Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([O:8][NH:9][C:10]([C:12]1[CH:13]=[N:14][C:15]([N:18]2[CH2:23][CH:22]3[CH:20]([CH:21]3[N:24]([CH2:36][CH2:37][N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])[CH2:25][C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)[CH2:19]2)=[N:16][CH:17]=1)=[O:11])C)C(C)C.Cl.O1CCOCC1>C(Cl)Cl>[OH:8][NH:9][C:10]([C:12]1[CH:13]=[N:14][C:15]([N:18]2[CH2:19][CH:20]3[CH:22]([CH:21]3[N:24]([CH2:36][CH2:37][N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])[CH2:25][C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)[CH2:23]2)=[N:16][CH:17]=1)=[O:11]
Reactant: CCN(CC)CCN(Cc1ccc2ccccc2c1)C1C2CN(c3ncc(C(=O)NOC(C)OCC(C)C)cn3)CC21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCN(CC)CCN(Cc1ccc2ccccc2c1)C1C2CN(c3ncc(C(=O)NO)cn3)CC21
Yield: 56.2 %

Procedure:
N-(1-Isobutoxyethoxy) 2-{6-[(2-diethylaminoethyl)naphthalen-2-ylmethylamino]-3-azabicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide (18 mg, 0.03 mmol) was dissolved in dry DCM (3 ml) and treated with 4M HCl in dioxane (0.015 ml, 0.06 mmol). A white precipitate immediately formed. This was filtered and washed with DCM to give the title compound as a white solid (8 mg, 57%). LCMS purity 98%, m/z 475 [M+H]+, 1H NMR (300 MHz, CD3OD) δ: 1.39 (6H, t, J=7.2 Hz), 2.26 (2H, br s), 2.77 (1H, s), 3.37 (4H, m), 3.55 (2H, d, J=10.5 Hz), 3.81 (4H, br s), 3.93 (2H, br d, J=10.5 Hz), 4.71 (2H, br s), 7.61 (2H, m), 7.76 (1H, d, J=8.4 Hz), 7.95-8.04 (3H, m), 8.20 (1H, s), 8.71 (2H, s).
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].C(O)(=O)C.[O-:17][C:18]#[N:19].[K+].[Cl-].[Na+]>O>[NH2:19][C:18]([NH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4])=[O:17]
Reactant: NC(C(=O)O)c1ccc(O)cc1
Reactant: N#C[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)NC(C(=O)O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To about 0.15 mole of α-amino-4-hydroxybenzeneacetic acid dissolved in 700 ml of water and 0.2 mole of glacial acetic acid is added about 0.2 mole of potassium cyanate. The resulting mixture is stirred at room temperature for about 30 minutes. The reaction mixture is saturated with sodium chloride and then extracted with ethyl acetate. The ethyl acetate is washed with water, dried over magnesium sulfate, filtered and evaporated to give α-(aminocarbonyl)amino-4-hydroxybenzeneacetic acid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](OS(C(F)(F)F)(=O)=O)=[C:7]([N+:19]([O-:21])=[O:20])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:29][Si:30]([C:33]#[CH:34])([CH3:32])[CH3:31]>CN(C)C=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:34]#[C:33][Si:30]([CH3:32])([CH3:31])[CH3:29])=[C:7]([N+:19]([O-:21])=[O:20])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1
Reactant: C#C[Si](C)(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(C#C[Si](C)(C)C)c([N+](=O)[O-])c1
Temperature: 90 °C
Yield: 102.3 %

