Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14]C)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:19][CH2:20][C@H:21]([OH:33])[CH2:22][N:23]1[CH2:32][CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24]1>CCO>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:11]([C:12](=[O:14])[NH:19][CH2:20][C@H:21]([OH:33])[CH2:22][N:23]2[CH2:32][CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24]2)[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: NC[C@H](O)CN1CCc2ccccc2C1
Reactant: COC(=O)c1cccc(NC(=O)OC(C)(C)C)c1
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1cccc(C(=O)NC[C@H](O)CN2CCc3ccccc3C2)c1
Temperature: 120 °C
Yield: 58.8 %

Procedure:
A mixture of methyl 3-((tert-butoxycarbonyl)amino)benzoate (500 mg, 2 mmol) and (S)-1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (618 mg, 3 mmol) in EtOH (1 mL) was heated at 120° C. for 3 h in a microwave reactor under N2. The reaction solution was concentrated and the residue was purified by column chromatography to give the title product (500 mg, Yield 58.8%). LCMS (m/z): 426.2 (M+1).
Reaction SMILES: [C:1]1([C:7]2[C:15]([CH:16]=O)=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:18].[NH2:19][OH:20]>C(O)C>[ClH:18].[C:1]1([C:7]2[C:15]([CH:16]=[N:19][OH:20])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1c(-c2ccccc2)nn2ccccc12
Reactant: NO
Agent: Cl
Solvent: CCO
Product: ON=Cc1c(-c2ccccc2)nn2ccccc12
Yield: 45.5 %

Procedure:
A mixture of 2-phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde (0.5 g) and hydroxylamine hydrochloride (0.17 g) in ethanol (5 ml) was refluxed for 1.5 hours and evaporated in vacuo. The residue was triturated with ethyl acetate and recrystallized from a mixture of ethanol and ethyl acetate to give 2-phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde oxime hydrochloride (0.28 g).
Reaction SMILES: [Cl:1][C:2]1[C:3](O)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH:17]3[CH2:19][CH2:18]3)=[C:13]([CH:16]=2)[C:14]#[N:15])=[N:6][CH:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O=P(Cl)(Cl)[Cl:34]>>[Cl:34][C:3]1[C:2]([Cl:1])=[CH:7][N:6]=[C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH:17]3[CH2:19][CH2:18]3)=[C:13]([CH:16]=2)[C:14]#[N:15])[N:4]=1
Reactant: N#Cc1cc(Nc2ncc(Cl)c(O)n2)ccc1C1CC1
Reactant: O=P(Cl)(Cl)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: N#Cc1cc(Nc2ncc(Cl)c(Cl)n2)ccc1C1CC1
Yield: 80 %

Procedure:
5-(5-chloro-4-hydroxypyrimidin-2-ylamino)-2-cyclopropylbenzonitrile, containing 1.2 equivalents of p-toluenesulfonic acid (1.00 g, 2.03 mmol) was weighed out and added to a flask with a magnetic stir bar. This was suspended in 11 mL POCl3 and the reaction was heated at reflux for 3 hours. This was evaporated, then quenched with cold 10% aqueous Na2CO3. The mixture was extracted 4 times with ethyl acetate and the combined organic layer was dried over sodium sulfate. This was filtered, concentrated onto a plug of silica, and purified by column chromatography. Pure product was concentrated and dried on the high vacuum to give 493 mg of 5-(4,5-dichloropyrimidin-2-ylamino)-2-cyclopropylbenzonitrile (80% yield, accounting for the mass of p-toluenesulfonic acid present in the starting material).
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=3[C:9]([CH3:18])=[CH:8][C:7]2=[O:19])[CH2:5][CH2:4][CH2:3][CH2:2]1.II.FC(F)(F)C(OC1C(OC(=O)C(F)(F)F)=C([I:33])C=CC=1)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=3[C:9]([CH3:18])=[C:8]([I:33])[C:7]2=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(Oc1cccc(I)c1OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CSc1ncc2c(C)cc(=O)n(C3CCCC3)c2n1
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CSc1ncc2c(C)c(I)c(=O)n(C3CCCC3)c2n1
Temperature: 25 °C
Reaction time: 0.45 h
Yield: 58 %

