Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:28])=O>C(Cl)(Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:21])([F:22])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[CH:7][C:3]=1[C:4]([Cl:28])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(C(=O)O)c(Cl)cc2F)c1=O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(C(=O)Cl)c(Cl)cc2F)c1=O
Reaction time: 3 h
Yield: 102.4 %

Procedure:
To a stirred solution of 2-chloro-5-(3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl)-4-fluoro-benzoic acid (4 g) in chloroform (100 ml) were added oxalyl chloride (1.8 g) and a few drops of N,N-dimethylformamide (DMF) at ambient temperature. The resulting mixture was stirred for three hours at same temperature and then filtered through Celite. The filtrate was concentrated under reduced pressure to give the titled compound (4.3 g) as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14](=[O:28])[CH2:15][C:16]1[S:20][C:19]([NH2:21])=[N:18][C:17]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:12][O:13][C:14](=[O:28])[CH2:15][C:16]1[S:20][C:19]([NH:21][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[OH:11])=[N:18][C:17]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: COC(=O)Cc1sc(N)nc1-c1ccccc1
Product: COC(=O)Cc1sc(NC(=O)c2cc(Br)ccc2O)nc1-c1ccccc1
Yield: 32.1 %

Procedure:
Using 5-bromosalicylic acid and 2-amino-4-phenylthiazole-5-acetic acid methyl ester as the raw materials, the same operation as the Example 195(3) gave the title compound.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16].[CH2:19]=[C:20]1[O:24][C:22](=[O:23])[CH2:21]1>CO>[C:22]([NH:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16])(=[O:23])[CH2:21][C:20]([CH3:19])=[O:24]
Reactant: C=C1CC(=O)O1
Reactant: C=C(C)C(=O)NCCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: C=C(C)C(=O)NCCCNC(=O)CC(C)=O
Temperature: 0 °C
Reaction time: 20 h
Yield: 50 %

Procedure:
Triethylamine (24 g, 0.24 mole) was added dropwise at 0° C. to a solution of N-(3-aminopropyl)methacrylamide hydrochloride (40 g, 0.24 mole) and diketene (20 g, 0.24 mole) in methanol (800 ml). After addition, the temperature was maintained at 0° C. for 2 hours under stirring. Stirring was continued at 20° C. for 20 hours. The solvent was then removed. The residue was dissolved in chloroform (1 liter), washed with 5% hydrochloric acid (200 ml), washed with saturated NaHCO3 (200 ml), dried over anhydrous magnesium sulfate, and filtered. Excess solvent was removed. The residue was recrystallized from benzene (500 ml) and ethyl ether (500 ml) to give N-(3-acetoacetamidopropyl)methacrylamide (m.p.=93°-94° C.) at a yield of 50%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:23][C:24](O)=[O:25])=[C:7]([CH3:22])/[C:8]/2=[CH:11]/[C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:4][C:3]=1[O:27][CH3:28].C(Cl)(=O)C([Cl:32])=O>C1COCC1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:23][C:24]([Cl:32])=[O:25])=[C:7]([CH3:22])/[C:8]/2=[CH:11]/[C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:4][C:3]=1[O:27][CH3:28]
Reactant: COc1cc2c(cc1F)/C(=C\c1ccc(S(C)(=O)=O)cc1)C(C)=C2CC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: COc1cc2c(cc1F)/C(=C\c1ccc(S(C)(=O)=O)cc1)C(C)=C2CC(=O)Cl

Procedure:
(Z)-6-fluoro-5-methoxy-2-methyl-1-(p-methylsulfonylbenzylidene)-3-indenylacetic acid (70 mmol) in THF (500 ml) is allowed to react with oxalylchloride (2 M in CH2Cl2 ; 70 mmol) under reflux conditions (24 hours). The solvent is evaporated to yield the title compound, which is used as such in the next step.
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6]1)([OH:3])=[O:2].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.Cl[CH2:38][C:39]([NH2:41])=[O:40].Cl>O>[C:1]([CH2:4][N:5]1[CH2:16][CH2:15][N:14]([CH2:38][C:39](=[O:40])[NH2:41])[CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6]1)([OH:3])=[O:2]
Reactant: NC(=O)CCl
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: Cl
Agent: [OH-]
Solvent: O
Product: NC(=O)CN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Temperature: 80 °C
Yield: 94.4 %