Procedure:
To Trifluoro-methanesulfonic acid 4-tert-butyl-2-nitro-phenyl ester (3.715 g, 11.35 mmol), dichlorobis(triphenylphoshpine)palladium(II) (336 mg, 0.478 mmol), cuprous iodide (168 mg, 0.882 mmol) was added dimethylformamide (45 mL), triethylamine (1.72 g, 17.0 mmol), and trimethylsilylacetylene (2.229 g, 22.70 mmol). The resulting mixture was heated at 90° C. under an atmosphere of nitrogen for 15 minutes. This was partitioned between ethylacetate and water. The ethylacetate layer was washed with brine, dried over anhydrous MgSO4, concentrated in vacuo, and purified by flash chromatography with elution with CH2Cl2 to yield (4-tert-Butyl-2-nitro-phenylethynyl)-trimethyl-silane (3.193 g, 11.61 mmol).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)=[O:7].Br[CH2:35][CH2:36][CH2:37][OH:38].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[F:31][C:28]([F:29])([F:30])[C:26]1[CH:25]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:32])[F:33])[CH:27]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:35][CH2:36][CH2:37][OH:38])[CH2:10][C@H:9]1[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1ccc2ccccc2c1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CCCO)C[C@H]1Cc1ccc2ccccc2c1
Reaction time: 17 h
Yield: 105.8 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)piperazine (1.0 g) and 3-bromopropanol (330 mg) in N,N-dimethylformamide (2.5 ml) was stirred at room temperature in the presence of powdered potassium carbonate (444 mg). After 17 hours, the reaction mixture was diluted with ethyl acetate (30 ml) and then washed successively with water and brine, and dried over magnesium sulfate. Evaporation of the solvent in vacuo gave (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(3-hydroxypropyl)-2-(2-naphthylmethyl)piperazine (1.19 g).
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:17][C@H:18]([OH:30])[C:19]2[C:27]3[S:26][C:25](=[O:28])[NH:24][C:23]=3[C:22]([OH:29])=[CH:21][CH:20]=2)=[CH:11][CH:10]=1)(=O)=O.[C:38]1([C:44]2[S:45][CH:46]=[C:47]([C:49]([N:51]3[CH2:56][C:55]4([CH2:61][CH2:60][NH:59][CH2:58][CH2:57]4)[O:54][CH2:53][CH2:52]3)=[O:50])[N:48]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(N(CC)CC)C>CC#N>[OH:30][C@H:18]([C:19]1[C:27]2[S:26][C:25](=[O:28])[NH:24][C:23]=2[C:22]([OH:29])=[CH:21][CH:20]=1)[CH2:17][N:16]([CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:59]2[CH2:60][CH2:61][C:55]3([O:54][CH2:53][CH2:52][N:51]([C:49]([C:47]4[N:48]=[C:44]([C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=5)[S:45][CH:46]=4)=[O:50])[CH2:56]3)[CH2:57][CH2:58]2)=[CH:10][CH:11]=1)[C:31](=[O:32])[O:33][C:34]([CH3:35])([CH3:37])[CH3:36]
Reactant: O=C(c1csc(-c2ccccc2)n1)N1CCOC2(CCNCC2)C1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(OCCOS(C)(=O)=O)cc1)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(Cc1ccc(OCCN2CCC3(CC2)CN(C(=O)c2csc(-c4ccccc4)n2)CCO3)cc1)C[C@H](O)c1ccc(O)c2[nH]c(=O)sc12
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A solution of (R)-2-(4-((tert-butoxycarbonyl(2-hydroxy-2-(4-hydroxy-2-oxo-2,3-dihydrobenzo[d]thiazol-7-yl)ethyl)amino)methyl)phenoxy)ethyl methanesulfonate (example 108, step c) (0.619 g) in MeCN (3 mL) was added dropwise to a solution of (2-phenylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone (example 112, step b) (0.274 g) and triethylamine (0.22 mL) in MeCN (7.3 mL) at RT under argon. The resulting mixture was stirred at 80° C. under argon for 16 h. After cooling to RT the solvent was removed in vacuo. The residue was taken up in DCM, washed with brine and water, dried over sodium sulphate, filtered and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with 0-70% EtOAc in petroleum ether (40-60° C.) to give the subtitled compound as a yellow solid. Yield 0.42 g.
Reaction SMILES: [CH3:1][CH:2]1[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH:5]([CH:14]([CH:16]=[CH:17][CH3:18])[CH3:15])[N:4]=[CH:3]1.S(O)(O)(=O)=O.[NH2:24][OH:25].Cl>O>[CH3:1][CH:2]([CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH:5]([CH:14]([CH:16]=[CH:17][CH3:18])[CH3:15])[NH2:4])[CH:3]=[N:24][OH:25]
Reactant: NO
Reactant: CC=CC(C)C1CC=CCCC=CCC(C)C=N1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: CC=CC(C)C(N)CC=CCCC=CCC(C)C=NO
Yield: 195.2 %

Procedure:
The procedure described in Example (1b) is repeated, except that 122.7 g (0.5 mol) of 3-methyl-12-(3-penten-2-yl)-1-aza-1,5,9-cyclododecatriene, 41.1 g (0.25 mol) of hydroxylamine sulfate, 50 ml of concentrated hydrochloric acid and 250 ml of water are used. Working up yields 135.9 g (0.488 mol) of 2-methyl-11-(3-penten-2-yl)-11-amino-undeca-4,8-dienal oxime; yield 97.6% of theory. nD20 =1.5091.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][CH2:12][C:13]([CH2:15]Cl)=O>C(O)(C)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:7][CH:15]=[C:13]([CH2:12][Cl:11])[N:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)c1ccc(Br)cc1
Solvent: CC(C)O
Product: ClCc1coc(-c2ccc(Br)cc2)n1
Temperature: 25 °C

