Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])CCC.C[O-].[Na+].CO.Cl>CN(C=O)C.O>[CH3:1][O:5][C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH:12]=2)=[O:7]
Reactant: CCCCOC(=O)c1ncc2cc(Oc3ccc(OC)cc3)ccc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1ncc2cc(Oc3ccc(OC)cc3)ccc2c1O
Yield: 85 %

Procedure:
To a mixture of 4-hydroxy-7-(4-methoxy-phenoxy)-isoquinoline-3-carboxylic acid butyl ester (prepared according to U.S. Pat. No. 7,928,120) (20 mg, 0.054 mmol) in DMF (0.5 mL) was added 0.5 M NaOMe/MeOH (0.32 mL, 0.16 mmol). The resultant mixture was microwaved at 80° C. for 1.5 h. Reaction mixture was diluted with water (70 mL) and acidified by 1 N HCl to pH=4. Precipitate was collected and dried in vacuo to provide the title compound 15 mg (0.046 mmol) in 85% yield. LC-MS ESI+: 326.10 (M+1)+.
Reaction SMILES: FC(C1N=C2C(C=C(C(O)=O)C(C(F)(F)F)=N2)=CC=1F)(F)C.FC([C:27]1[N:36]=[C:35]2[C:30]([CH:31]=[C:32]([C:41]([CH:43]3[C:48](=[O:49])[CH2:47][CH2:46][CH2:45][C:44]3=[O:50])=[O:42])[C:33]([C:37]([F:40])([F:39])[F:38])=[N:34]2)=[CH:29][C:28]=1F)(F)C>>[F:40][C:37]([F:38])([F:39])[C:33]1[C:32]([C:41]([CH:43]2[C:48](=[O:49])[CH2:47][CH2:46][CH2:45][C:44]2=[O:50])=[O:42])=[CH:31][C:30]2[C:35](=[N:36][CH:27]=[CH:28][CH:29]=2)[N:34]=1
Reactant: CC(F)(F)c1nc2nc(C(F)(F)F)c(C(=O)C3C(=O)CCCC3=O)cc2cc1F
Agent: CC(F)(F)c1nc2nc(C(F)(F)F)c(C(=O)O)cc2cc1F
Product: O=C1CCCC(=O)C1C(=O)c1cc2cccnc2nc1C(F)(F)F

Procedure:
From 7-(1,1-difluoroethyl)-6-fluoro-2-trifluoromethyl-[1,8]-naphthyridine-3-carboxylic acid, 2-[7-(1,1-difluoroethyl)-6-fluoro-2-trifluoromethyl-[1,8]-naphthyridine-3-carbony]-cyclohexane-1,3-dione, yellow solid, 1H NMR (CDCl3) δ: 8.08 (1H, s), 7.95 (1H, d), 2.85 (2H, broad s), 2.42 (2H, broad s), 2.23 (3H, t), (2H, quintet). Molecular ion: (MH)+418.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[C:9]([Cl:15])[CH:8]=1)[OH:6])[CH3:2].[C:17](OC(=O)C)(=[O:19])[CH3:18]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([O:6][C:17](=[O:19])[CH3:18])[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[C:9]([Cl:15])[CH:8]=1)[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C(O)c1ccc(SC)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C(OC(C)=O)c1ccc(SC)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
A solution of (3-chloro-4-methylsulfanyl-phenyl)-hydroxy-acetic acid ethyl ester (1.43 g, 5.49 mmol) in pyridine (2 mL) was treated with acetic anhydride (2 mL) and 4-dimethylaminopyridine (50 mg, 0.41 mmol). The reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was then diluted with methylene chloride (100 mL). The organic layer was washed with a 1N aqueous hydrochloric acid solution (2×30 mL), washed with a saturated aqueous sodium chloride solution (1×30 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 4/1 hexanes/ethyl acetate) afforded acetoxy-(3-chloro-4-methylsulfanyl-phenyl)-acetic acid ethyl ester (1.51 g, 91%) as a light yellow oil: EI-HRMS m/e calcd for C13H15ClO4S (M+) 302.0379, found 302.0387.
Reaction SMILES: F[C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]2[O:11]C(N)=[N:9][N:8]=2)=[CH:4][CH:3]=1.NN.[OH2:17]>>[OH:17][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]([NH:8][NH2:9])=[O:11])=[CH:4][CH:3]=1
Reactant: Nc1nnc(Cc2ccc(F)cc2)o1
Reactant: O
Agent: NN
Product: NNC(=O)Cc1ccc(O)cc1
Temperature: 195 °C