Procedure:
The pH of a solution of 1.40 g of 1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane in about 4 ml water was adjusted to 9.5 using 40% aqueous benzyltrimethylammonium hydroxide. To the resulting solution was added 412 mg α-chloroacetamide. The temperature was increased to 80° C. and base was added as necessary to maintain the pH at 9.5-10. After 3 hours the solution was cooled to room temperature and acidified to pH 3 with concentrated HCl. The resulting solution was evaporated under reduced pressure to a colorless sludge. The mixture was taken up in about 25 ml MeOH and re-evaporated. The thick residue was triturated with a 1:1 mixture of acetone and ethanol to provide a granular solid and colorless solution. The solid was collected by filtration, washed with acetone/ethanol followed by acetone and finally ether, then dried in a vacuum oven at 50° for 2 hours. Obtained was 1.54 g of the title compound as a colorless powder. The product was twice crystallized from ethanol/water.
Reaction SMILES: C1C=NC=C(C(O)=O)C=1.Br[C:11]1[O:15][C:14]([C:16]([NH:18][C@@H:19]([CH2:24][N+:25]([CH3:28])([CH3:27])[CH3:26])[CH2:20][C:21]([O-:23])=[O:22])=[O:17])=[CH:13][CH:12]=1.[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:32]=1)#[CH:30]>>[CH2:38]([O:37][C:33]1[CH:32]=[C:31]([C:29]#[C:30][C:11]2[O:15][C:14]([C:16]([NH:18][C@@H:19]([CH2:24][N+:25]([CH3:28])([CH3:27])[CH3:26])[CH2:20][C:21]([O-:23])=[O:22])=[O:17])=[CH:13][CH:12]=2)[CH:36]=[CH:35][CH:34]=1)[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: C#Cc1cccc(OCCCCCC)c1
Reactant: C[N+](C)(C)C[C@@H](CC(=O)[O-])NC(=O)c1ccc(Br)o1
Agent: O=C(O)c1cccnc1
Product: CCCCCCOc1cccc(C#Cc2ccc(C(=O)N[C@H](CC(=O)[O-])C[N+](C)(C)C)o2)c1
Yield: 20 %

Procedure:
According to the method described in example S115, (R)-3-(5-bromofuran-2-carboxamido)-4-(trimethylammonio)butanoate was reacted with 1-ethynyl-3-(hexyloxy)benzene. The crude product was purified by silica gel chromatography (CH2Cl2/MeOH 3:2) to give the title compound as a white powder (11.1 mg, 20%). 1H NMR (400 MHz, D2O) δ 6.94-6.89 (m, 2H), 6.81-6.79 (m, 1H), 6.57 (s, 1H), 6.46-6.44 (m, 1H), 6.30 (s, 1H), 4.80-4.76 (m, 1H), 3.67-3.45 (m, 4H), 3.01 (s, 9H), 2.44-2.35 (m, 2H), 1.38-1.32 (m, 2H), 1.10-0.95 (m, 6H), 0.61 (t, 3H, J=6.4 Hz); MS ESI [M+H]+, calcd for [C26H34N2O5+H]+ 455.25; found m/z 455.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:14]([CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])[C:13]2[C:22]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:23][CH:24]=[CH:25][C:12]=2[N:11]=1.[OH-].[Na+].Cl>O1CCCC1.CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:14]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:13]2[C:22]([N:26]([CH2:27][CH3:28])[CH2:29][CH3:30])=[CH:23][CH:24]=[CH:25][C:12]=2[N:11]=1
Reactant: CCOC(=O)CCn1c(Nc2ccc(Cl)cc2Cl)nc2cccc(N(CC)CC)c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCN(CC)c1cccc2nc(Nc3ccc(Cl)cc3Cl)n(CCC(=O)O)c12
Yield: 78 %

