Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C:10]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:12])=[CH:6][CH:7]=1
Reactant: O=C(O)C#Cc1ccc(Br)cc1
Reactant: Nc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(C#Cc1ccc(Br)cc1)Nc1ccccc1
Temperature: 75 °C
Yield: 34.7 %

Procedure:
A mixture of 8.50 g (37.77 mmol) (4-bromophenyl) propiolic acid (S. Chimichi, et. al., J. Heterocyclic Chem. 20, 105 (1983)), 5.39 g (45.32 mmol, 1.2 equivs.) thionyl chloride and 50 mL benzene was stirred and heated at 75° C. for 3 hrs. The reaction was allowed to cool to room temperature and solvent was evaporated. The reaction vessel was charged with 50 mL of fresh benzene and the mixture cooled in an ice bath under an atmosphere of nitrogen. Added next, dropwise in 50 mL benzene, was 7.04 g (75.54 mmol, 2 equivs.) aniline. After addition was complete, the ice bath was removed and the mixture stirred at room temperature overnight. The mixture was poured into 150 mL water and the layers were separated. The aqueous layer was extracted with three 100 mL portions of ethyl acetate. The combined organic layers were then washed sequentially with 100 mL portions of 5% aqueous hydrochloric acid, water, 5 % aqueous sodium carbonate and water. The organic layer was dried, filtered and solvent was evaporated from the filtrate. The resulting solid was recrystallized from absolute ethanol to provide 3.93 g (13.09 mmol, 35%)3-(4-bromophenyl)-N-phenylpropiolamide as a white powder, mp=159°-160.5° C. NMR (CDCl3 /TMS): 7.15 (t, 1H), 7.32-7.40 (m, 4H), 7.49 (d, 2H), 7.57 (d, 2H), 7.80 (bs, 1H). IR (KBr): 3304, 2214, 1638. High resolution mass spectrum: Calculated; 298.994575 (for 79Br isotope). Measured; 298. 994225.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[N:18]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:19]=1[CH2:20][C:21](Cl)=[O:22]>>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([CH:2]([NH:1][C:21]([CH2:20][C:19]2[CH:24]=[CH:25][C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:18]=2)=[O:22])[CH2:3][CH2:4][N:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]2)=[CH:12][CH:13]=1
Reactant: Cc1ccc(C(N)CCN2CCCCC2)cc1
Reactant: O=C(Cl)Cc1ccc2ccccc2n1
Product: Cc1ccc(C(CCN2CCCCC2)NC(=O)Cc2ccc3ccccc3n2)cc1
Yield: 90.5 %

Procedure:
The procedure of Example 1 was repeated using 697 mg (3.0 mmol.) of 1-[3-amino-3-(4-methylphenyl)propyl]piperidine and 575 mg (3.0 mmol.) of quinaldinoyl chloride, to obtain 1.09 g (yield: 94%) of the subject compound as a pale yellow oily product.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:18][C:17]2[C:19]3[C:24]([CH2:25][CH2:26][C:16]=2[N:15]=1)=[CH:23][C:22]([C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[CH:33]=[C:32]([C:37]1[NH:41][C:40]([C@@H:42]4[CH2:46][CH2:45][CH2:44][N:43]4[C:47](=[O:57])[C@@H:48]([NH:52][C:53](=[O:56])[O:54][CH3:55])[CH:49]([CH3:51])[CH3:50])=[N:39][CH:38]=1)[CH:31]=[CH:30]2)=[CH:21][CH:20]=3)=[O:8])=[O:4].BrC1C=C2C(=CC=1)C=C(C1NC([C@@H]3CCCN3C(=O)[C@@H](N[C:91](=O)[O:92][CH3:93])C(C)C)=NC=1)C=C2>>[CH3:1][O:2][C:3]([NH:5][C@H:6]([C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1)[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:18][C:17]2[C:19]3[C:24]([CH2:25][CH2:26][C:16]=2[N:15]=1)=[CH:23][C:22]([C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[CH:33]=[C:32]([C:37]1[NH:41][C:40]([C@@H:42]4[CH2:46][CH2:45][CH2:44][N:43]4[C:47](=[O:57])[C@@H:48]([NH:52][C:53](=[O:56])[O:54][CH3:55])[CH:49]4[CH2:51][CH2:93][O:92][CH2:91][CH2:50]4)=[N:39][CH:38]=1)[CH:31]=[CH:30]2)=[CH:21][CH:20]=3)=[O:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(-c4ccc5c(c4)CCc4nc([C@@H]6CCCN6C(=O)[C@H](NC(=O)OC)c6ccccc6)[nH]c4-5)ccc3c2)[nH]1)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(-c4ccc5c(c4)CCc4nc([C@@H]6CCCN6C(=O)[C@H](NC(=O)OC)c6ccccc6)[nH]c4-5)ccc3c2)[nH]1)C1CCOCC1

