Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[F:22][C:23]1[N:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1>>[F:22][C:23]1[N:28]=[CH:27][C:26]([O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=2)=[CH:25][CH:24]=1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Reactant: Oc1ccc(F)nc1
Product: N#Cc1ccc(N(CCOc2ccc(F)nc2)CC(F)(F)F)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 27B from 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile (Example 15B) and 6-fluoro-3-pyridinol (step A above): MS (ESI) m/z 408 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH:15]=[N:14][C:13]([C:16]([F:19])([F:18])[F:17])=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][NH:23][C@@H:22]1[CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:7](=[O:9])[C:6]2[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[N:11]2[CH:15]=[N:14][C:13]([C:16]([F:19])([F:18])[F:17])=[N:12]2)[C@@H:22]1[CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32]
Reactant: Cc1ccc(-n2cnc(C(F)(F)F)n2)c(C(=O)O)c1
Reactant: C[C@@H]1CCCN[C@@H]1CNC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2cnc(C(F)(F)F)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 5-methyl-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)benzoic acid (0.24 g, 0.869 mmol), tert-butyl (((2S,3R)-3-methylpiperidin-2-yl)methyl)carbamate (0.22 g, 0.96 mmol) and DIPEA (0.3 mL, 1.738 mmol) in DCM (20 mL) was added HATU (0.33 g, 0.869 mmol). The mixture was stirred at rt for 1 h. The mixture was diluted with DCM and was washed with satd. NaHCO3 and brine and dried over Na2SO4. The solvent was removed in vacuo to obtain the title compound with no further purification for next step. ESI-MS (m/z): 482 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][CH:11]=[C:2]([NH:17][C:16]2[CH:18]=[CH:19][C:13]([Br:12])=[CH:14][CH:15]=2)[CH:3]=1
Reactant: COC(=O)c1cccc(Br)c1
Reactant: Nc1ccc(Br)cc1
Product: COC(=O)c1cccc(Nc2ccc(Br)cc2)c1

Procedure:
Reaction of methyl 3-bromobenzoate with 4-bromoaniline according to general procedure A provided methyl ester of Compound 9 as a green oil (46% yield). 1H NMR (CDCl3, 500 MHz): δ=7.71 (s, 1H), 7.61 (d, J=7.7 Hz, 1H), 7.38 (d, J=8.6 Hz, 2H), 7.34 (t, J=7.9 Hz, 1H), 7.23 (d, J=8.1 Hz, 1H), 6.96 (d, J=8.7 Hz, 2H), 5.81 (s, 1H), 3.91 (s, 3H). 13C NMR (CDCl3, 125 MHz): δ=167.2, 143.1, 141.9, 132.6, 131.7, 129.7, 122.6, 122.1, 119.9, 118.8, 113.8, 52.4.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.N1C=CC=CC=1.[C:17](Cl)(=[O:19])[CH3:18]>O1CCCC1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:17](=[O:19])[CH3:18])=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CC(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])cn1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-5-nitropyridine (13.9 g, 100 mmol) and pyridine (24 ml, 300 mmol) in tetrahydrofuran (300 ml) was added dropwise acetyl chloride (10.7 ml, 150 mmol) with ice-cooling, the mixture was stirred at room temperature for 1 hour. To the mixture was added dropwise acetyl chloride (10.7 ml, 150 mmol) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice-water and the desired product (14.5 g, 80.1%) as a solid was collected by filtration.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.Cl[CH2:14][O:15][CH2:16][CH2:17]Cl.C(OCC)C>CN1CCCC1=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:11]#[N:12])[CH2:17][CH2:16][O:15][CH2:14]2)=[CH:6][CH:5]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: ClCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: N#CC1(c2ccc(Cl)cc2)CCOC1
Temperature: 25 °C