Procedure:
A mixture of 5-(4-fluoro-benzyl)-[1,3,4]oxadiazol-2-ylamine 10.182 g (52.7 mmol), water 80 mL and anhydrous hydrazine 20 mL was refluxed under nitrogen on an oil bath (190-200 ° C.) for 23 hours. The mixture was cooled and allowed to crystallize at R.T. under nitrogen overnight. The precipitated product was collected by filtration, washed with ice-cold water (10 mL) and dried on high vacuum. The crude product was re-crystallized from water 60 mL (reflux under nitrogen, than to +4° C. in a refrigerator overnight). The product was filtered, washed with ice-cold water and dried on high vacuum. Y=6.210 g (56.5%) of a large white crystals. 1H-NMR(DMSO-d6, 400 MHz): 7.267 (app d, J=8.6 Hz, J=5.5 Hz, 2H), 7.097 (app t, J=9.0 Hz, 2H), 5.509 (br s, 2H), 5.339 (s, 2H), 3.884 (s, 2H); 19F-NMR(DMSO-d6, 376.5 MHz): −117.14 (m, 1F).
Reaction SMILES: [C:1]([C:4]1[CH:28]=[CH:27][C:7]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([CH:24]=[CH:25][CH:26]=2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]#[N:23])[CH:17]=2)=[O:14])=[C:6]([CH2:29][CH2:30][CH3:31])[C:5]=1[OH:32])(=[O:3])[CH3:2].[N-:33]=[N+:34]=[N-:35].[Na+].[Cl-].[NH4+]>CN(C)C=O.O>[C:1]([C:4]1[CH:28]=[CH:27][C:7]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([CH:24]=[CH:25][CH:26]=2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[N:33]=[N:34][NH:35][N:23]=3)[CH:17]=2)=[O:14])=[C:6]([CH2:29][CH2:30][CH3:31])[C:5]=1[OH:32])(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1c(OCc2cccc(C(=O)Nc3cccc(C#N)c3)c2)ccc(C(C)=O)c1O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1c(OCc2cccc(C(=O)Nc3cccc(-c4nn[nH]n4)c3)c2)ccc(C(C)=O)c1O
Temperature: 25 °C

Procedure:
Heat a mixture of 3-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-N-(3-cyano-phenyl)-benzamide, sodium azide (1.12 g, 17.3 mmol), and ammonium chloride in dimethylformamide at 110 C for 24 hours. Cool to room temperature and dilute with water. Filter and wash several times with water. Dry filtered material and dissolve in hot acetone. Purify the resulting solution via chromatography, eluting with hexanes:acetone with 1% acetic acid to afford the title compound. 1H NMR (DMSO-d6) δ 0.88 (t, 3H), 1.52 (sextet, 2H), 2.58 (s, 3H), 2.62 (t, 2H), 5.37 (s, 2H), 6.76 (d, 1H), 7.57 (d, 1H), 7.61 (d, 1H), 7.68 (d, 1H), 7.74 (d, 1H), 7.82 (d, 1H), 7.97 (m, 2H), 8.09 (m, 1H), 8.59 (s, 1H), 10.56 (s, 1H), 12.85 (s, 1H); MS (APCI-neg mode) m/z (rel intensity) 470 (100).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][N:11]=[N:10][C:9]=2[S:13]CCC(OCC)=O)=[CH:4][CH:3]=1.[O-]CC.[K+]>C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][N:11]=[N:10][C:9]=2[SH:13])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCSc1nnsc1-c1ccc(C)cc1
Agent: CC[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1ccc(-c2snnc2S)cc1
Reaction time: 1.5 h
Yield: 123.4 %

Procedure:
A suspension of 13.8 g of 3-[[5-(4-methylphenyl)-1,2,3-thiadiazol-4-yl]thio]propanoic acid, ethyl ester in 250 ml of dry ethanol was treated with 200 ml of 1M potassium ethoxide in ethanol. After standing 1.5 hours, the solvent was removed in vacuo to about 100 ml and 400 ml of anhydrous ether was added. The solid was collected, washed with ether, dissolved in methanol and filtered. The filtrate was concentrated to a small volume and then diluted with 400 ml of anhydrous ether. The solid was collected and dried in vacuo, giving 11.5 g of 5-(4-methylphenyl)-1,2,3-thiadiazole-4-thiol, monopotassium salt as a yellow solid, mp >125° C. (dec.).
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:26])[CH:11]=[C:12]1[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:19][C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2.CO.[Li+].[OH-].Cl>O>[CH:14]1[C:13]2[C:12](=[CH:11][C:10]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:27])=[O:2])=[O:26])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[O:19][C:18]=2[CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)CCCCCNC(=O)C=C1c2ccccc2Oc2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCCCNC(=O)C=C1c2ccccc2Oc2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.9 %