Procedure:
Title compound was synthesized using methods analogous to the preparation of methyl (S)-1-((S)-2-(5-(6-(2-((S)-1-((R)-2-methoxycarbonylamino-2-phenylacetyl)pyrrolidin-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-7-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate, substituting methyl (S)-2-((S)-2-(5-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate for methyl (S)-1-((S)-2-(5-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate. MS (ESI) m/z 891 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]([OH:15])=[O:14])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[CH:12]=1.S(OOS([O-])(=O)=O)([O-])(=O)=[O:17].[K+].[K+].C(#N)C.O.C(OCC)(=O)C>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]([OH:15])=[O:14])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[C:7](=[O:17])[C:6]=2[CH:12]=1
Reactant: CC1(C)Cc2cc(Cl)cc(C(=O)O)c2O1
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CC1(C)Oc2c(C(=O)O)cc(Cl)cc2C1=O

Procedure:
A solution of 5-chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxylic acid (654) (2.39 g, 10.5 mmol), potassium persulfate (8.55 g, 31.6 mmol), cupric sulfate pentahydrate (2.62 g, 10.5 mmol) and acetonitrile/water (1:1) (90 mL) were heated at reflux for 1 hour. Ethyl acetate and water were added and the layers separated. The aqueous phase was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to provide 5-chloro-2,2-dimethyl-3-oxo-2,3-dihydrobenzofuran-7-carboxylic acid (655) as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:32]([NH:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:33])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCCCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Product: CCCCCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)Nc1ccccc1
Yield: 26.9 %

Procedure:
Using the general method of Example 149, 1-(4-aminobutyl)-2-pentyl-1H-imidazo[4,5-c]quinolin-4-amine (800 mg, 2.5 mmol) was reacted with phenyl isocyanate (0.26 mL, 2.5 mmol) to provide 299 mg of N-[4-(4-amino-2-pentyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-phenylurea as an off white solid, m.p. 159.0-160.4° C. Analysis: Calculated for C26H32N6O2.1.0H2O: %C, 67.51; %H, 7.41; %N, 18.17; Found: %C, 67.73; %H, 7.33; %N, 17.97.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([CH3:10])C=O)[CH:2]=1.[C:11]([O:15][C:16](=[O:37])[NH:17][CH:18]([C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH3:36])[CH2:32][CH2:31]1)=[O:29])CCC1C=CC=CC=1Cl)([CH3:14])([CH3:13])[CH3:12].ClC1C=CC=CC=1C=CC=O>>[C:11]([O:15][C:16](=[O:37])[NH:17][CH:18]([C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH3:36])[CH2:32][CH2:31]1)=[O:29])[CH2:10][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C=O)c1cccnc1
Reactant: CC1CCN(C(=O)C(CCc2ccccc2Cl)NC(=O)OC(C)(C)C)CC1
Agent: O=CC=Cc1ccccc1Cl
Product: CC1CCN(C(=O)C(CCc2cccnc2)NC(=O)OC(C)(C)C)CC1