Procedure:
To a solution of the NaH (60% by weight, 4 g, 98 mmol) and 1-methylpyrrolidin-2-one (82.5 mL) at −20° C., was added dropwise a mixture of 2-(4-chlorophenyl)acetonitrile (5 g, 33 mmol) and 2-chloroethyl chloromethyl ether (4 mL, 33 mmol) in diethyl ether (16.5 mL, 33 mmol). The mixture was allowed to warm to room temperature over 24 hours. The reaction was then slowly quenched with ice water and extracted with ether (3×). The organic layers were combined, washed with H2O (3×) and brine, dried over Na2SO4, concentrated in vacuo, and purified by silica flash chromatography (13% EtOAc/hexane) to give the desired compound as a yellow oil. MS m/e=208.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:25])[C:12]3[CH:13]=[C:14](I)[CH:15]=[C:16]4[C:21]=3[N:20]([CH:22]=2)[N:19]([CH3:23])[CH2:18][CH2:17]4)=[O:9])=[CH:4][CH:3]=1.[CH2:28]([OH:31])[C:29]#[CH:30].C(NCC)C>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:25])[C:12]3[CH:13]=[C:14]([C:30]#[C:29][CH2:28][OH:31])[CH:15]=[C:16]4[C:21]=3[N:20]([CH:22]=2)[N:19]([CH3:23])[CH2:18][CH2:17]4)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: CN1CCc2cc(I)cc3c(=O)c(C(=O)NCc4ccc(Cl)cc4)cn1c23
Solvent: CCNCC
Product: CN1CCc2cc(C#CCO)cc3c(=O)c(C(=O)NCc4ccc(Cl)cc4)cn1c23
Temperature: 25 °C
Reaction time: 5 h
Yield: 74 %

Procedure:
A dry flask is charged with N-(4-chlorobenzyl)-5-iodo-1-methyl-7-oxo-2,3-dihydro-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxamide (Preparation 40, 0.100 g), cuprous iodide (0.012 g), dichlorobistriphenylphosphine palladium (0.0072 g), propargyl alcohol (0.022 g), and diethylamine (4 mL). The reaction mixture is stirred at room temperature for 5 h and concentrated at reduced pressure. The residue is chromatographed, using 20 g of silica gel packed and eluted with EtOAc/CH2Cl2 (1/1), to obtain the title compound in 74% yield as a tan colored solid. Physical characteristics: M.p. 165-167° C.; 1H NMR (DMSO-d6) δ10.21, 8.67, 8.13, 7.74, 7.38, 5.41, 4.55, 4.35, 3.49, 3.12, 2.85; 13C NMR (DMSO-d6) δ173.69, 162.80, 144.92, 137.79, 133.56, 132.88, 130.54, 128.44, 127.97, 127.49, 126.10, 124.99, 117.98, 109.97, 90.12, 81.73, 48.60, 47.63, 43.24, 40.64, 17.64; MS (ESI+) m/z 422 (M+H)+; HRMS (FAB) m/z 422.1282 (C23H20ClN3O3+H); TLC (silica gel GF): Rf=0.22 acetone/chloroform (1/4).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8](=[N:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[NH:9][C:10]#[N:11])[CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[C:29]([NH:1][C:2]1[CH:3]=[C:4]([C:8](=[N:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[NH:9][C:10]#[N:11])[CH:5]=[N:6][CH:7]=1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: N#CNC(=NCCc1ccccc1Cl)c1cncc(N)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CNC(=NCCc1ccccc1Cl)c1cncc(NC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.3 %

Procedure:
To a solution of 5-amino-N-cyano-N'-[2-(2-chlorophenyl)ethyl]-3-pyridinecarboximidamide (100 mg, 0.33 mmol) in DMF (3 ml) were added triethylamine (101 mg, 1 mmol) and benzoyl chloride (94 mg, 0.67 mmol), and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was neutralized by adding ice and a saturated aqueous sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (Wako Gel C-200, 30 g; eluted with chloroform:methanol=200:1) to give the title compound (38 mg, 0.09 mmol, yield 29%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.Cl[C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+].CC(N(C)C)=O>C1(C)C=CC=CC=1>[O:12]=[C:9]1[C:10]2[CH:11]=[C:2]([O:1][C:22]3[CH:14]=[N:15][CH:16]=[C:17]([CH:21]=3)[C:18]([NH2:20])=[O:19])[CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1
Reactant: O=C1CCCc2ccc(O)cc21
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: NC(=O)c1cncc(Oc2ccc3c(c2)C(=O)CCC3)c1
Temperature: 25 °C