Procedure:
6-(2-(9H-xanthen-9-ylidene)acetamido)hexanoic acid methyl ester (365 mg, 1 mmol) and 300 ml of CH3OH were stirred at room temperature while 25 ml of 4 N solution of LiOH in H2O was added. The mixture was stirred for 24 hours at room temperature. The mixture was neutralized with concentrated hydrochloric acid to pH 7 and evaporated under vacuum to remove methanol. The residue was adjusted to pH 3 with concentrated hydrochloric acid. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (256 mg, 73% yield) as a white solid. LC-MS (m/z) 352 (M+1).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([N:39]([S:45]([C:48]1[CH:53]=[CH:52][C:51]([CH2:54][O:55][Si](C(C)(C)C)(C)C)=[CH:50][CH:49]=1)(=[O:47])=[O:46])[CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:11][CH2:12][C:13]([F:38])([F:37])[CH2:14][NH:15][C:16](=[O:36])[C@H:17]([CH:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:18][C:19]([O:21][CH3:22])=[O:20])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:38][C:13]([F:37])([CH2:12][CH2:11][C@H:10]([N:39]([S:45]([C:48]1[CH:49]=[CH:50][C:51]([CH2:54][OH:55])=[CH:52][CH:53]=1)(=[O:47])=[O:46])[CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:9][OH:8])[CH2:14][NH:15][C:16](=[O:36])[C@H:17]([CH:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[NH:18][C:19]([O:21][CH3:22])=[O:20]
Reactant: CCCCCN([C@@H](CCC(F)(F)CNC(=O)[C@@H](NC(=O)OC)C(c1ccccc1)c1ccccc1)CO[Si](C)(C)C(C)(C)C)S(=O)(=O)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCCCN([C@H](CO)CCC(F)(F)CNC(=O)[C@@H](NC(=O)OC)C(c1ccccc1)c1ccccc1)S(=O)(=O)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.7 %

Procedure:
To a stirred solution of the material from Step 11 (51 mg, 0.056 mmol) in THF (1 mL) at 0° C. was added 1.0 M TBAF (111 μL, 0.11 mmol) in THF. The reaction mixture was stirred at room temperature overnight, concentrated to dryness in vacuo, and the residue was purified by flash chromatography on silica gel using EtOAc-hexanes to afford 30 mg of the title compound. 1H NMR (DMSO-d6): δ 8.37 (b, 1H), 7.76 (d, J=7.92 Hz, 2H), 7.49 (d, J=7.92 Hz, 2H), 7.46 (d, J=9.20 Hz, 1H), 7.37-7.30 (m, 4H), 7.30-7.18 (m, 4H), 7.17-7.09 (m, 2H), 5.41 (t, J=5.68 Hz, 1H), 5.10-5.00 (m, 1H), 4.74 (b, 1H), 4.59 (d, J=5.61 Hz, 2H), 4.27 (d, J=11.54 Hz, 1H), 3.63-3.51 (m, 1H), 3.42 (s, 3H), 3.39-3.15 (m, 2H), 3.27-3.20 (m, 2H), 3.12-2.90 (m, 2H), 1.65-1.06 (m, 10H), 0.84 (t, J=7.24 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:12]S(C(C)(C)C)=O)[CH2:9][CH2:10][CH3:11])[CH:5]=[N:6][CH:7]=1.Cl>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH2:12])[CH2:9][CH2:10][CH3:11])[CH:5]=[N:6][CH:7]=1
Reactant: CCCC(NS(=O)C(C)(C)C)c1cncc(Br)c1
Agent: Cl
Product: CCCC(N)c1cncc(Br)c1
Reaction time: 5 h
Yield: 86.4 %