Procedure:
tert-Butyl{1-[(4-methylpiperidin-1-yl)carbonyl]-3-pyridin-3-ylpropyl}carbamate is prepared from pyridin-3-yl propionaldehyde (Kitbunnadaj, R. et al. J. Med. Chem, 2004, 47, 2414-2417) in the same manner that tert-butyl{3-(2-chlorophenyl)-1-[(4-methylpiperidin-1-yl)carbonyl]propyl}carbamate is prepared from 3-(2-chlorophenyl)propenal in Example 5.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH3:20])[C:14]=1[C:21]1[N:26]=[C:25]([CH3:27])[C:24]([CH:28]([CH:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33][CH2:32][CH2:31]2)[OH:29])=[C:23]([O:40][CH3:41])[CH:22]=1)[CH3:12].C(N(CC)CC)C>ClCCl>[CH2:19]([C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:11][CH3:12])[C:14]=1[C:21]1[N:26]=[C:25]([CH3:27])[C:24]([C:28]([CH:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33][CH2:32][CH2:31]2)=[O:29])=[C:23]([O:40][CH3:41])[CH:22]=1)[CH3:20]
Reactant: CCc1cccc(CC)c1-c1cc(OC)c(C(O)C2CCCc3ccccc32)c(C)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cccc(CC)c1-c1cc(OC)c(C(=O)C2CCCc3ccccc32)c(C)n1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
Dimethyl sulfoxide (60 μL, 0.85 mmol) is added at −78° C. to a solution of oxalyl chloride (36 μL, 0.41 mmol) in dichloromethane (2 mL). After stirring at −78° C. for 10 minutes, a solution of [6-(2,6-diethyl-phenyl)-4-methoxy-2-methyl-pyridin-3-yl]-(1,2,3,4-tetrahydro-naphthalen-1-yl)-methanol (138 mg) in dichloromethane (2 mL) is added and the mixture is stirred for 40 minutes more. Triethylamine (0.24 mL, 1.7 mmol) is then added. After 10 minutes, the mixture is allowed to warm to room temperature and quenched with water. Extraction with dichloromethane, drying (Na2SO4), and concentration followed by flash chromatography provides [6-(2,6-diethylphenyl)-4-methoxy-2-methylpyridin-3-yl]-(1,2,3,4-tetrahydronaphthalene-1-yl)methanone. 1H NMR (CDCl3) 7.30 (dd, 1H), 7.16-7.12 (m, 4H), 7.0 (t, 1H), 6.9 (d, 1H), 6.6 (s, 1H), 4.4 (s, 1H), 3.8 (s, 3H), 2.90-2.76 (m, 2H), 2.43-2.33 (m, 4H), 2.3 (s, 3H), 2.03-1.84 (m, 4H), 1.15-1.04 (m, 6H).
Reaction SMILES: [C:1](Cl)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C([N:19]1[CH2:24][CH2:23][C:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:21][CH2:20]1)C1C=CC=CC=1.C(OCC)(=O)C>C(Cl)(Cl)Cl>[CH2:4]([O:3][C:1]([N:19]1[CH2:20][CH2:21][C:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:23][CH2:24]1)=[O:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: c1ccc(CN2CCC(c3ccccc3)(N3CCCC3)CC2)cc1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1CCC(c2ccccc2)(N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.3 %

Procedure:
60 g (3.5 equiv.) of Cbz chloride were added dropwise over a period of 10 minutes to a solution of 33 g (1 equiv.) of 1-benzyl-4-phenyl-4-(pyrrolidin-1-yl)piperidine in 330 ml of chloroform, and the resulting reaction mixture was stirred for 30 minutes at room temperature. The progress of the reaction was monitored by thin-layer chromatography (ethyl acetate). When the reaction was complete, the solvent was distilled off completely and the residue was adjusted to ˜pH 6 with 10% HCl solution and washed 3× with 100 ml of EtOAc. In an ice bath, the aqueous solution was adjusted to ˜pH 9 with NaOH solution and then extracted 3× with 100 ml of chloroform. The combined organic phases were dried with Na2SO4. After removal of the solvent under reduced pressure, purification was carried out by column chromatography (silica gel; 20% EtOAc/heptane). 11 g (29%) of product were obtained in the form of a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]3[C:22]([OH:24])=[O:23])=[O:15])[CH:5]=[CH:4][C:3]1=2.S(=O)(=O)(O)O.[CH2:31](O)[CH3:32]>>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]3[C:22]([O:24][CH2:31][CH3:32])=[O:23])=[O:15])[CH:5]=[CH:4][C:3]1=2
Reactant: CCO
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)C3CCCCC3C(=O)O)ccc21
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1CCCCC1C(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C