Procedure:
Combine 7-hydroxy-1-tetralone (J. Med. Chem. (1998), 41(7), 1068-1083), (3.37 g, 20.7 mmol), 6-chloronicotinamide (available from Aldrichj Chemical Company, Milwaukee, USA) (2.95 g, 18.8 mmol, K2CO3 (3.91 g, 28.3 mmol), DMA (dimethylacetamide) (45 ml) and toluene (25 ml) in a round bottom flask, equipped with Dean-Stark trap, condenser, and nitrogen inlet. Reflux the suspension for 2-3 hours before cooling to ambient temperature. Remove the solids via filtration, wash solids with EtOAc, and concentrate the filtrate/wash on a rotary evaporator. Dissolve the remaining oil in EtOAc, wash with water (2×) and brine, dry (MgSO4) and concentrate. Triturate the resulting brown solid with boiling EtOAc, cool, and collect solid via filtration to give 4.76 g of the title compound as a yellow solid. Mass spectrum (ion spray): m/z=283 (M+1); 1HNMR (DMSO-d6): 8.56 (s, 1H), 8.25 (d, 1H), 8.02 (s, 1H), 7.52 (s, 1H), 7.48 (s, 1H), 7.42 (d, 1H), 7.35 (d, 1H), 7.12 (d, 1H), 2.95 (t, 2H), 2.60 (t, 2H), 2.05 (m, 2H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[NH2:11][CH2:12][CH:13]([OH:15])[CH3:14].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>ClCCl.C(Cl)(Cl)Cl>[OH:15][CH:13]([CH3:14])[CH2:12][NH:11][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=1
Reactant: O=C(O)c1cccc(I)c1
Reactant: CC(O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(O)CNC(=O)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.5 %

Procedure:
3-Iodobenzoic acid (2.00 g, 8.06 mmol) was dissolved in dichloromethane (80 mL), and the mixture was stirred at room temperature for 2 hours after adding 1-amino-2-propanol (1.25 mL, 16.1 mmol), 1-ethyl-3-(3dimethylaminopropyl)carbodiimide hydrochloride (1.86 g, 9.67 mmol), and 1-hydroxybenzotriazole.monohydrate (1.23 g, 8.06 mmol). The mixture was diluted with chloroform, and washed with a saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and crystallized from diethyl ether to give N-(2-hydroxypropyl)-3-iodobenzamide (1.71 g, 70%).
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][CH:13]([NH:16][CH:17]3[CH2:19][CH2:18]3)[CH2:12][CH2:11]2)[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[O:20]1[C:24]([C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][N:26]=2)=[CH:23][N:22]=[CH:21]1>>[C:1]([C:5]1[N:9]=[C:8]([N:10]2[CH2:11][CH2:12][CH:13]([N:16]([CH:17]3[CH2:19][CH2:18]3)[C:29](=[O:30])[C:28]3[CH:32]=[CH:33][C:25]([C:24]4[O:20][CH:21]=[N:22][CH:23]=4)=[N:26][CH:27]=3)[CH2:14][CH2:15]2)[O:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccc(-c2cnco2)nc1
Reactant: CC(C)(C)c1noc(N2CCC(NC3CC3)CC2)n1
Product: CC(C)(C)c1noc(N2CCC(N(C(=O)c3ccc(-c4cnco4)nc3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from [1-(3-tert-butyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-cyclopropyl-amine and 6-oxazol-5-yl-nicotinic acid following a procedure analogous to that described in Example 1. LC (method 7): tR=1.16 min; Mass spectrum (ESI+): m/z=437 [M+H]+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH2:13]([C:20]1[CH:33]=[CH:32][C:23]2[C@@H:24]3[C@H:29]([CH2:30][CH2:31][C:22]=2[CH:21]=1)[NH:28][CH2:27][CH2:26][CH2:25]3)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(CC2C=CC3[C@@H]4[C@H](CCC=3C=2)NCCC4)CCCCC1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:28]3[C@@H:29]4[C@@H:24]([C:23]5[CH:32]=[CH:33][C:20]([CH2:13][C:14]6[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=6)=[CH:21][C:22]=5[CH2:31][CH2:30]4)[CH2:25][CH2:26][CH2:27]3)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: c1ccc(Cc2ccc3c(c2)CC[C@@H]2NCCC[C@H]32)cc1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Agent: c1cc2c(cc1CC1CCCCC1)CC[C@@H]1NCCC[C@H]21
Product: O=C(c1ccc2[nH]cnc2c1)N1CCC[C@@H]2c3ccc(Cc4ccccc4)cc3CC[C@@H]21
Yield: 12 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and a mixture of cis-8-benzyl-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline and cis-8-cyclohexylmethyl-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline (ca. 30:70) following a procedure analogous to that described in Example 1 and separated from the also formed Example 83 by HPLC on reversed phase (MeOH/H2O/NH4OH). Yield: 12% of theory; LC (method 1): tR=3.35 min; Mass spectrum (ESI+): m/z=422 [M+H]+.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH:5]1([CH:11]2[CH:15]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[O:14][B:13]([CH:22](Cl)[CH:23]([CH3:31])[CH2:24][CH:25]([CH3:30])[C:26]([CH2:28][CH3:29])=[CH2:27])[O:12]2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>C1COCC1>[CH:16]1([CH:15]2[CH:11]([CH:5]3[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]3)[O:12][B:13]([CH:22]([CH2:1][CH3:2])[CH:23]([CH3:31])[CH2:24][CH:25]([CH3:30])[C:26]([CH2:28][CH3:29])=[CH2:27])[O:14]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC[Mg]Br
Reactant: C=C(CC)C(C)CC(C)C(Cl)B1OC(C2CCCCC2)C(C2CCCCC2)O1
Solvent: C1CCOC1
Product: C=C(CC)C(C)CC(C)C(CC)B1OC(C2CCCCC2)C(C2CCCCC2)O1
Temperature: -78 °C
Reaction time: 24 h