Procedure:
The sulfide, 8-cyclopentyl-5-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (7.03 g, 25.51 mmol) and iodine (7.12 g, 28.06 mmol) were combined in dry dichloromethane (120 mL). The mixture was shielded from light and stirred at room temperature for 27 minutes. Bis(trifluoroacetoxy)iodobenzene (13.16 g, 30.61 mmol) was added in one portion and the reaction mixture was heated to 37° C. for 2 h, then cooled to room temperature for 2 h. 50% Aqueous (w/v) sodium thiosulfate (114 mL) was added and the two phases were stirred for 30 minutes then separated. The aqueous phase was extracted with dichloromethane (50 mL) and the combined organic phases were washed with 50% aqueous (w/v) sodium thiosulfate (50 mL) and water (4×130 mL). The organic phase was dried, filtered and concentrated in vacuo to give crude product which was purified by chromatography (15% heptane/dichloromethane) to give 8-cyclopentyl-6-iodo-5-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (5.94 g, 58%) as a white solid. MS (ESI); M++1: Calc'd, 401. Found 401. 1H NMR δ (300 MHz, CDCl3) 8.91 (s, 1H), 6.12-6.00 (m, 1H), 2.70 (s, 3H), 2.62 (s, 3H), 2.30-2.24 (m, 2H), 2.15-2.08 (m, 2H), 1.93-1.81 (m, 2H), 1.75-1.57 (m, 2H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][CH:36]=1)[C:6]([NH:8][C:9]1[C:10]([CH3:33])=[C:11]([C:18]([C:20]2[CH:21]=[CH:22][C:23]([N+:30]([O-:32])=[O:31])=[C:24]([CH:29]=2)[C:25]([O:27][CH3:28])=[O:26])=[O:19])[N:12]2[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]2)=[O:7].[CH3:37]I>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][CH:36]=1)[C:6]([N:8]([CH3:37])[C:9]1[C:10]([CH3:33])=[C:11]([C:18]([C:20]2[CH:21]=[CH:22][C:23]([N+:30]([O-:32])=[O:31])=[C:24]([CH:29]=2)[C:25]([O:27][CH3:28])=[O:26])=[O:19])[N:12]2[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]2)=[O:7]
Reactant: CI
Reactant: COC(=O)c1cc(C(=O)c2c(C)c(NC(=O)c3cccc(OC)c3)c3ccccn23)ccc1[N+](=O)[O-]
Product: COC(=O)c1cc(C(=O)c2c(C)c(N(C)C(=O)c3cccc(OC)c3)c3ccccn23)ccc1[N+](=O)[O-]
Yield: 84 %

Procedure:
This compound is prepared according to the protocol described in the example above by methylating 1.9 g (3.9 mmol) of methyl 5-({1-[(3-methoxybenzoyl)amino]-2-methylindolizin-3-yl}carbonyl)-2-nitrobenzoate with methyl iodide. 1.85 g of a red solid are obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][OH:16])=[CH:4][CH:3]=1.O.[NH2:18][NH2:19]>>[NH:18]([C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][OH:16])=[CH:4][CH:3]=1)[NH2:19]
Reactant: NN
Reactant: OCc1ccccc1Oc1ccc(Cl)nc1
Solvent: O
Product: NNc1ccc(Oc2ccccc2CO)cn1
Temperature: 120 °C

Procedure:
A mixture of [2-(6-chloro-pyridin-3-yloxy)-phenyl]-methanol (235 mg, 1 mmol) and hydrazine monohydrate (5 mL) was heated at 120° C. for 4 hours. The reaction was then cooled and concentrated in vacuo to an oil. The residue was then diluted with saturated NaHCO3, and the aqueous extracted with methylene chloride. The organics were washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford the above named compound.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[CH2:13])[CH:11]=[O:12])=[CH:6][CH:5]=1)[CH3:3].[CH3:14][Li]>C(OCC)C>[CH3:3][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10](=[CH2:13])[CH:11]([OH:12])[CH3:14])=[CH:8][CH:9]=1)[CH3:1]
Reactant: C=C(C=O)c1ccc(C(C)C)cc1
Reactant: [Li]C
Solvent: CCOCC
Product: C=C(c1ccc(C(C)C)cc1)C(C)O
Temperature: -78 °C