Procedure:
4-bromo-benzamide (4.03 g, 20.11 mmol), and 1,3-dichloro-acetone (3.83 g, 30.17 mmol) are placed in a 250 mL flask and dissolved in 150 mL of isopropyl alcohol. The mixture is heated to reflux for 5 hours and cooled to ambient temperature. The reaction is concentrated to dryness. The resulting solid is triturated with diethyl ether and filtered to remove unreacted 4-bromo-benzamide. The filtrate is concentrated to the title compound as an oily solid (3.1 g) and is used without further purification. MS (m/e) 273.9 (M+1)
Reaction SMILES: [CH:1]([C:3]1[C:20]([O:21]C)=[CH:19][CH:18]=[CH:17][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]CC)=[O:13])=[O:2].[I-].[Mg+2].[I-].Cl>O1CCCC1.CCOCC>[CH:1]([C:3]1[C:20]([OH:21])=[CH:19][CH:18]=[CH:17][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:2]
Reactant: CCOC(=O)CCCCCCOc1cccc(OC)c1C=O
Agent: Cl
Agent: [I-]
Agent: [Mg+2]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=Cc1c(O)cccc1OCCCCCCC(=O)O

Procedure:
To a stirred solution of ethyl 7-(2-formyl-3-methoxyphenoxy)heptanoate (4.15 g, 0.0135 M) in dry tetrahydrofuran (60 ml) was added dropwise a solution of magnesium iodide (5.82 g, 0.0202 M) in dry ether (97.5 ml). The mixture was then stirred under reflux (5 hr). The cooled mixture was poured into 10% hydrochloric acid (65 ml). The organic layer was separated and the aqueous phase extracted with ethyl acetate. The combined organic solution were washed with water and evaporated to dryness. The residue, ethyl 7-(2-formyl-3-hydroxyphenoxyheptanoate, was dissolved in 2 N sodium hydroxide solution (50 ml) with stirring at room temperature (10 hr). The solution was decanted from a residue and acidified with concentrated hydrochloric acid with cooling. The precipitated solid was filtered off and washed well with water to give 7-(2-formyl-3-hydroxyphenoxy)heptanoic acid, m.p. 106°-107° C. from benzene/petrol.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([OH:18])[CH:12]=2)=[CH:7][CH:6]=1.Br[CH2:20][CH:21]([O:24][CH3:25])[O:22][CH3:23]>C1COCC1>[CH3:23][O:22][CH:21]([O:24][CH3:25])[CH2:20][O:18][C:13]1[CH:12]=[C:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:10][CH:9]=2)[CH:16]=[CH:15][C:14]=1[CH3:17]
Reactant: COc1ccc(-c2ccc(C)c(O)c2)cc1
Reactant: COC(CBr)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(C)c(OCC(OC)OC)c2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To NaH (357 mg (600 mg 60% in mineral oil, hexane washed 3×), 14.86 mmol) was added dry THF (100 ml), 4′-methoxy-4-methyl-biphenyl-3-ol (1.59 g, 7.43 mmol), and 2-bromo-1,1-dimethoxy ethane (1.76 g, 10.40 mmol). The reaction was stirred at 60° C. overnight, cooled, passed through a silica plug and concentrated to 1.66 g (74%) of product as a white solid: mp 3940° C.; 1H NMR (300 MHz, DMSO-d6): δ 2.17 (3H, s), 3.38 (6H, s), 3.79 (3H, s), 4.09 (2H, d, J=5.2 Hz), 4.73 (1H, t, J=5.2 Hz), 7.00 (2H, d, J=8.8 Hz), 7.09 (1H, dd, J=7.7 Hz, 1.5 Hz), 7.15 (1H, d, J=1.2 Hz), 7.18 (1H, d, J=7.8 Hz), 7.62 (2H, d, J=8.8 Hz); MS (ESI) m/z 303 ([M+H]+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[OH:11][C:12]1[CH:25]=[CH:24][C:15]2[C:16]([C:20]([O:22][CH3:23])=[O:21])=[C:17]([CH3:19])[O:18][C:14]=2[CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:19][C:17]1[O:18][C:14]2[CH:13]=[C:12]([O:11][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[CH:9][S:10][C:3]=34)[CH:25]=[CH:24][C:15]=2[C:16]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)c1c(C)oc2cc(O)ccc12
Reactant: Clc1ccnc2ccsc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)c1c(C)oc2cc(Oc3ccnc4ccsc34)ccc12