Procedure:
Ethylmagnesium bromide (3.0 M in diethyl ether, 35.6 mmol) was added dropwise in 20 minutes to a stirred solution of [4R- [2(S*,S*,S*),4α,5β]]-4,5-dicyclohexyl-2-(6-chloro-2-ethyl-3,5-dimethylhexen-6-yl) -1,3,2-dioxaborolane (14.5 g, 35.6 mmol) in THF (200 mL) cooled with a -78° C. bath. The bath was allowed to warm to 20°-25° C. and the mixture was stirred for 24 h. The solution was concentrated under vacuum and ether (200 mL) was added to the residue. The ethereal solution was washed with saturated aqueous ammonium chloride (2∞200 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to liquid [4R-[2(S*,S*,S*),4α,5β]]-4,5-dicyclohexyl -2-(2,6-diethyl-3,5-dimethylhexen-6-yl)-1,3,2-dioxaborolane (14a) as a liquid (12.9 g, 90%); 300 MHz 1H-NMR (CDCl3) δ0.87-2.27 (m, 43), 3.81 (m, 2), 4.66 and 4.71 (AB, 2); 75 MHz 13C-NMR (CDCl3): 12.3, 14.1, 17.6, 19.5, 22.0, 25.8, 25.9, 26.1, 27.1, 27.6, 28.2, 28.5, 31.6, 37.4, 43.1, 83.1, 105.8, 156.8. HRMS: calcd for C26H48BO2 [(M+1)+] 403.3747; found, 403.3732.
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[S:10][CH:9]=[N:8][C:6]=2[N:7]=1.[I:17]I.C[Si]([N-][Si](C)(C)C)(C)C.[K+].O>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[C:5]2[S:10][C:9]([I:17])=[N:8][C:6]=2[N:7]=1
Reactant: II
Reactant: Clc1nc(N2CCOCC2)c2scnc2n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Clc1nc(N2CCOCC2)c2sc(I)nc2n1
Temperature: -50 °C
Reaction time: 8 h

Procedure:
4-(5-Chlorothiazolo[4,5-d]pyrimidin-7-yl)morpholine 16 was dissolved in tetrahydrofuran and iodine (3 eq) was added. The solution was cooled to −50° C. and potassium bis(trimethylsilyl)amide (1.2 eq of 0.5M solution in toluene) was added over a period of 10 minutes. The solution was warmed to room temperature and stirred overnight. Water was added to quench the reaction and the tetrahydrofuran was removed in vacuo. The residue was brought up in methylene chloride, washed with saturated sodium bicarbonate solution and dried with magnesium sulfate. The solution was concentrated a purified by silica gel chromatography to yield 4-(5-chloro-2-iodothiazolo[4,5-d]pyrimidin-7-yl)morpholine 27.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([CH:27]=1)[C:7]([NH:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([S:21](=[O:24])(=[O:23])[NH2:22])[CH:19]=2)[O:14][CH2:13][CH2:12]1)=[O:8].[CH2:30]([N:34]=[C:35]=[S:36])[CH2:31][CH2:32][CH3:33]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([CH:27]=1)[C:7]([NH:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([S:21]([NH:22][C:35]([NH:34][CH2:30][CH2:31][CH2:32][CH3:33])=[S:36])(=[O:23])=[O:24])[CH:19]=2)[O:14][CH2:13][CH2:12]1)=[O:8]
Reactant: CCCCN=C=S
Reactant: COc1ccc(Cl)cc1C(=O)NCC1CCOc2cc(OC)c(S(N)(=O)=O)cc21
Product: CCCCNC(=S)NS(=O)(=O)c1cc2c(cc1OC)OCCC2CNC(=O)c1cc(Cl)ccc1OC