Procedure:
6.1 g of aldehyde 44 is dissolved in 250 ml of diethyl ether and cooled under nitrogen to −78° C. 35.8 ml of a methllithium solution (1.6 M in diethyl ether) is now added in drops. After 1.5 hours at this temperature, it is quenched with saturated ammonium chloride solution, extracted with ethyl acetate, washed with sodium chloride solution, dried on sodium sulfate, and the solvent is removed. The residue is purified by chromatography on silica gel with ethyl acetate/hexane, whereby 2.8 g of title compound 45 accumulates as a colorless oil.
Reaction SMILES: [OH:1][C@:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:3]([OH:5])=O.[NH2:13][C@H:14]([C:16]([N:18]1[C:24](=[O:25])[CH:23]([CH3:26])[C:22]2[CH:27]=[CH:28][CH:29]=[CH:30][C:21]=2[C:20]2[C:31]([NH2:35])=[CH:32][CH:33]=[CH:34][C:19]1=2)=[O:17])[CH3:15]>>[OH:1][C@:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:3]([NH:13][C@H:14]([C:16]([N:18]1[C:24](=[O:25])[CH:23]([CH3:26])[C:22]2[CH:27]=[CH:28][CH:29]=[CH:30][C:21]=2[C:20]2[C:31]([NH2:35])=[CH:32][CH:33]=[CH:34][C:19]1=2)=[O:17])[CH3:15])=[O:5]
Reactant: C[C@@](O)(C(=O)O)c1ccccc1
Reactant: CC1C(=O)N(C(=O)[C@H](C)N)c2cccc(N)c2-c2ccccc21
Product: CC1C(=O)N(C(=O)[C@H](C)NC(=O)[C@@](C)(O)c2ccccc2)c2cccc(N)c2-c2ccccc21

Procedure:
Following one or more of the general procedures outlined above, using (S)-(+)-2-hydroxy-2-phenylpropionic acid and 5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, as described in Example 7-B, the title compound was prepared. The molecular weight as determined by mass spectrometry (FD) was: 458 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[N:4]=1)#[N:2].N.[H][H]>[Ni].C(O)C>[NH2:2][CH2:1][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[N:4]=1
Reactant: N#Cc1cccc(Cl)n1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: NCc1cccc(Cl)n1
Yield: 94.4 %

Procedure:
A 3.3 g portion of Raney nickel was suspended in 30 ml of ethanol, and the suspension was mixed with 1.42 g of 2-cyano-6-chloropyridine and 10 ml of 28% aqueous ammonia and stirred at room temperature for 4 hours in a stream of hydrogen. The reaction mixture was filtered through celite and the filtrate was concentrated to obtain 1.38 g of the title compound as a mixture.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8]([C:11](=[O:29])[C:12]([N:14]3[CH2:19][CH2:18][C:17](=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:21]#[N:22])[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:10][C:3]=12.[NH:30]1[CH:34]=[CH:33][N:32]=[N:31]1.C([O-])([O-])=O.[K+].[K+]>CO.[Cu]>[O:29]=[C:11]([C:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([N:31]3[N:32]=[CH:33][CH:34]=[N:30]3)=[C:3]2[NH:10][CH:9]=1)[C:12]([N:14]1[CH2:19][CH2:18][C:17](=[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:21]#[N:22])[CH2:16][CH2:15]1)=[O:13]
Reactant: c1c[nH]nn1
Reactant: N#CC(=C1CCN(C(=O)C(=O)c2c[nH]c3c(Cl)ccnc23)CC1)c1ccccc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: N#CC(=C1CCN(C(=O)C(=O)c2c[nH]c3c(-n4nccn4)ccnc23)CC1)c1ccccc1
Temperature: 160 °C
Yield: 31 %

Procedure:
A mixture of compound of example 101 (34 mg, 0.084 mmol), 1,2,3-triazole (0.40 mL, 6.9 mmol), copper metal (5.4 mg, 0.084 mmol), and K2CO3 (11.5 mg, 0.083 mmol) in a sealed tube was heated at 160° C. for 5 h. The reaction mixture was diluted with MeOH (2 mL), filtered through Celite and concentrated. The residue was purified by preparative HPLC to yield title compound (3.1 mg, 0.026 mmol, 39%) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[CH2:11][CH2:10][C:9](=[O:16])[O:8][C:7]=1[CH:6]=[CH:5]2.Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:23][C:22]([O:21][C:19](=[O:20])[CH2:18][O:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[CH2:11][CH2:10][C:9](=[O:16])[O:8][C:7]=1[CH:6]=[CH:5]2)([CH3:25])[CH3:24]
Reactant: O=C1CCc2c(ccc3cc(O)ccc23)O1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)COc1ccc2c3c(ccc2c1)OC(=O)CC3
Temperature: 60 °C
Reaction time: 17 h
Yield: 90.8 %