Procedure:
This material was prepared by the reaction of 7-chloro-thieno[3,2-b]pyridine with methyl 6-hydroxy-2-methylbenzofuran-3-carboxylate 89c and Cs2CO3 in a manner as previously described. 1H NMR (CDCl3) δ 8.48 (1H,d, J=5.3 Hz), 7.99 (1H, d, J=8.3 Hz), 7.74 (1H, d, J=5.6 Hz), 7.56 (1H, d, J=5.3 Hz), 7.29 (1H, d, J=2.0 Hz), 7.16 (1H, dd, J=8.6, 2.3 Hz), 6.53 (1H, d, J=5.3 Hz), 3.96 (3H, s), 2.79 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[N:5][N:6]=1.[Cl:7][CH2:8][CH2:9][N:10]([N:16]=[O:17])[C:11](N=[N+]=[N-])=[O:12]>N1C=CC=CC=1>[Cl:7][CH2:8][CH2:9][N:10]([N:16]=[O:17])[C:11](=[O:12])[NH:1][C:2]1[S:3][CH:4]=[N:5][N:6]=1
Reactant: [N-]=[N+]=NC(=O)N(CCCl)N=O
Reactant: Nc1nncs1
Solvent: c1ccncc1
Product: O=NN(CCCl)C(=O)Nc1nncs1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
Ten grams of 2-amino-1,3,4-thiadiazole was dissolved in 100 ml of pyridine, and cooled with ice. While stirring the solution, 26.5 g of N-(2-chloroethyl)-N-nitrosocarbamoyl azide was gradually added, and after the addition, the stirring was continued for 60 minutes. The reaction solution was poured into ice water, and the precipitated crystals were washed with water, dried and recrystallized from methanol, to obtain 17.8 g (Yield 75%) of 2-{3-(2-chloroethyl)-3-nitrosoureido}-1,3,4-thiadiazole. The physical properties of this compound were identical with those of the compound obtained by Example 1.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[O:3]1.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:20]=[C:21]([N:25]=[C:26]=[O:27])[CH:22]=[CH:23][CH:24]=1>O1CCCC1>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:26]([NH:25][C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:17])([F:28])[F:29])[CH:20]=3)=[O:27])=[N:13][CH:14]=2)[O:5]1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)nc2)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ambient solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (0.350 g, 1.59 mmol) in tetrahydrofuran (4 mL) was added 3-trifluoromethylphenyl isocyanate (1.59 mmol). The solution was stirred at room temperature for 1 hour and was then concentrated under reduced pressure. The solid was washed with diethyl ether (2 mL) and air-dried to give the title compound. MS (ESI) m/z 408 [M+H]+.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23](O)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[NH:26]1[CH2:31][CH2:30][CH:29]([OH:32])[CH2:28][CH2:27]1>>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([N:26]3[CH2:31][CH2:30][CH:29]([OH:32])[CH2:28][CH2:27]3)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: OC1CCNCC1
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)N3CCC(O)CC3)cs2)c1-c1ccc(F)cc1

Procedure:
Using 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid and piperidin-4-ol and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: Cl[C:2]([CH2:10][Cl:11])([CH2:5][CH:6]([C:8]#[N:9])[CH3:7])[CH:3]=O.[ClH:12]>C(#N)C.Cl[Ni]Cl>[Cl:12][C:8]1[C:6]([CH3:7])=[CH:5][C:2]([CH2:10][Cl:11])=[CH:3][N:9]=1
Reactant: CC(C#N)CC(Cl)(C=O)CCl
Reactant: Cl
Agent: Cl[Ni]Cl
Solvent: CC#N
Product: Cc1cc(CCl)cnc1Cl

Procedure:
4 grams of 2-chloro-2-chloromethyl-4-cyano-4-methylbutyraldehyde dissolved in 30 mL of acetonitrile is pumped concomitantly with anhydrous HCl into a pre-heated (180°-230° C.) flow reactor packed with NiCl2 -impregnated clay. Short path distillation gives 2-chloro-3-methyl-5-chloromethylpyridine as a liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[CH2:7][CH2:6][CH2:5]2.[C:20](OCC)(=[O:27])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C1CCN2C(=NCCC2)CC1>C(O)C>[CH3:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]1[C:10]2[C:2](=[CH:3][C:4]3[CH2:5][CH2:6][CH2:7][C:8]=3[CH:9]=2)[NH:1][C:20](=[O:27])[C:21]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: Cc1ccccc1C(=O)c1cc2c(cc1N)CCC2
Reactant: CCOC(=O)CC(=O)OCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: CCOC(=O)c1c(-c2ccccc2C)c2cc3c(cc2[nH]c1=O)CCC3
Yield: 98.1 %