Procedure:
2-Methyl-propane-2-sulfinic acid 1-(5-bromo-pyridin-3-yl)-butylamide (16 g, 48 mmol) is treated with aqueous HCl (3.0 N solution, 400 mL, 1.2 mol) at room temperature and stirred for 5 hours. The reaction mixture is quenched by addition of saturated aqueous sodium carbonate solution until pH 8 and extracted with dichloromethane (3×300 mL). The combined organic phases are dried over Na2SO4, filtered, and concentrated to afford 1-(5-bromo-pyridin-3-yl)-butylamine (9.5 g, 86%) of as a light brown oil.
Reaction SMILES: N1CCOCC1.[C:7]1([C:13](=O)[CH2:14][C:15](=O)[CH3:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl.[C:20]([C:23]1[CH:28]=[CH:27][C:26]([NH:29][NH2:30])=[CH:25][CH:24]=1)([OH:22])=[O:21].N#N.[N-]=C=O>CO.C(Cl)Cl>[CH3:16][C:15]1[CH:14]=[C:13]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:29]([C:26]2[CH:25]=[CH:24][C:23]([C:20]([OH:22])=[O:21])=[CH:28][CH:27]=2)[N:30]=1
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: CC(=O)CC(=O)c1ccccc1
Agent: Cl
Agent: N#N
Agent: [N-]=C=O
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCN1
Product: Cc1cc(-c2ccccc2)n(-c2ccc(C(=O)O)cc2)n1
Reaction time: 2.5 h
Yield: 48.1 %

Procedure:
A suspension of polymer-supported morpholine (Example 12), 1-phenyl-1,3-butanedione (81.5 mg, 0.5 mmol) and 4-carboxyphenyl hydrazine hydrochloride (113 mg, 0.6 mmol) in MeOH (2 mL) was shaken for 2.5 hours. The methanol was blown off under a stream of N2. DCM (4 mL) and polymer-supported isocyanate (Example 4A, 350 mg) were added and the reaction mixture shaken for 16 hours. An additional portion of polymer-supported isocyanate (120 mg) was added. After 4 hours the resin was filtered and washed with DCM (2×1.5 mL). The combined organic phases, when concentrated to dryness, gave 4-(3-methyl-5-phenyl-pyrazol-1-yl)-benzoic acid (67 mg, 48%), mp 159-162° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:21](=[CH:22][CH:23]=1)[C:8]1([CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][CH2:9]1)[C:7](=[O:24])[CH:6]([C:25]([NH:27][CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])=[O:26])[CH:5]2[OH:36].C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:21](=[CH:22][CH:23]=1)[C:8]1([CH2:9][CH2:10][N:11]([CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:12][CH2:13]1)[C:7](=[O:24])[C:6]([C:25]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:26])=[C:5]2[OH:36]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1C(=O)C2(CCN(Cc3ccccc3)CC2)c2ccc(Cl)cc2C1O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCN(Cc3ccccc3)CC2)C1=O
Reaction time: 0.42 h
Yield: 96 %

Procedure:
A solution of 1,1-dimethylethyl N-((6-chloro-4-hydroxy-2-oxo-1′-(phenylmethyl)-4H-spiro[naphthalene-1,4′-piperidin]-3-yl)carbonyl)glycinate (117 mg, 229 μmol) in TFA (1701 μL, 22896 μmol) was stirred at 23° C. After 25 minutes, the reaction was concentrated and the product was precipitated by addition of water (20 mL). The solid was collected by filtration, and the residue was washed with water (10 mL) and diethyl ether (5 mL), and dried under vacuum, affording 100 mg (77%) of N-((6-chloro-4-hydroxy-2-oxo-1′-(phenylmethyl)-spiro[naphthalene-1,4′-piperidin]-3-yl)carbonyl)glycine as the trifluoroacetate salt. MS m/e=455.2 (M+H)+. Calculated for C26H24ClF3N2O7 454.13.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[C:13]([F:16])([F:15])[F:14])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][C:18]=2[CH3:25])=[N:5]1)([CH3:3])[CH3:2].B(Br)(Br)Br.C1CCCCC=1>>[CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[C:13]([F:16])([F:15])[F:14])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=2[CH3:25])=[N:5]1)([CH3:3])[CH3:2]
Reactant: COc1ccc(-c2nn(C(C)C)c3c(C(F)(F)F)cccc23)c(C)c1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: Cc1cc(O)ccc1-c1nn(C(C)C)c2c(C(F)(F)F)cccc12
Yield: 139.1 %