Procedure:
A solution of 3.42 g (10 mmoles) of 2-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl) carbonyl]cyclohexane carboxylic acid, described in Example III, in 100 cm3 of ethyl alcohol containing 0.1 cm3 of 98% sulfuric acid, is heated for 12 hours at reflux. The solution is concentrated under reduced pressure and the resulting crude ester is dissolved in 100 cm3 of ethyl ether. The ether solution is washed with sodium bicarbonate and then with water, dried on sodium sulfate and evaporated to dryness. After drying, 3.6 g of ethyl 2-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)carbonyl]cyclohexane carboxylate are obtained in the form of a colorless thick oil.
Reaction SMILES: [Br:1][CH:2]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[C:3]([C:5]1([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[CH2:8][CH2:7][CH2:6]1)=O.[NH:24]1[CH2:28][CH2:27][NH:26][C:25]1=[S:29].C(O)C>C(O)(=O)C>[BrH:1].[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:2]2[S:29][C:25]3=[N:24][CH2:28][CH2:27][N:26]3[C:3]=2[C:5]2([C:9]3[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=3)[CH2:8][CH2:7][CH2:6]2)=[CH:18][CH:19]=1
Reactant: S=C1NCCN1
Reactant: O=C(C(Br)c1ccc(Cl)cc1)C1(c2ccc(Cl)c(Cl)c2)CCC1
Solvent: CC(=O)O
Solvent: CCO
Product: Br
Product: Clc1ccc(C2=C(C3(c4ccc(Cl)c(Cl)c4)CCC3)N3CCN=C3S2)cc1
Temperature: 25 °C
Yield: 21.2 %

Procedure:
A mixture of 2-bromo-2-(4-chlorophenyl)1-[1-(3,4-dichlorophenyl)cyclobutyl]ethanone (3.68 g), imidazolidine-2-thione (0.87 g), ethanol (60 ml) and acetic acid (35 ml) was heated under reflux for 18 hours then allowed to cool to ambient temperature. The solvents were removed in vacuo and the residue was triturated with ethanol (30 ml). The resulting solid was collected by filtration and crystallised from acetic acid. The resulting product was collected by filtration, washed with acetic acid (10 ml) and dried in vacuo at 100° C. to give 2-(4-chlorophenyl)-3-[1-(3,4-dichlorophenyl)cyclobutyl]-5,6-dihydroimidazo[2,1-b]thiazole hydrobromide as a colourless solid (0.93 g), m.p. 302-304° C. (decomposes).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[N:11][C:10]([C:13]([OH:15])=O)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C(OC([N:23]1[CH2:28][CH2:27][NH:26][C:25]([CH3:30])([CH3:29])[CH2:24]1)=O)(C)(C)C.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].CC1(C)CNCCN1C(C1N=CN(C2C=CC=CC=2)N=1)=O>>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[N:11][C:10]([C:13]([N:26]3[CH2:27][CH2:28][NH:23][CH2:24][C:25]3([CH3:30])[CH3:29])=[O:15])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ncn(-c2cccc(Cl)c2)n1
Reactant: CC1(C)CN(C(=O)OC(C)(C)C)CCN1
Agent: CC1(C)CNCCN1C(=O)c1ncn(-c2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CNCCN1C(=O)c1ncn(-c2cccc(Cl)c2)n1

Procedure:
This intermediate was prepared from 1-(3-chloro-phenyl)-1H-[1,2,4]-triazole-3-carboxylic acid and 3,3-dimethyl-piperazine-1-carboxylic acid tert-butyl ester in two steps according to the preparation of (2,2-dimethyl-piperazin-1-yl)-(1-phenyl-1-H-[1,2,4]triazol-3-yl)-methanone trifluoroacetate and purified using HPLC.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([O:18][CH2:19][CH2:20][Cl:21])=[CH:12][CH:13]=3)[C:8](=[O:22])[C:7]=2[CH:6]=1.[OH:23]O>S(=O)(=O)(O)O>[Cl:21][CH2:20][CH2:19][O:18][C:11]1[CH:12]=[CH:13][C:14]2[C:15]3[CH:16]=[CH:17][C:5]([O:4][CH2:3][CH2:2][Cl:1])=[CH:6][C:7]=3[C:8](=[O:23])[O:22][C:9]=2[CH:10]=1
Reactant: O=C1c2cc(OCCCl)ccc2-c2ccc(OCCCl)cc21
Reactant: OO
Agent: O=S(=O)(O)O
Product: O=c1oc2cc(OCCCl)ccc2c2ccc(OCCCl)cc12
Temperature: 0 °C