Procedure:
A mixture of 5-amino-6-(2-methylbenzoyl)indan (5.02 g), diethyl malonate (6.4 g) and DBU (0.3 ml) was heated at 170°-180° C. for 1 hour. To this reaction mixture was added ethanol to give crystals of ethyl 4-(2-methylphenyl)-2-oxo-1,2,7,8-tetrahydro-6H-cyclopenta[g]quinoline-3-carboxylate (6.81 g, 98.1%). Recrystallization from ethanol-chloroform gave colorless crystals, m.p. 296°-298° C.
Reaction SMILES: [CH:1]1([CH2:7][S:8][C:9]2[N:14]=[C:13]([C:15]([O:17]C)=O)[CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][C:20]#[N:21]>>[CH:1]1([CH2:7][S:8][C:9]2[N:14]=[C:13]([C:15](=[O:17])[CH2:19][C:20]#[N:21])[CH:12]=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC#N
Reactant: COC(=O)c1cccc(SCC2CCCCC2)n1
Product: N#CCC(=O)c1cccc(SCC2CCCCC2)n1

Procedure:
Addition of CH3CN to methyl 6-((cyclohexylmethyl)thio)picolinate following the method used in Example 6 gave 3-(6-((cyclohexylmethyl)thio)pyridin-2-yl)-3-oxopropanenitrile as a yellow oil which was used in the next step without further purification. Yield (0.63 g, quant.).
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[C:22]([S:26]([NH:29][C@H:30](C#C)[CH2:31][C:32]([OH:34])=[O:33])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1.N1CCC[CH:39]([C:40](OCC)=O)[CH2:38]1>>[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[C:22]([S:26]([N:29]2[CH2:40][CH2:39][CH2:38][CH:31]([C:32]([OH:34])=[O:33])[CH2:30]2)(=[O:27])=[O:28])[CH:23]=[CH:24][CH:25]=1
Reactant: C#C[C@H](CC(=O)O)NS(=O)(=O)c1cccc(OCCCCNc2ccccn2)c1
Reactant: CCOC(=O)C1CCCNC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1CCCN(S(=O)(=O)c2cccc(OCCCCNc3ccccn3)c2)C1

Procedure:
The procedure for the preparation of the product of EXAMPLE 17 was repeated using ethyl nipecotate (Aldrich) in the place of ethyl (3S)-3-aminopent-4-ynoate hydrochloride to provide the title product. 1H (CD3OD): δ 7.88 (1H, t); 7.82 (1H, d); 7.52 (1H, t); 7.33 (1H, d); 7.24 (1H, s); 7.22 (1H, d); 7.06 (1H, d); 6.87 (1H, t); 4.13 (2H, t); 3.69 (1H, d); 3.47 (3H, m); 2.57 (2H, m); 2.45 (1H, t); 1.94 (5H, m); 1.80 (1H, br. d); 1.60 (1H, br. q); 1.41 (1H, br. q).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([C:17]4[NH:18][C:19]5[CH2:24][CH2:23][NH:22][CH2:21][C:20]=5[N:25]=4)=[N:13][NH:14]3)=[CH:10][CH:9]=2)[C:5]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:4][C:3]=1[OH:31].[N:32]1[C:41]2[C:36](=[CH:37][C:38]([CH:42]=O)=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1>>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([C:17]4[NH:18][C:19]5[CH2:24][CH2:23][N:22]([CH2:42][C:38]6[CH:37]=[C:36]7[C:41](=[CH:40][CH:39]=6)[N:32]=[CH:33][CH:34]=[CH:35]7)[CH2:21][C:20]=5[N:25]=4)=[N:13][NH:14]3)=[CH:10][CH:9]=2)[C:5]([CH2:26][C:27]([F:28])([F:29])[F:30])=[CH:4][C:3]=1[OH:31]
Reactant: Oc1cc(CC(F)(F)F)c(-c2ccc3c(-c4nc5c([nH]4)CCNC5)n[nH]c3c2)cc1F
Reactant: O=Cc1ccc2ncccc2c1
Product: Oc1cc(CC(F)(F)F)c(-c2ccc3c(-c4nc5c([nH]4)CCN(Cc4ccc6ncccc6c4)C5)n[nH]c3c2)cc1F