Procedure:
Prepared according to Method D step C from 1-isopropyl-3-(4-methoxy-2-methylphenyl)-7-(trifluoromethyl)-1H-indazole (0.062 g, 0.2 mmol), boron tribromide (0.067 mL, 0.7 mmol) and 1.0 mL of cyclohexene to give the product (0.093 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:30](COCC[Si](C)(C)C)[C:16]2[N:17]=[CH:18][C:19]3[N:20]([C:21]([CH:24]4[CH2:29][CH2:28][CH2:27][O:26][CH2:25]4)=[N:22][CH:23]=3)[C:15]=2[CH:14]=1.C(O)(C(F)(F)F)=O.[NH4+].[OH-].O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[NH:30][C:16]2[N:17]=[CH:18][C:19]3[N:20]([C:21]([CH:24]4[CH2:29][CH2:28][CH2:27][O:26][CH2:25]4)=[N:22][CH:23]=3)[C:15]=2[CH:14]=1
Reactant: COc1ccc2c(c1)c(-c1cc3c(ncc4cnc(C5CCCOC5)n43)n1COCC[Si](C)(C)C)cn2C
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COc1ccc2c(c1)c(-c1cc3c(ncc4cnc(C5CCCOC5)n43)[nH]1)cn2C
Temperature: 25 °C
Reaction time: 15 h
Yield: 38.9 %

Procedure:
To a mixture of 7-(5-methoxy-1-methyl-1H-indol-3-yl)-1-(tetrahydro-2H-pyran-3-yl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (0.245 g, 0.461 mmol; prepared using J.1 from Preparation #I.1 with tetrahydro-2H-pyran-2-carboxylic acid [Acella], and L.1 with mercury(II) trifluoroacetate) in DCM (5 mL) was added TFA (0.887 mL, 11.5 mmol). After stirring at rt for about 15 h, the mixture was concentrated in vacuo. The material was dissolved in MeOH (5 mL) and then treated with a 30% aqueous NH4OH solution (1.79 mL, 13.8 mmol). The mixture was heated to about 60° C. for about 1 h then cooled to rt. Water was added (10 mL) and the solids were collected by filtration then washed with water (10 mL). The material was dried in a vacuum oven at about 60° C. for about 16 h to provide 7-(5-methoxy-1-methyl-1H-indol-3-yl)-1-(tetrahydro-2H-pyran-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (0.072 g, 39%): LC/MS (Table 2, Method a) Rt=2.16 min; MS m/z 402 (M+H)+. Syk IC50=A.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](=[O:36])(=[O:35])[N:15]([C@H:20]([CH2:33][OH:34])[CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:38](OC(=O)C)(=[O:40])[CH3:39]>C(Cl)Cl>[C:29]([O:28][C:26]([NH:25][CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]([N:15]([S:14]([C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:37])=[CH:13][CH:12]=1)(=[O:36])=[O:35])[CH2:16][CH:17]([CH3:18])[CH3:19])[CH2:33][O:34][C:38](=[O:40])[CH3:39])=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(NC(=O)OC(C)(C)C)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)OC[C@H](CCCCNC(=O)OC(C)(C)C)N(CC(C)C)S(=O)(=O)c1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (1S)-{4-[(5-tert-butoxycarbonylamino-1-hydroxymethyl-pentyl)-isobutyl-sulfamoyl]-phenyl}-carbamic acid tert-butyl ester (intermediate product (VII) of example 1, step D, 97 mg, 0.18 mmol) in anhydrous CH2Cl2 (3 mL) was added N,N-dimethylaminopyridine (22 mg, 0.18 mmol) and acetic anhydride (0.014 mL, 0.18 mmol). The mixture was stirred at room temperature for 1 hour. The solvent was evaporated. Ethyl acetate (50 mL) was added and the organic layer was washed with water (30 mL), then dried with Na2SO4 and concentrated. The residue was purified by flash chromatography eluting with ethyl acetate. The yield obtained was quantitative (100 mg).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH:7]=[O:8])[CH:6]=1.[CH:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(N(CC)CC)C>O1CCCC1>[C:9]([C:2]1[S:3][CH:4]=[C:5]([CH:7]=[O:8])[CH:6]=1)#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: O=Cc1csc(Br)c1
Reactant: C#CCCCCCCCCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCC#Cc1cc(C=O)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-bromo-4-thiophenecarboxaldehyde (45.3 g), 1-dodecyne (43.4 g), and triethylamine (99 ml), in dry tetrahydrofuran (250 ml) was chilled to 5° C. and degassed under nitrogen. bis(Triphenylphosphine)palladium(II)chloride (1.66 g) and copper(I)iodide (0.23 g) were added to the reaction mixture. The mixture was degassed and stirred overnight, under nitrogen, as it was allowed to warm to room temperature. The precipitate was filtered off, washed with ethyl acetate, and the filtrate was evaporated. Ethyl acetate was added to the residue. The solution was washed with brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was chromatographed through a silica gel pad eluting with heptane/1% ethyl acetate. The appropriate fractions were collected and evaporated. The residue and that from a similar reaction on a 0.05 mole scale were combined and distilled to give 30.7 g (79.5%), bp 181-185° C. @ 0.35 mm Hg.
Reaction SMILES: [CH3:1][O-:2].[Na+].F[C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:22])[C:10]([C:16]3[N:20]([CH3:21])[N:19]=[N:18][N:17]=3)=[CH:11][N:12]2[CH3:15])=[CH:7][CH:6]=1.CO>O>[CH3:1][O:2][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:22])[C:10]([C:16]3[N:20]([CH3:21])[N:19]=[N:18][N:17]=3)=[CH:11][N:12]2[CH3:15])=[CH:7][CH:6]=1
Reactant: C[O-]
Reactant: Cn1nnnc1-c1cn(C)c2cc(F)ccc2c1=O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc2c(=O)c(-c3nnnn3C)cn(C)c2c1

