[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC1(CI)COC1
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Agent: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Product: CC1(Cn2nc3nc(C(C)(C)C)nc(N4CCC(F)(F)C4)c3n2)COC1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(iodomethyl)-3-methyloxetane and isolated as white solid. MS (m/e): 367.3 (MH+).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Al+3].[Cl-].[Cl-].[Cl-].[F:11][C:12]([F:28])([F:27])[C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[C:22](=O)[C:23]([NH2:25])=O.[OH-].[Na+]>C1COCC1>[F:27][C:12]([F:11])([F:28])[C:13]1[CH:14]=[C:15]2[C:19]([NH:18][CH:17]=[C:16]2[CH2:22][CH2:23][NH2:25])=[CH:20][CH:21]=1
Reactant: NC(=O)C(=O)c1c[nH]c2ccc(C(F)(F)F)cc12
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: NCCc1c[nH]c2ccc(C(F)(F)F)cc12
Temperature: 5 °C
Reaction time: 8 h

Procedure:
Add LiAlH4 (37.95 g, 1.00 mol) to THF (650 mL) under ice-bath cooling. Prepare a solution of AlCl3 (50 g, 375 mmol) in THF (600 ml) and add dropwise to the LiAlH4 solution over 45 min at 5–10° C. While maintaining the temperature at about 5° C., add a solution of 2-(5-(trifluoromethyl)-1H-indol-3-yl)-2-oxo-acetamide (21.4 g, 83.5 mmol) in THF (600 ml) and stir overnight with warming to ambient temperature. Cool the mixture with ice water and treat with 30% NaOH (100 ml) while maintaining the temperature at less than about 30° C. After stirring for about 30 minutes, filter, wash with THF (2 L), and evaporate the filtrate to give the title compound. Form of the HCl salt by dissolving the title compound in diethyl ether and adding of a solution of HCl in diethyl ether (until acidic). Collect the solid by filtration, wash with diethyl ether, and dry under reduced pressure to give the hydrochloride salt of the title compound.
Reaction SMILES: C([N:8]1[CH:14]2[CH2:15][CH2:16][CH2:17][CH:9]1[CH2:10][N:11]([C:18](=[O:21])[CH2:19][CH3:20])[CH2:12][CH2:13]2)C1C=CC=CC=1>CCO.[Pd]>[C:18]([N:11]1[CH2:12][CH2:13][CH:14]2[NH:8][CH:9]([CH2:17][CH2:16][CH2:15]2)[CH2:10]1)(=[O:21])[CH2:19][CH3:20]
Reactant: CCC(=O)N1CCC2CCCC(C1)N2Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCC(=O)N1CCC2CCCC(C1)N2
Yield: 97 %

Procedure:
A solution in EtOH (39 ml) of 10-benzyl-3-propionyl-3,10-diaza-bicyclo[4.3.1]decane obtained in Example 9 (2.40 g) was hydrogenated at 45 psi and at room temperature for 19 hours in the presence of Pd/C 10% (0.89 g). The mixture was filtered off on celite and the catalyst washed with EtOH. The solution was concentrated to obtain 1.60 g of a light oil corresponding to the compound 3-propionyl-3,10-diazabicy-clo[4.3.1]decane (10a).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[C:15]([NH:17][CH:18]([CH3:20])[CH3:19])[N:14]=[C:13]([O:21][C:22]3[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=3)[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(N(CC)CC)C.[CH3:36][C:37]([OH:41])([C:39]#[CH:40])[CH3:38]>CN(C)C=O.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.[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][CH3:9])[NH:10][C:11]1[N:16]=[C:15]([NH:17][CH:18]([CH3:20])[CH3:19])[N:14]=[C:13]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:40]#[C:39][C:37]([CH3:38])([OH:41])[CH3:36])[N:12]=1
Reactant: COc1ccc(Nc2nc(NC(C)C)nc(Oc3ccc(I)cc3)n2)cc1Cl
Reactant: C#CC(C)(C)O
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(Nc2nc(NC(C)C)nc(Oc3ccccc3C#CC(C)(C)O)n2)cc1Cl
Reaction time: 6 h
Yield: 70.1 %

Procedure:
A mixture of compound N-(3-Chloro-4-methoxy-phenyl)-6-(4-iodo-phenoxy)-N′-isopropyl-[1,3,5]triazine-2,4-diamine (0.4 g, 0.78 mmol), triethylamine (0.27 ml, 1.95 mmol) in dimethylformamide (3 mL) was added bis(triphenylphosphine)palladium(II)chloride (27 mg, 0.04 mmol), CuI (15 mg, 0.08 mmol) and 2-methyl-3-butyn-2-ol (0.11 ml, 1.17 mmol). It is stirred under nitrogen atmosphere for 6 hrs. The mixture was then cooled, diluted with water (20 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with water (2×10 mL), dried over anhydrous sodium sulphate and concentrated under vacuum. The residue thus obtained was purified by column chromatography (10-20% EtOAc-Hexane) to afford the title compound as a pale yellow solid (0.256 g, 70%). mp 138-140° C.; HPLC: Inertsil ODS 3V (250×4.6 mm) 5 microns [solvent A=0.01 M KH2PO4 (pH 7.0); solvent B=CH3CN], Gradient elution program: T/% B=0/60, 10/60, 25/80, 40/80, 45/60, 50/60; 254 nm, Rt 16.80 min, 97.77% purity; MS (CI): m/z 468 (M+H, 100).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([I:11])[CH:5]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:13](=[O:15])[CH3:14])=[C:6]([I:11])[CH:5]=1
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ccc(N)c(I)c1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(NC(C)=O)c(I)c1
Temperature: 60 °C