Procedure:
The title compound was prepared from 2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-5-(2,2,2-trifluoro-ethyl)-phenol (100 mg, 0.21 mmol) and quinoline-6-carbaldehyde (72.9 mg, 0.46 mmol) using the method of Example 51. The crude material was purified initially over silica and finally by Prep TLC (Mobile Phase: 10% MeOH-DCM) to afford the title compound as an off white solid in 22.9% yield, 28 mg.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C([Li])CCC.CN([CH:25]=[O:26])C>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[O:10][C:9]([CH:25]=[O:26])=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2occc2n1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2o1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a solution of 2-chloro-4-morpholinofuro[3,2-d]pyrimidine 38 (40 mg, 1.0 eq) dissolved in THF (1.7 ml) at −78° C. was added 1.6M solution of n-butyllithium (0.14 ml, 1.3 eq, 1.6M in hexanes). Reaction mixture was stirred at −78° C. for 30 minutes. DMF (0.05 ml, 4.0 eq) was added and reaction mixture was allowed to slowly warm up to room temperature and stirred for 90 minutes. Reaction mixture was quenched with water, and extracted with dichloromethane. The combined organic layers were dried (Na2SO4) and concentrated. The crude reaction mixture was purified by flash chromatography to yield 2-chloro-4-morpholinofuro[3,2-d]pyrimidine-6-carbaldehyde 39 (22 mg, 50%): 1H NMR (CDCl3, 400 MHz) δ 9.92 (s, 1H), 7.48 (s, 1H), 4.12 (m, 4H), 3.86 (dd, 4H); MS (Q1) 268 (M)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=1.CN([CH:22]=[O:23])C.[Li]CCCC>C1COCC1>[F:13][C:12]([F:15])([F:14])[C:9]1[CH:10]=[CH:11][C:6]([O:5][C:4]2[CH:3]=[C:2]([CH:18]=[CH:17][CH:16]=2)[CH:22]=[O:23])=[N:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(Oc2cccc(Br)c2)nc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cccc(Oc2ccc(C(F)(F)F)cn2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.8 %

Procedure:
To a solution of 2-(3-bromophenoxy)-5-(trifluoromethyl)pyridine (8.0 g, 25.15 mmol) in THF under inert atmosphere at −78° C. was added DMF (3.8 mL, 50.3 mmol) dropwise, followed by n-BuLi (31.4 mL, 50.3 mmol) dropwise. The reaction mixture was stirred for 1 h. The reaction mixture was quenched with saturated NH4Cl solution and the temperature was allowed to warm to room temperature. The mixture was extracted with ethyl acetate, dried over Na2SO4, and concentrated to dryness. Purification by column chromatography (EtOAc:Hexane, 40:60) gave the pure title compound (1.6 g). 1H NMR (500 MHz, CDCl3): δ 7.1 (d, 1H, J=8.5 Hz), 7.4 (m, 1H), 7.6 (m, 1H), 7.7 (d, 1H, J=7.5 Hz), 7.9 (1H), 8.4 (s, 1H), 10.0 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]([CH3:14])[S:12][C:11](=[O:15])[NH:10][N:9]=2)=[CH:4][CH:3]=1.O1[CH:21]=[CH:20][C:19](=[O:22])[CH:18]=[CH:17]1.C(O)(=O)C>O>[O:22]=[C:19]1[CH:20]=[CH:21][N:1]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:13]([CH3:14])[S:12][C:11](=[O:15])[NH:10][N:9]=3)=[CH:6][CH:7]=2)[CH:17]=[CH:18]1
Reactant: CC1SC(=O)NN=C1c1ccc(N)cc1
Reactant: O=c1ccocc1
Solvent: O
Solvent: CC(=O)O
Product: CC1SC(=O)NN=C1c1ccc(-n2ccc(=O)cc2)cc1

Procedure:
A stirred mixture of 5-(4-aminophenyl)-6-methyl-3H,6H-1,3,4-thiadiazine-2-one (0.54 g), 4H-pyran-4-one (0.26 g), glacial acetic acid (0.15 g) and water (20 ml) was heated under reflux for 24 hours to give a solid, 0.54 g. Recrystallisation from aqueous ethanol gave the title compound, 0.28 g, which darkened at 265° C. and sublimed at 273°-275° C.