Procedure:
A mixture of sodium methoxide (0.47 g), 7-fluoro-1-methyl-3-(1-methyl-1H-tetrazol-5-yl)-4-quinolone (2.0 g) and methanol (40 ml) was boiled under reflux for 43 hours. The mixture was cooled and poured into water (100 ml). The solid was collected by filtration, washed with boiling industrial methylated spirit (50 ml) and dried to give the novel compound 7-methoxy-1-methyl-3-(1-methyl-1H-tetrazol-5-yl)-4-quinolone, m.p. 270°-273°.
Reaction SMILES: Cl.C(O)(=O)C.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=O)[CH:21]([CH3:24])[CH2:22][CH3:23])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1>[Zn].[Hg]Cl.CCOCC.O.C1(C)C=CC=CC=1>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([CH3:24])[CH2:22][CH3:23])=[CH:16][CH:15]=2)=[CH:12][CH:13]=1
Reactant: CCC(C)C(=O)c1ccc(-c2ccc(OC)cc2)cc1
Agent: Cl
Agent: Cl[Hg]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(C)Cc1ccc(-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 73.4 %

Procedure:
13.6 g of zinc powder, 1.4 g of mercury chloride, 0.7 ml of conc. hydrochloric acid, and 20 ml of water were mixed with shaking for five minutes, and then the supernatant solution was flowed out. To the obtained zinc amalgam, 10 ml of water, 24 ml of conc. hydrochloric acid, 1 ml of acetic acid, 14 ml of toluene, and 38 m moles(10.2 g) of 4'-methoxy-4-(2-methylbutyryl)biphenyl were added, and then refluxed for 20 hours. In the mean time, 5 ml portions of conc. hydrochloric acid was successively added every five hours. The reaction solution was cooled to room temperature, then, after the addition of water, ether extracted. The extract was washed with water, dried, and concentrated, and then purified by column chromatography, to obtain 7.1 g of 4'-methoxy-4-(2-methylbutyl)biphenyl. (yield: 74%)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][C:10]2[C:11]([CH:20]([CH3:22])[CH3:21])=[CH:12][C:13]([O:18][CH3:19])=[C:14]([CH:17]=2)[C:15]#[N:16])=[CH:4][N:3]=1.[CH2:23](N)[CH2:24][NH2:25]>CO>[NH:16]1[CH2:23][CH2:24][N:25]=[C:15]1[C:14]1[C:13]([O:18][CH3:19])=[CH:12][C:11]([CH:20]([CH3:22])[CH3:21])=[C:10]([CH:17]=1)[O:9][C:5]1[C:6]([NH2:8])=[N:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1C#N
Reactant: NCCN
Solvent: CO
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1C1=NCCN1

Procedure:
To a cooled (0° C.) suspension of 5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzonitrile (0.138 g, 0.461 mmol) in dry methanol (15 ml) was bubbled with HCl gas for 10 minutes and refrigerated overnight. Solvent was evaporated under reduced pressure to give a yellow solid which was redissolved in dry methanol (10 ml). Ethylene diamine (0.034 ml, 0.509 mmol) was added and the reaction mixture was refluxed for 20 hours and concentrated under reduced pressure. The residue was purified by silica gel chromatography (gradient: 7-50% methanol in methylene chloride/0.1% concentrated NH4OH) to yield 5-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-isopropyl-4-methoxy-phenoxy]-pyrimidine-2,4-diamine which was crystalized from methanol/ethyl acetate/ether as a white solid, (0.053 g, 33%).