Procedure:
A solution of 13.5 g (0.04 mole) of 2,7-bis(2-chloroethoxy)fluoren-9-one in 100 ml of concentrated sulfuric acid is slowly reacted with 12 ml of a 30% hydrogen peroxide solution at room temperature. The reaction which is strongly exothermic is controlled by cooling the stirred reaction mixture in an ice-water bath. The cooled reaction mixture is poured onto 500 ml of an ice-water mixture and the resulting 3,8-bis(2-chloroethoxy)-6H-dibenzo [b,d]pyran-6-one which separates is isolated.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([NH:18][C:19]1[C:20]2[CH2:28][N:27]([C:29]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:30]=3[C:31]#[N:32])[CH2:26][CH2:25][C:21]=2[N:22]=[CH:23][N:24]=1)[C:11]1[CH:12]=[N:13][C:14]([CH3:17])=[N:15][CH:16]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O.CCOC(C)=O>C1COCC1>[OH:8][CH2:9][C@@H:10]([NH:18][C:19]1[C:20]2[CH2:28][N:27]([C:29]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:30]=3[C:31]#[N:32])[CH2:26][CH2:25][C:21]=2[N:22]=[CH:23][N:24]=1)[C:11]1[CH:16]=[N:15][C:14]([CH3:17])=[N:13][CH:12]=1
Reactant: Cc1ccc(N2CCc3ncnc(N[C@H](CO[Si](C)(C)C(C)(C)C)c4cnc(C)nc4)c3C2)c(C#N)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(N2CCc3ncnc(N[C@H](CO)c4cnc(C)nc4)c3C2)c(C#N)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (S)-2-(4-(2-(tert-butyldimethylsilyloxy)-1-(2-methylpyrimidin-5-yl)ethylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (630 mg, 1.22 mmol) in THF (10 mL) was added 1M TBAF in THF (5 mL). The reaction mixture was stirred at room temperature for 10 minutes, and then treated with water and EtOAc. The organic layer was washed with aq. NaHCO3 and brine, dried (MgSO4), and concentrated. The residue was washed by ethyl ether to yield a light colored solid.
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[NH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1>CS(C)=O>[NH2:9][C:3]1[C:2]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[N:7][C:6]([Br:8])=[CH:5][N:4]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: NCc1ccc(O)cc1
Solvent: CS(C)=O
Product: Nc1ncc(Br)nc1NCc1ccc(O)cc1
Yield: 11.7 %

Procedure:
A solution of 3,5-dibromo-pyrazin-2-ylamine (220 mg, 0.87 mmol) and 4-aminomethyl-phenol (225.0 mg, 1.83 mmol) in DMSO (2.5 mL) was heated at 98° C. under nitrogen for 24 hours. HPLC showed that 35% of product was formed and 40% of starting material presented. The reaction solution was partitioned between EtOAc and water. After condensation of organic layer, the residue was purified on a silica gel column eluting with 3% methanol in dichloromethane to provide 4-[(3-amino-6-bromo-pyrazin-2-ylamino)-methyl]-phenol (30 mg) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]([Br:17])=[CH:16][C:3]=12.CC(C)([O-])C.[Na+].[Cl:24][C:25]1[CH:26]=[C:27]([S:31](Cl)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1>C1COCC1.C(OCC)(=O)C.O>[Br:17][C:15]1[S:14][C:4]2=[N:5][C:6]([CH3:13])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]([NH:1][S:31]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([Cl:24])[CH:26]=3)(=[O:33])=[O:32])=[C:3]2[CH:16]=1
Reactant: CCOC(=O)c1c(C)nc2sc(Br)cc2c1N
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)nc2sc(Br)cc2c1NS(=O)(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.5 %