Procedure:
To a solution of ethyl 3-[2-[(2,4-dichlorophenyl)amino]-7-(diethylamino)-1H-benzimidazol-1-yl]propanoate (Reference Example 28; 100 mg, 0.223 mmol) in a mixture of tetrahydrofuran (2 mL) and methanol (1 mL) was added 1N sodium hydroxide solution (0.446 mL, 0.446 mmol) at 0° C. After the resultant mixture was stirred at room temperature for 1 hr, the mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate to give the title compound as a solid (73.3 mg, 0.174 mmol, 78%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=[O:15]>C(Cl)Cl>[N+:1]([C:16]1[CH:17]=[CH:18][C:11]([Cl:10])=[CH:12][C:13]=1[CH:14]=[O:15])([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: O=Cc1cccc(Cl)c1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: O=Cc1cc(Cl)ccc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
Concentrated nitric acid (29.3 ml) was added dropwise to 500 ml of concentrated sulfuric acid with ice cooling externally while stirring. In addition, 50 g of m-chlorobenzaldehyde was added dropwise to the resulting mixture at 5° C. or less. After stirring was continued at room temperature for 1 hour the reaction mixture was poured onto ice to precipitate solids which were collected by filtration. After washing with water the solids thus-obtained were dissolved in methylene chloride and the methylene chloride layer was washed with a dilute aqueous sodium hydroxide, washed with water and dried over sodium sulfate. Removal of the solvent by distillation gave 62.3 g of 2-nitro-5-chlorobenzaldehyde, m.p. 65°-69° C.
Reaction SMILES: I[C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.C(N(CC)CC)C.[C:25]1(=[O:39])[N:29]([CH2:30][CH2:31][C:32]#[CH:33])[C:28](=[O:34])[C:27]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:26]12>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:28]1(=[O:34])[N:29]([CH2:30][CH2:31][C:32]#[C:33][C:2]2[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=2)[C@@H:7]2[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]2)[C:25](=[O:39])[C:26]2=[CH:38][CH:37]=[CH:36][CH:35]=[C:27]12
Reactant: C#CCCN1C(=O)c2ccccc2C1=O
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCC#Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reaction time: 3 h
Yield: 78.8 %

Procedure:
5-Iodo-2'-deoxyuridine (354 mg, 1 mmol) was dissolved in 10 mL of dimethylformamide. Cuprous iodide (76 mg, 0.4 mmol), tetrakis(triphenylphosphine)palladium(0) (230 mg, 0.2 mmol), and triethylamine (200 mg, 2.0 mmol) were added. 4-Phthalimidobut-1-yne (300 mg, 1.5 mmol) was added all at once and the reaction kept at 60° C. for three hours. The clear yellow reaction was then evaporated and methylene chloride was added. Scratching of the flask induced crystallization of nearly all of the product which was filtered and recrystallized from 95% ethanol to give 335 mg (78%) of title compound as fine, feathery needles.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3](OS(C2C=CC(C)=CC=2)(=O)=O)[CH:2]=1.[CH2:22]([OH:28])[CH2:23][CH2:24][CH2:25][C:26]#[CH:27]>CCCCCCC.CCOC(C)=O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:27]#[C:26][CH2:25][CH2:24][CH2:23][CH2:22][OH:28])[CH:2]=1
Reactant: C#CCCCCO
Reactant: Cc1ccc(S(=O)(=O)Oc2cnc3ccccc3c2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: OCCCCC#Cc1cnc2ccccc2c1

Procedure:
This product was prepared from toluene-4-sulfonic acid quinolin-3-yl ester and hex-5-yn-1-ol following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/EtOAc 6:4; yield (110 mg, 98%); 1H NMR δ (CDCl3): 8.89 (s, 1H), 8.21 (s, 1H), 8.11 (d, J=8.62 Hz, 1H), 7.80-7.68 (dm, 2H), 7.62-7.52 (m, 1H), 3.74 (t, J=7.17 Hz, 2H), 2.52 (t, J=7.13 Hz, 2H), 1.83-1.67 (br m, 5H); LCMS m/z: 225.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[O:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH:9]=2)=[O:7])=[CH:4][C:3]=1[S:19](Cl)(=[O:21])=[O:20].[NH3:23]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[O:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH:9]=2)=[O:7])=[CH:4][C:3]=1[S:19](=[O:21])(=[O:20])[NH2:23]
Reactant: N
Reactant: O=C(c1ccc(Cl)c(S(=O)(=O)Cl)c1)c1cc2ccccc2o1
Product: NS(=O)(=O)c1cc(C(=O)c2cc3ccccc3o2)ccc1Cl
Reaction time: 8 h