Procedure:
To a solution of the crude 4-amino-3-iodo-benzoic acid methyl ester in 20 mL of acetic acid was added acetic anhydride (1.25 mL). The reaction was heated at 60° C. for 1 h. The reaction mixture was quenched with water, extracted with ethyl acetate, dried over Na2SO4, and concentrated in vacuo. Purification by flash chromatography (SiO2, 1:3 EtOAc/Hexane) afforded 4-acetylamino-3-iodo-benzoic acid methyl ester: MS (m/z) 320.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11](=O)[NH:10][C:9]([C:14]([NH2:16])=O)=[CH:8]2.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:11]1[C:12]2[C:7](=[CH:6][CH:5]=[CH:4][C:3]=2[O:2][CH3:1])[CH:8]=[C:9]([C:14]#[N:16])[N:10]=1
Reactant: COc1cccc2cc(C(N)=O)[nH]c(=O)c12
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cccc2cc(C#N)nc(Cl)c12
Yield: 82 %

Procedure:
A solution of 8-methoxy-1-oxo-1,2-dihydroisoquinoline-3-carboxamide (800 mg, 3.66 mmol) in POCl3(40 mL) was heated to reflux for 1 hour. The reaction mixture was subsequently concentrated in vacuo to give the title compound (660 mg, 82%). 1H NMR (400 MHz, CDCl3) δ ppm 7.98 (s, 1H), 7.78 (t, 1H, J=8.0 Hz), 7.48 (d, 1H, J=8.0 Hz), 7.20 (d, 1H, J=8.0 Hz), 4.05 (s, 3H); ESI-MS m/z [M+H]+ 219.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.[OH-:25].[K+].[Cl-].[Na+]>C(O)(C)(C)C>[CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]([NH2:21])=[O:25])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(C#N)cc3)ccc21
Reactant: [OH-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(C(N)=O)cc3)ccc21
Yield: 83 %

Procedure:
A mixture of 2.5 g (8 millimoles) of 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphth-2-yl)-ethynyl]-benzonitrile (Example 1), 60 ml of tert.-butanol and 7.5 g of potassium hydroxide powder was refluxed for 4 hours. The mixture was cooled, poured onto saturated sodium chloride solution and extracted twice with ether. The ether phases were washed with sodium chloride solution, dried over Na2SO4 and evaporated down to give 2.2 g (83%) of the pure title compound of melting point 220°-223° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C:7]([CH3:28])([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][N:17]2C(=O)C3=CC=CC=C3C2=O)[N:14]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].O.NN>C(O)C>[C:1]([O:5][C:6](=[O:29])[C:7]([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][NH2:17])[N:14]=1)([CH3:28])[CH3:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCN2C(=O)c3ccccc3C2=O)cs1
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCN)cs1
Yield: 81.6 %

Procedure:
2-Methyl-2-{[4-(2-phthalimidoethyl)-1,3-thiazol-2-yl]thio}propionic acid tert-butyl ester (136 g) synthesized in Example 6 was dissolved in ethanol (800 mL), hydrazine monohydrate (47.2 g) was added, and the mixture was refluxed for 4 hr. White precipitate was filtered off from the reaction mixture, and the filtrate was concentrated under reduced pressure. Water was added thereto, and the mixture was extracted with dichloroethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (77.6 g) as a brown oil.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[NH2:10][C:11]1[N:16]=[CH:15][CH:14]=[CH:13][N:12]=1.O>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=C(P(C1C=CC=CC=1)C1C=CC=CC=1)C=2.C(=O)([O-])[O-].[Cs+].[Cs+]>[N:12]1[CH:13]=[CH:14][CH:15]=[N:16][C:11]=1[NH:10][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccccc1Br
Reactant: Nc1ncccn1
Agent: [Pd]
Agent: CC1(C)c2ccc(P(c3ccccc3)c3ccccc3)cc2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1ccccc1Nc1ncccn1
Temperature: 25 °C
Yield: 63.6 %

Procedure:
A solution of 2-bromobenzaldehyde (0.35 mL, 3.0 mmol), 2-aminopyrimidine (0.34 g, 3.6 mmol), tris(dibenzylideneacetone)dipalladium (28 mg, 0.030 mmol), 9,9-dimethyl-4,6-bis(diphenylphosphino)xanthene (38 mg, 0.066 mmol) and cesium carbonate (28 mg, 0.030 mmol) in 1,4-dioxane (6.0 mL) was stirred at 100° C. for 19 hours under argon atmosphere. After cooling to room temperature, the reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane to hexane/ethyl acetate=8/2) to obtain 2-(2-pyrimidylamino)benzaldehyde (0.38 g, 64%).