Procedure:
A mixture of 2.18 g (10.2 mmol) of 1,2-dihydro-8-hydroxy-3H-naphtho[2,1-b]pyran-3-one from the preceding example, 4.84 g (24.8 mmol) of t-butyl bromoacetate, 5.63 g (40.7 mmol) of anhydrous granular potassium carbonate and 55.5 mL of 2-butanone was heated at 60° C. for 24 hr. A second portion of t-butyl bromoacetate (0.5 mL, 3.1 mmol) was added and the reaction was allowed to proceed for another 17 hr. After being cooled to room temperature, the mixture was filtered and the solids were washed with ethyl acetate and ether. The filtrate and washes were combined and concentrated in vacuo, and the crude product was flash chromatographed on 360 g of silica gel, eluting with hexane-ethyl acetate (7:1 then 6:1) affording 3.04 g (91.0%) of the title compound as a white solid, mp 95°-96° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.O.[NH2:17][NH2:18]>CO>[NH:17]([C:2]1[N:7]=[C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[C:4]([CH3:9])[N:3]=1)[NH2:18]
Reactant: C1COCCN1
Reactant: NN
Reactant: Cc1cc(Cl)nc(Cl)n1
Solvent: CO
Solvent: O
Product: Cc1cc(N2CCOCC2)nc(NN)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.3 %

Procedure:
To a solution of 2,4-dichloro-6-methylpyrimidine (0.41 g, 2.50 mmol) in MeOH (5 mL) was added morpholine (0.5 mL, 5.73 mmol). The solution was stirred for 30 min at room temperature, and then hydrazine monohydrate (1.0 mL, 20.6 mmol) was added. The solution was then heated at 60° C. and stirred for 16 h. The solution was then cooled to room temperature and purified by reverse phase HPLC to afford 0.31 g of the title compound (59%) as a waxy white solid. MH+210.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:22])=[C:4]([C:18]([F:21])=[CH:19][CH:20]=1)[C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=2)[NH:9][CH:8]=1)=[O:6].[F:23][C:24]1[CH:25]=[C:26]([S:30](Cl)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1.Cl>O1CCCC1.N1C=CC=CC=1>[C:16]([C:13]1[CH:14]=[C:15]2[C:7]([C:5]([C:4]3[C:3]([F:22])=[C:2]([NH:1][S:30]([C:26]4[CH:27]=[CH:28][CH:29]=[C:24]([F:23])[CH:25]=4)(=[O:32])=[O:31])[CH:20]=[CH:19][C:18]=3[F:21])=[O:6])=[CH:8][NH:9][C:10]2=[N:11][CH:12]=1)#[N:17]
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: N#Cc1cnc2[nH]cc(C(=O)c3c(F)ccc(N)c3F)c2c1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: N#Cc1cnc2[nH]cc(C(=O)c3c(F)ccc(NS(=O)(=O)c4cccc(F)c4)c3F)c2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.9 %

Procedure:
To 3-(3-amino-2,6-difluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (28, 130 mg, 0.436 mmol) in 3.5 mL of tetrahydrofuran, 0.31 mL of pyridine was added. 3-Fluoro-benzenesulfonyl chloride (30, 127 mg, 0.654 mmol) was added and the solution was stirred at room temperature for 48 hours. The reaction mixture was poured into 1 M aqueous hydrochloric acid and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The crude material was purified by silica gel column chromatography eluting with ethyl acetate and hexane. Appropriate fractions were combined and the solvent removed under reduced pressure to provide the desired compound (P-0005, 167 mg). MS(ESI)[M+H+]+=457.6.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[C:15]([N+:17]([O-])=O)[C:14]([O:20][CH2:21][C:22](OCCCC)=[O:23])=[CH:13][C:12]=2[F:29])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[N:3]([C:11]2[C:12]([F:29])=[CH:13][C:14]3[O:20][CH2:21][C:22](=[O:23])[NH:17][C:15]=3[CH:16]=2)[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2
Reactant: CCCCOC(=O)COc1cc(F)c(-n2nc3c(c2Cl)CCCC3)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: O=C1COc2cc(F)c(-n3nc4c(c3Cl)CCCC4)cc2N1
Yield: 82.1 %