Procedure:
4-(5-Chloro-2-methoxybenzamidomethyl)-6-(n-butylaminothiocarbonylaminosulfonyl)-7-methoxychroman is prepared analogously to Example 4 from 4-(5-chloro-2-methoxybenzamidomethyl)-6-sulfamoyl-7-methoxychroman and n-butyl isothiocyanate. Melting point: 167° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH3:18])([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:19]=1.Br[C:21]1[CH:22]=[CH:23][C:24]([F:29])=[C:25]([CH:28]=1)[C:26]#[N:27]>>[F:29][C:24]1[CH:23]=[CH:22][C:21]([C:2]2[CH:3]=[CH:4][C:5]3[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH3:18])([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)[C:6]=3[CH:19]=2)=[CH:28][C:25]=1[C:26]#[N:27]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: CC1(c2cccs2)OCC(=O)Nc2ccc(Br)cc21
Product: CC1(c2cccs2)OCC(=O)Nc2ccc(-c3ccc(F)c(C#N)c3)cc21

Procedure:
Prepared from 7-bromo-5-methyl-5-thien-2-yl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 5-bromo-2-fluorobenzonitrile generally according to the coupling procedure described in examples 82 and 1. 1H-NMR (DMSO-d6) δ 10.14 (s, 1H), 8.27 (dd, J=5.6, 2.4 Hz, 1H), 8.06 (m, 1H), 7.68 (dd, J=8.8, 2.4 Hz, 1H), 7.63 (d, J=2.0 Hz, 1H), 7.60 (t, J=9.3 Hz, 1H), 7.55 (dd, J=5.4, 1.5 Hz, 1H), 7.27 (d, J=8.8 Hz, 1H), 6.98 (m, 1H), 6.89 (dd, J=3.9, 1.5 Hz, 1H), 4.16 (d, J=15.6 Hz, 1H), 4.05 (d, J=15.6 Hz, 1H), 2.10 (s, 3H); MS (ES) m/z 379 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][NH:3]1.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.N1C=CC=CC=1.CC1(C)N([O])C(C)(C)CCC1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[F:12][C:13]1[CH:18]=[C:17]([N:3]2[CH:4]=[CH:5][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:7][C:2]2=[O:1])[CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: COC(=O)c1cc[nH]c(=O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CC1(C)CCCC(C)(C)N1[O]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccn(-c2cccc(F)c2)c(=O)c1
Temperature: 25 °C