Procedure:
3.3 g 2-(4-Chloro-3-chlorosulfonylbenzoyl)-benzo[b]furan are introduced into 19 ml 25% aqueous ammonia solution, and after standing overnight, the liquid is distilled off. After addition of water, the pH is adjusted to 6 by means of dilute HCl, agitation is continued for a further 30 minutes, and the product is crystallized from a small amount of glacial acetic acid. Colorless crystals, m.p. 181° C.
Reaction SMILES: CO.C(OC(=O)[N:9]([CH2:31][C:32]1[CH:41]=[CH:40][C:35]2[O:36][CH2:37][CH2:38][O:39][C:34]=2[CH:33]=1)[CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([F:28])[CH:26]=3)[C:21]([CH3:29])=[CH:20][C:19]2=[O:30])[CH2:12][CH2:11]1)(C)(C)C.[ClH:43].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:43].[O:36]1[C:35]2[CH:40]=[CH:41][C:32]([CH2:31][NH:9][CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]4[C:27]5[C:22](=[CH:23][CH:24]=[C:25]([F:28])[CH:26]=5)[C:21]([CH3:29])=[CH:20][C:19]4=[O:30])[CH2:12][CH2:11]3)=[CH:33][C:34]=2[O:39][CH2:38][CH2:37]1
Reactant: Cc1cc(=O)n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2cc(F)ccc12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(=O)n(CCN2CCC(NCc3ccc4c(c3)OCCO4)CC2)c2cc(F)ccc12
Reaction time: 4 h

Procedure:
To 1.5 mL of methanol solution containing 0.17 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-fluoro-4-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 1.5 mL of 4 mol/L hydrogen chloride/ethyl acetate solution was added, and stirred for 4 hours. Ethyl acetate was added, and the resulting solid was filtered to give 0.15 g of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluoro-4-methylquinolin-2(1H)-one hydrochloride as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6])=[O:4].C=C[C@@H]1[C@@H]2C[C@@H]([C@H](O)C3C4C(=CC=CC=4)N=CC=3)N(CC2)C1.[H][H]>C1(C)C=CC=CC=1>[C:3]([O:2][CH3:1])(=[O:4])[C@@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:6]
Reactant: COC(=O)C(=O)c1ccccc1
Reactant: [H][H]
Agent: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccccc12
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](O)c1ccccc1
Yield: 96.6 %

Procedure:
The cross-linked Ir—Au cluster composition obtained in Example 12 (10.0 mg), methyl benzoyl formate (164.2 mg, 1.0 mmole), (−)cinchonidine (3.8 mg, 0.013 mmole) and toluene (5 ml) were mixed in an autoclave and agitated for hie hours at room temperature in a hydrogen atmosphere at a pressure of 50 atmospheres. The cross linked Ir—Au cluster composition was removed by filtration after the reaction. The filtrate was concentrated, and the residue was purified using PTLC to obtain (R)-methyl mandelate (160.5 mg, 96.5% yield). The asymmetric yield was 52.9% ee.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16]C)=[O:15])=[CH:10][C:9]2=[O:18])[CH:5]=[CH:6][CH:7]=1.[Li+].[OH-]>O.CO>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][C:9]2=[O:18])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccn(-c2cccc(F)c2)c(=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccn(-c2cccc(F)c2)c(=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 1-(3-fluorophenyl)-2-oxo-1,2-dihydropyridine-4-carboxylate 89-2 (50 mg, 0.202 mmol) in water (0.5 mL) and methanol (0.5 mL) was added LiOH (20 mg, 0.835 mmol). After stirring at room temperature for 30 minutes, the mixture was concentrated with rotavap and the residue extracted with ethyl acetate, which was then evaporated to give crude 1-(3-fluorophenyl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid 89-3.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][NH:12]3)[N:5]=[C:4]2[N:17]([CH3:20])[N:18]=[CH:19][C:3]=12.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[C:31]([CH:36]=[CH:37][CH:38]=2)[NH:32][C:33](=[O:35])[CH3:34])O1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:12]1[C:13]2[C:9](=[C:8]([C:6]3[N:5]=[C:4]4[N:17]([CH3:20])[N:18]=[CH:19][C:3]4=[C:2]([C:29]4[CH:30]=[C:31]([NH:32][C:33](=[O:35])[CH3:34])[CH:36]=[CH:37][CH:38]=4)[CH:7]=3)[CH:16]=[CH:15][CH:14]=2)[CH:10]=[N:11]1
Reactant: Cn1ncc2c(Cl)cc(-c3cccc4[nH]ncc34)nc21
Reactant: CC(=O)Nc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(=O)Nc1cccc(-c2cc(-c3cccc4[nH]ncc34)nc3c2cnn3C)c1
Temperature: 130 °C