Procedure:
A suspension of 3-chloro-2-(2-fluoro-4-butyloxycarbonylmethoxy-5-nitrophenyl)-4,5,6,7-tetrahydro-2H-indazole (10 g) and iron powders (10 g) in acetic acid was refluxed for 5 hours. After completion of the reaction, the reaction mixture was filtered by the use of celite, and the filtrate was combined with water and extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified by column chromatography using a mixture of hexane and ethyl acetate as an eluent to give 3-chloro-2-[7-fluoro-2H-1,4-benzoxazin-3(4H)-on-6-yl]-4,5,6,7-tetrahydro-2H-indazole (6.2 g). nD29.0 1.5628.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([O:17][S:18]([C:21]4[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[N:4]([S:28]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH:3]=1.[Li]C(C)(C)C.[F:43][C:44]1[CH:45]=[C:46]([CH:49]=[CH:50][CH:51]=1)[CH:47]=[O:48]>C1COCC1.CCCCC>[F:43][C:44]1[CH:45]=[C:46]([CH:47]([OH:48])[C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[C:13]([O:17][S:18]([C:21]5[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=5)(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=4)[CH:9]=3)[N:4]([S:28]([C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[CH:3]=2)[CH:49]=[CH:50][CH:51]=1
Reactant: O=Cc1cccc(F)c1
Reactant: Cc1ccc(S(=O)(=O)Oc2cccc(-c3cnc4c(c3)c(I)cn4S(=O)(=O)c3ccc(C)cc3)c2)cc1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)Oc2cccc(-c3cnc4c(c3)c(C(O)c3cccc(F)c3)cn4S(=O)(=O)c3ccc(C)cc3)c2)cc1
Temperature: 10 °C
Reaction time: 0.08 h
Yield: 52.5 %