Procedure:
To a stirred solution of ethyl 4-amino-2-bromo-6-methylthieno[2,3-b]pyridine-5-carboxylate (Description 66) (390 mg, 1.24 mmol) in THF (12 mL) was added sodium tert-butoxide (297 mg, 3.09 mmol) and 3-chlorobenzenesulfonyl chloride (0.35 mL, 2.47 mmol). The reaction mixture was stirred at RT under nitrogen for ca. 3 h. The reaction mixture was diluted with ethyl acetate (ca. 30 mL) and water (ca. 50 mL). The organic layer was separated and the aqueous layer re-extracted with ethyl acetate (ca. 30 mL×2). The combined organic phase was dried over Na2SO4 and then concentrated in vacuo. Purification by chromatography on silica, eluting with a gradient of 0-20% ethyl acetate in DCM, afforded the title compound (252 mg). LCMS (A) m/z: 490/492 [M+1]+, Rt 1.48 min (acidic).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]([N:21]([CH3:29])[C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][N:23]=1)[CH3:20]>>[CH2:19]([N:21]([CH3:29])[C:22]1[N:23]=[CH:24][C:25]([NH:28][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:26][CH:27]=1)[CH3:20]
Reactant: CCN(C)c1ccc(N)cn1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: CCN(C)c1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 16 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(ethyl-methyl-amino)-pyridin-3-yl]-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N2-ethyl-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C19H17F3N4O2 (m/e) 390, obsd 391 (M+H).
Reaction SMILES: C(O[C:4](=[O:19])[C@@H:5]([NH2:18])[C@@H:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1)[OH:7])C.[BH4-].[K+].N[C@H:23]([CH2:36]O)[C@@H:24](C1C=CC(S(C)(=O)=O)=CC=1)O.C(=O)([O-])[O-].[K+].[K+]>CO.CC(C)=O.C1(C)C=CC=CC=1>[CH3:24][C:23]1([CH3:36])[NH:18][C@H:5]([CH2:4][OH:19])[C@@H:6]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([CH3:17])(=[O:15])=[O:16])=[CH:12][CH:13]=2)[O:7]1
Reactant: CS(=O)(=O)c1ccc([C@@H](O)[C@H](N)CO)cc1
Reactant: CCOC(=O)[C@@H](N)[C@H](O)c1ccc(S(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Solvent: CO
Product: CC1(C)N[C@H](CO)[C@@H](c2ccc(S(C)(=O)=O)cc2)O1
Temperature: 80 °C

Procedure:
(2S,3R)-Ethyl-2-amino-3-[4-(methylsulfonyl)phenyl]-3-hydroxy-propanoate (Compound IV) (100 g, 0.3480 moles) in 500 mL of methanol reacts with potassium borohydride (28.2 g, 0.5220 moles) over 4-8 hours at 50-60° C. to quantitatively yield (1R,2R)-2-amino-1-[4-(methylsulfonyl)phenyl]-1,3-propandiol (Compound VII: R1 is methylsulfonyl) (85.36 g, 0.3480 moles) in solution. Toluene (500 mL) and acetone (500 mL) replace methanol which distills off. Addition of potassium carbonate (6.9 g, 0.0696 moles) with heating at 75-85° C. for 12-18 hours yields (4R,5R)-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine (Compound VIII: R1 is methylsulfonyl and R2 and R3 are methyl). Addition of potassium carbonate (19.0 g, 0.1914 moles) and acetyl chloride (30.0 g, 0.3828 moles) at 20-25° C. for 2-4 hours then addition of water (500 mL) precipitates the crude product. Filtration, washing with water (250 mL) then drying yields (4R,5R)-3-acetyl-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine (Compound II).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH2:29][CH2:30][CH:31]1[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]1>>[CH3:22][N:20]1[CH:21]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[N:7]=[C:2]([NH:29][CH2:30][CH:31]5[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]5)[CH:3]=[CH:4][CH:5]=4)=[N:9][NH:10][C:11]3=[CH:12][N:13]=2)[CH:18]=[N:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: Cn1cc(-c2cc3c(-c4cccc(F)n4)nn(C4CCCCO4)c3cn2)cn1
Product: Cn1cc(-c2cc3c(-c4cccc(NCC5CCNCC5)n4)n[nH]c3cn2)cn1
Yield: 55 %

Procedure:
Following the procedures as described in Example 189, 3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and tert-butyl 4-(aminomethyl)piperidine-1-carboxylate were reacted and the product was deprotected to give 183 as a white solid (55% over two steps). 1H NMR (400 MHz, DMSO) δ 9.01 (s, 1H), 8.66 (s, 1H), 8.16 (s, 1H), 7.92 (s, 1H), 7.47 (t, J=7.8 Hz, 1H), 7.30 (d, J=7.3 Hz, 1H), 6.76-6.70 (m, 1H), 6.50 (d, J=8.3 Hz, 1H), 3.90 (s, 3H), 3.44-3.34 (m, 4H), 2.99 (d, J=12.2 Hz, 2H), 2.55-2.44 (m, 2H), 1.85-1.71 (m, 3H), 1.27-1.09 (m, 2H). LC/MS: m/z 389.2 [M+1]