Procedure:
4-Chloro-6-(1H-indazol-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine 7 (80 mg, 0.28 mmol) and 3′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acetanilide (1.4 equiv.) were suspended in 2 ml acetonitrile. Sodium carbonate (3 equiv., 92 mg) and bis(triphenylphosphine)palladium(II) chloride (0.05 equiv.) were added as a solution in water (0.5 ml). The reaction mixture was heated in microwave at 130° C. for 20 min. Water was added to the mixture, and the precipitated product was filtered and purified by column chromatography to yield 112. NMR (CDCl3): 2.27 (3H, s), 4.33 (3H, s), 7.34 (1H, br), 7.52-7.68 (5H, m), 7.84 (1H, d), 7.85 (1H, s), 8.10 (1H, s), 8.26 (1H, s), 8.96 (1H, s). MS: MH+ 383.12 (100%)
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([CH3:32])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH2:30][CH3:31])[N:9]=3)[CH2:2]1.[OH:33][C:34]([CH3:39])([CH3:38])[C:35](O)=[O:36].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>[CH2:30]([C:22]1[N:21]([C:10]2[N:9]=[C:8]3[C:13]([N:14]=[C:6]([CH2:5][CH:3]4[CH2:2][N:1]([C:35](=[O:36])[C:34]([OH:33])([CH3:39])[CH3:38])[CH2:4]4)[N:7]3[CH3:32])=[C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[N:11]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=1)[CH3:31]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Reactant: CC(C)(O)C(=O)O
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: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)C(C)(C)O)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 56.5 %

Procedure:
To a mixture of 8-azetidin-3-ylmethyl-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (60 mg, 0.14 mmol), 2-hydroxyisobutyric acid (17 mg, 0.17 mmol) and DIPEA (29 μL, 0.17 mmol) in DCM (1 mL) was added HATU (63 mg, 0.17 mmol). The resulting yellow mixture was stirred for 1.5 h at r.t. then the reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with DCM and MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-6%) affording 721 as a foam (41 mg, 56%). LCMS (method I): RT 3.00 min, [M+H]+ 519.2. 1H NMR (CDCl3, 400 MHz): δ 8.00-7.97 (1 H, m), 7.75-7.74 (1 H, m), 7.27-7.25 (2 H, m), 4.62 (1 H, s), 4.33 (5 H, s), 4.20 (1 H, s), 3.93 (1 H, s), 3.86 (4 H, t, J=4.72 Hz), 3.76 (3 H, s), 3.64 (1 H, s), 3.34 (3 H, q, J=7.44 Hz), 3.15-3.14 (2 H, m), 1.43-1.42 (9 H, m)
Reaction SMILES: [OH:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=[O:12])[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>CN(C)C=O.O>[Si:19]([O:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=[O:12])[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=c1[nH]c2ccc(O)cc2c(=O)o1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]c(=O)oc(=O)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
To a mixture of 5-hydroxyisatoic anhydride (1.6 g, 9.0 mmol) and imidazole (670 mg, 9.9 mmol) in N,N-dimethylformamide (10 mL) was added tert-butyldimethylsilyl chloride (1.42 g, 9.45 mmol). After stirring for 2 h, the reaction mixture was diluted with ice and water. After warming to room temperature, the resulting precipitate was filtered and washed with water and hexane. The solid was vacuum dried at 55° C./0.1 mm for 14 h to give 2.55 g (96%) of the title compound as a light gray solid; mp 198-200° C. (dec).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:26])[CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[Cl:25])=[CH:7][C:6]=1[Cl:27].[OH:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[Cl:27][C:6]1[CH:7]=[C:8]([NH:11][C:12](=[O:26])[CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[Cl:25])[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][N:32]1[CH2:33][CH2:34][CH:29]([OH:28])[CH2:30][CH2:31]1
Reactant: O=C(COc1ccc(C(F)(F)F)cc1Cl)Nc1ccc(OCCBr)c(Cl)c1
Reactant: OC1CCNCC1
Product: O=C(COc1ccc(C(F)(F)F)cc1Cl)Nc1ccc(OCCN2CCC(O)CC2)c(Cl)c1