Procedure:
To a solution of toluene-4-sulfonic acid 3-[3-iodo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-phenyl ester (50 mg, 0.077 mmol, prepared as exemplified in method 6) in THF (2 mL) at −90° C. under nitrogen atmosphere was added a solution of tBuLi in pentane (1.7 M, 90 uL) dropwise. After stirring for 5 min, 3-fluoro-benzaldehyde (40 uL, 0.38 mmol) was added and the reaction mixture was slowly warmed up to 10° C. over 2 h, then quenched with a saturated solution of ammonium chloride and extracted with EtOAc three times. The extracts were combined and adsorbed on silica gel. Purification on silica gel with a gradient of MeOH/CH2Cl2 afforded 26 mg of toluene-4-sulfonic acid 3-[3-[(3-fluorophenyl)-hydroxy-methyl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-phenyl ester. The material was dissolved in dichloromethane (0.3 mL) under nitrogen atmosphere. Triethylsilane (24 uL, 0.149 mmol) was added, followed by boron trifluoride etherate (7 μL, 0.149 mmol) dropwise. After stirring for 15 h, the reaction was quenched with a saturated solution of sodium bicarbonate and extracted with dichloromethane three times. The extracts were combined and concentrated under vacuum. The crude was treated with 2 mL of EtOH and 2 mL of aqueous KOH (50 wt %). The reaction mixture was stirred at 70° C. for 1 h. The mixture was acidified to pH 4 with 1 N aqueous HCl, and extracted with EtOAc three times. The extracts were combined and adsorbed on silica gel. Purification on silica gel with a gradient of MeOH/CH2Cl2 afforded 3-[3-(3-fluoro-benzyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-phenol as a beige solid (8 mg, 66% yield). 1H NMR (500 MHz, DMSO-d6) δ 4.11 (s, 3H), 6.74 (dd, J=2.5, 8.5 Hz, 1H), 6.97 (dt, J=2.0, 8.5 Hz, 1H), 7.00 (s, 1H), 7.05 (d, J=8.0 Hz, 1H), 7.13 (d, J=10.5 Hz, 1H), 7.17 (d, J=8.0 Hz, 1H), 7.25 (t, J=7.5 Hz, 1H), 7.30 (q, J=8.0 Hz, 1H), 7.40 (d, J=2.5 Hz, 1H), 8.07 (d, J=2.0 Hz, 1H), 8.42 (d, J=2.0 Hz, 1H), 9.56 (broad s, 1H), 11.6 (s, 1H). MS: m/z 319 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH3:17])=[C:9]2[C:18](N(OC)C)=[O:19])[CH:5]=[CH:6][CH:7]=1.[CH3:24][Mg]Br.CCOCC>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH3:17])=[C:9]2[C:18](=[O:19])[CH3:24])[CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)c1c(C)c2ccccc2n1-c1cccc(F)c1
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)c1c(C)c2ccccc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a mixture of 1-(3-fluorophenyl)-N-methoxy-N,3-dimethyl-1H-indole-2-carboxamide (0.27 g, 0.86 mmol) in tetrahydrofuran (5 mL) was added 3.0 M methylmagnesium bromide in ether (2.3 mL, 6.9 mmol). The reaction was stirred at room temperature overnight. The reaction was quenched with saturated NH4Cl solution and extracted with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified on silica gel (eluting with 0-15% EtOAc/hexane) to give the desired product (0.165 g, 71%). LCMS calculated for C17H15FNO(M+H)+: m/z=268.1. Found: 268.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([C:40](O)=[O:41])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:43][CH3:44])=[O:5])[CH3:2].ClC(OCC)=O.C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:27]=[C:28]([C:36]([F:39])([F:37])[F:38])[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=3)[C:22]([CH2:40][OH:41])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:43][CH3:44])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(C(=O)O)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(CO)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
(2R*,4S*)-4-{[3,5-Bis(trifluoromethyl)benzyl]-(5-carboxypyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (100 mg) is dissolved in tetrahydrofuran (2 ml), then thereto are added ethyl chloroformate (0.02 ml) and triethylamine (0.04 ml) under ice-cooling, and the mixture is stirred for 30 minutes. The reaction solution is filtered, sodium borohydride (18 mg) is added to the filtrate, and the mixture is stirred for 1 hour and 40 minutes. To the reaction solution is added 1N-hydrochloric acid and the mixture is extracted with ethyl acetate. The organic layer is washed successively with water, a saturated aqueous sodium hydrogen carbonate solution and a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane: ethyl acetate=4:1→3:2) to give (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(hydroxymethyl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (80 mg). MS (m/z): 614 [M+H]+
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:21])[CH:7]=[C:8]([C:12]3[N:17]=[CH:16][N:15]4[CH:18]=[CH:19][CH:20]=[C:14]4[CH:13]=3)[O:9]2)=[CH:4][CH:3]=1.[OH:22][C:23]1[CH:24]=[C:25]([C:29]#[CH:30])[CH:26]=[CH:27][CH:28]=1>>[OH:22][C:23]1[CH:24]=[C:25]([C:29]#[C:30][C:2]2[CH:11]=[C:10]3[C:5]([C:6](=[O:21])[CH:7]=[C:8]([C:12]4[N:17]=[CH:16][N:15]5[CH:18]=[CH:19][CH:20]=[C:14]5[CH:13]=4)[O:9]3)=[CH:4][CH:3]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: C#Cc1cccc(O)c1
Reactant: O=c1cc(-c2cc3cccn3cn2)oc2cc(Br)ccc12
Product: O=c1cc(-c2cc3cccn3cn2)oc2cc(C#Cc3cccc(O)c3)ccc12
Yield: 71 %

Procedure:
7-(3-hydroxy-phenylethynyl)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one was prepared in 71% yield using the method described in example 23A, starting from 7-bromo-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one (example 120C) and 3-hydroxyphenylacetylene. The title compound was isolated as a brown powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][CH2:15][OH:16])[O:11][CH:12]=2)=[CH:4][CH:3]=1.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>N1C=CC=CC=1>[C:17]([O:16][CH2:15][CH2:14][CH2:13][C:10]1[O:11][CH:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OCCCc1nc(-c2ccc(Cl)cc2)co1
Solvent: O
Solvent: c1ccncc1
Product: O=C(OCCCc1nc(-c2ccc(Cl)cc2)co1)c1ccccc1
Temperature: 25 °C
Yield: 96 %

Procedure:
To a solution of 3-[4-(4-chlorophenyl)-2-oxazolyl] propanol (0.5 g) in pyridine (2 ml) was added benzoyl chloride (0.29 ml), followed by stirring for an hour at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed successively with an aqueous sodium hydrogen carbonate solution 2N-HCl and water, dried over MgSO4, and distilled to remove the solvent. The precipitated crystals were collected by filtration to give 3-[4-(4-chlorophenyl)-2-oxazolyl]propyl benzoate (0.687 g, 96%). Recrystallization from ether-hexane gave colorless prism crystals of mp 47°-47.5° C.