Procedure:
A mixture of methyl 2-oxo-1,2-dihydropyridine-4-carboxylate 89-1 (153 mg, 1.00 mmol), (3-fluorophenyl)boronic acid 6-6 (280 mg, 2.00 mmol), Cu(OAc)2 (36 mg, 0.2 mmol), molecular sieves (4 Å, activated, 200 mg), pyridine (162 μL, 2.0 mmol) and TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy, free radical, 172 mg, 1.1 mmol) in DCM (2.0 mL) was stirred at room temperature under dry air. The mixture was then filtered through celite (washed with ethyl acetate); and the filtrate was washed with 5% ammonia solution, dried with Na2SO4 and concentrated with rotavap. The residue was subjected to silica gel column chromatography with 1:3 ethyl acetate/DCM as eluent to give methyl 1-(3-fluorophenyl)-2-oxo-1,2-dihydropyridine-4-carboxylate as a solid 89-2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].[Cl:13][O-].[Na+]>C(O)C>[Cl:13][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][N:8]=1
Reactant: [O-]Cl
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1ccc2[nH]nc(Cl)c2c1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
5-Nitro-1H-indazole (2.0 g, 12.3 mmol) was suspended in 40 ml ethanol and sodium hypochlorite solution (123 ml, 2.0 M, 246 mmol) was added. The mixture was heated to 75° C. and stirred overnight. The solvent was evaporated to dryness to afford the title compound. (2.4 g, 100%), MS (ES+) m/e 198 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]2[N:11]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:10][CH:9]([CH2:16][OH:17])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:21]1[C:26]([C:27]#[N:28])=[CH:25][CH:24]=[CH:23][N:22]=1.O>CN(C)C=O>[C:1]1([CH:7]2[N:11]([C:12]([CH3:13])([CH3:14])[CH3:15])[CH2:10][CH:9]([CH2:16][O:17][C:21]3[C:26]([C:27]#[N:28])=[CH:25][CH:24]=[CH:23][N:22]=3)[O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1cccnc1Cl
Reactant: CC(C)(C)N1CC(CO)OC1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)N1CC(COc2ncccc2C#N)OC1c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To S -2-phenyl-3-tert. butyl-5-hydroxymethyloxazolidine (7 grams, 0.03 moles) in 35 ml. of N,N-dimethylformamide (DMF) is added 1.3 grams (0.03 moles of sodium hydride (57% dispersion in mineral oil). This mixture is heated 5 minutes over steam and then is allowed to stir 15 minutes at room temperature. 4.1 grams (0.03 moles) of 2-chloro-3-cyanopyridine in 20 ml of DMF is then added and the resultant reaction mixture is stirred 4 hours at room temperature. Water is then added and an oil separates. This oil is extracted three times with 25 ml of chloroform each time. This chloroform exrract is dried over sodium sulfate and concentrated under reduced pressure (20 mm) over steam to yield the product, S -2-phenyl-3-tert. butyl-5-(3-cyano-2-pyridyloxymethyl)oxazolidine, as an oil. This oil is then suspended in 1N HCl (50 ml), heated 5 minutes over steam and then is stirred for 15 minutes at room temperature. The solution obtained is then extracted twice with 25 ml of diethylether each time. The extracted aqueous layer is made basic by addition of saturated aqueous sodium carbonate solution. This aqueous solution is then extracted with ethyl acetate (3 × 25 ml) and the ethylacetate solution is dried over sodium sulfate. The dried ethyl acetate solution is then concentrated under reduced pressure (20 mm) over steam to yield an oil. This oil is chromatographed on alumina. The chromatographic fractions are concentrated to yield an oil which is dissolved in diethyl ether. Ethanolic HCl (saturated solution) is added to this ether solution until solid separation is substantially complete. The separated semi-solid is recrystallized from isopropanol/ether (ether added to isopropanol to the point of turbidity) to yield 1 gram of S -2-(3-tert. butylamino-2-hydroxypropoxy)-3-cyanopyridine hydrochloride, melting at 161°-163° C.
Reaction SMILES: [C:1]([OH:12])(=O)[C:2]1[CH:10]=[C:8]([OH:9])[C:6]([OH:7])=[C:4]([OH:5])[CH:3]=1.[C:13]1([CH:21]=[CH:20][CH:19]=[C:17]([OH:18])[C:15]=1[OH:16])[OH:14].P(Cl)(Cl)(Cl)=O.[Cl-].[Ca+2].[Cl-]>[Cl-].[Zn+2].[Cl-].O>[OH:14][C:13]1[C:15]([OH:16])=[C:17]([OH:18])[CH:19]=[CH:20][C:21]=1[C:1]([C:2]1[CH:3]=[C:4]([OH:5])[C:6]([OH:7])=[C:8]([OH:9])[CH:10]=1)=[O:12]
Reactant: Oc1cccc(O)c1O
Reactant: O=C(O)c1cc(O)c(O)c(O)c1
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(c1cc(O)c(O)c(O)c1)c1ccc(O)c(O)c1O

Procedure:
A reaction of the Fries type was used: ##STR4## 32 g of Gallic acid, 32 g of pyrogallol, 55 g of anhydrous zinc chloride and 100 cm3 of phosphorus oxychloride were mixed in a balloon flask equipped with a condenser and an ampoule of calcium chloride, and were heated to 80° C for 2 hours. After cooling the reaction mixture, a mixture of water and ice was added, whereupon the reaction product precipitated. The reaction product was washed once with water, treated with a solution of sodium bicarbonate, then washed again with water, and finally recrystallised from aqueous solution. Yield: 15 g of crystalline 2,3,3',4,4',5'-hexahydroxybenzophenone having a melting point of 270° C.