Procedure:
Prepared analogously to Example 145 starting from N-[4-(2-bromo-ethoxy)-3-chloro-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide (Z28b) and 4-hydroxy-piperidine.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[Cu](C#N)[C:12]#[N:13]>O.C(OCC)(=O)C>[C:12]([C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2)#[N:13]
Reactant: N#C[Cu]C#N
Reactant: Brc1cccc2cc[nH]c12
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1cccc2cc[nH]c12
Temperature: 200 °C
Reaction time: 2.5 h
Yield: 54.8 %

Procedure:
Combine 7-bromoindole (4.72 g, 24.0 mmol) and copper cyanide (4.30 g, 48.1 mmol) in 1-methyl-2-pyrrolidine (40 mL). Heat to 200° C. After 2.5 hours, cool to room temperature, add water-ethyl acetate (200 mL, 1/1) to give a solid. Filter through the celite, extract the filtrate with ethyl acetate, combine the organic layers, wash with brine, dry over Na2SO4, filter and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with hexanes: ethyl acetate (10:1) to give (1.87 g) of the title compound as a yellow solid: 1H NMR (300 MHz, DMSO-d6)) 6.64–6.66 (m, 1H), 7.17 (t, 1H, J=7.6 Hz), 7.51–7.53 (m, 1H), 7.60–7.62 (m, 1H), 7.94 (d, 1H, J=8.0 H), 12.03 (br, 1H).
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[C:10]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:9]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:18][C:8]=2[C:7]=1[OH:25])=[O:5])C.[NH2:26][CH2:27][C:28]([OH:30])=[O:29]>C[O-].[Na+].CO>[OH:25][C:7]1[C:8]2[S:18][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:16][C:9]=2[C:10]([CH2:12][CH:13]([CH3:15])[CH3:14])=[N:11][C:6]=1[C:4]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:5]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(CC(C)C)c2nc(-c3ccccc3)sc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)Cc1nc(C(=O)NCC(=O)O)c(O)c2sc(-c3ccccc3)nc12
Temperature: 25 °C
Yield: 77.8 %

Procedure:
A mixture of 7-hydroxy-4-isobutyl-2-phenyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (35 mg, 0.10 mmole) and glycine (146 mg, 1.95 mmole) in 0.5 M sodium methoxide/methanol (3.7 ml) was refluxed for 4 days before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (12 ml) and extracted three times with methyl t-butyl ether. The remaining aqueous layer was acidified to pH=3 with 1N HCl (2.5 ml). The solid precipitate was filtered, washed with water and dried in vacuo to give the title compound as a white solid (30 mg). 1H NMR (DMSO-d6, 200 MHz): δ=9.18 (br s, 1H), 8.15 (m, 2H), 7.62 (m, 3H), 4.02 (d, J=5.9 Hz, 2H), 3.12 (d, 2H, J=7.4 Hz), 2.41 (m, 1H), 0.93 (d, 2H, J=6.6 Hz); MS: (+) m/z 385.98 (M+1); (−) m/z 383.99 (M−1)