Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([NH2:13])[CH:7]=1.C[O:16][C:17](=O)[CH:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[O:31])=[CH:26][CH:25]=1)[C:19](=O)[CH2:20][CH3:21].O1CCOCC1>O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]2[C:7]=1[C:17](=[O:16])[C:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([N:32]3[CH2:33][CH2:34][CH2:35][CH2:36]3)=[O:31])=[CH:26][CH:25]=1)=[C:19]([CH2:20][CH3:21])[NH:13]2
Reactant: COC(=O)COc1ccc(Cl)c(N)c1
Reactant: CCC(=O)C(Cc1ccc(C(=O)N2CCCC2)cc1)C(=O)OC
Solvent: O
Solvent: C1COCCO1
Product: CCc1[nH]c2c(Cl)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(C(=O)N2CCCC2)cc1
Temperature: 120 °C

Procedure:
A mixture of (3-amino-4-chlorophenoxy)acetic acid methyl ester (1.0 g), 3-oxo-2-[4-(pyrrolidine-1-carbonyl)benzyl]pentanoic acid methyl ester (1.9 g), polyphosphoric acid (6.0 g) and dioxane (20 mL) was heated at 120° C. for 18 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane, ethyl acetate and methanol (9:1:0 to 0:9:1 by volume) to afford title compound, 0.079 g.
Reaction SMILES: [O:1]([CH2:8][CH2:9]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[O:1]([CH2:8][CH2:9][N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: BrCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: c1ccc(OCCN2CCCCC2)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 96.4 %

Procedure:
A mixture of 20 g of 2-phenoxyethyl bromide thus obtained, 7.92 g of piperidine and 12.86 g of potassium carbonate was added into 100 ml of ethyl alcohol and stirred for 6 hours at 100° C. The mixture obtained was filtered and condensed under reduced pressure to give 18.4 g of 1-(2-phenoxyethyl)piperidine having a boiling point of 111° C. to 112° C. at 7 mmHg in a yield of 90%.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:15]=[CH:14][C:7]2[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=2[CH:5]=1.[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([C:26]([F:29])([F:28])[F:27])=[CH2:25])[C:21]([F:30])=[C:20]([Cl:31])[C:19]=1[F:32]>CN(C=O)C>[Cl:31][C:20]1[C:21]([F:30])=[C:22]([C:24]2([C:26]([F:29])([F:28])[F:27])[O:1][N:2]=[C:3]([C:4]3[CH:15]=[CH:14][C:7]4[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=4[CH:5]=3)[CH2:25]2)[CH:23]=[C:18]([Cl:17])[C:19]=1[F:32]
Reactant: C=C(c1cc(Cl)c(F)c(Cl)c1F)C(F)(F)F
Reactant: CC1(C)OB(O)c2ccc(C(Cl)=NO)cc21
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2ccc(C3=NOC(c4cc(Cl)c(F)c(Cl)c4F)(C(F)(F)F)C3)cc21
Temperature: 0 °C
Reaction time: 12 h
Yield: 21.4 %

Procedure:
To a solution of N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]-oxaborole-5-carbimidoyl chloride (3.0 g, 12.63 mmol) and 1,3-dichloro-2,4-difluoro-5-(3,3,3-trifluoroprop-1-en-2-yl)-benzene (3.93 g, 14.19 mmol) in DMF (20 mL) at rt was added TEA (2.7 mL, 18.95 mmol). The reaction mixture was stirred for 12 h, poured into ice-water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE-EA (1:1) to give the title compound 5-(5-(3,5-dichloro-2,4-difluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol[1.3 g, yield: 21.4% (3 steps)] as a white solid. 1H NMR (500 MHz, DMSO-d6): δ 9.23 (s, 1 H), 7.87 (t, J=7.5 Hz, 1H), 7.83 (s, 1H), 7.75 (s, 2H), 4.59 (d, J=18.5 Hz, 1H), 4.37 (d, J=18.5 Hz, 1H), 1.50 (s, 3H), 1.48 (s, 3H) ppm; HPLC purity: 100.0% at 220 nm and 100.0% at 254 nm; MS: m/z=479.8 (M+1, ESI+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.[F:10][C:11]([Si](C)(C)C)([F:13])[F:12].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:9])[C:11]([F:13])([F:12])[F:10])=[CH:6][N:7]=1
Reactant: O=Cc1ccc(Cl)nc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1ccc(Cl)nc1)C(F)(F)F
Yield: 99.1 %

Procedure:
According to Reference Example 8-12, by use of 6-chloro-3-pyridinecarboxaldehyde (1.00 g, 7.06 mmol), (trifluoromethyl)trimethylsilane (1.25 mL, 8.48 mmol), tetrabutylammonium fluoride (a 1.0 mol/L solution in tetrahydrofuran, 706 μL, 0.706 mmol) and tetrahydrofuran (20 mL), the mixture was stirred and reacted at room temperature for 1 hour. Then, purification by silica gel column chromatography (chloroform/methanol=9/1) was performed to give 2-chloro-5-(2,2,2-trifluoro-1-hydroxyethyl)pyridine (Compound DC) (1.48 g, yield: 99%).
Reaction SMILES: C(O)C.[CH:4]1([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[C@@H:26]([CH3:30])[NH:25][CH2:24]5)[C:15]=3[O:17][CH:18]([F:20])[F:19])[C:10](=[O:31])[C:9]([C:32]([OH:34])=[O:33])=[CH:8]2)[CH2:6][CH2:5]1.[OH-].[Na+:36]>O>[CH:4]1([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[C@@H:26]([CH3:30])[NH:25][CH2:24]5)[C:15]=3[O:17][CH:18]([F:20])[F:19])[C:10](=[O:31])[C:9]([C:32]([O-:34])=[O:33])=[CH:8]2)[CH2:6][CH2:5]1.[Na+:36]
Reactant: C[C@H]1NCc2cc(-c3ccc4c(=O)c(C(=O)O)cn(C5CC5)c4c3OC(F)F)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[C@H]1NCc2cc(-c3ccc4c(=O)c(C(=O)[O-])cn(C5CC5)c4c3OC(F)F)ccc21
Reaction time: 1 h

Procedure:
In 9.4 ml of 25% water-containing ethanol is suspended 1.2 g of (R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid, and 2.57 ml of 1 mole/liter aqueous sodium hydroxide solution is added thereto, after which the resulting mixture is exposed to ultrasonic wave for 1 hour to form a uniform solution. Subsequently, the reaction mixture is washed twice with chloroform, and concentrated, and the crystals deposited are collected by filtration to obtain 0.49 g of sodium (R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylate.
Reaction SMILES: [I-].[CH:2]([NH:4][C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N+:10]=1[CH3:15])=[O:3].[I-].[N+](C1C=CC=CC=1C=CC1C=CC=C[N+]=1C)([O-])=O>>[CH3:15][N:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]1[CH2:8][CH2:7][C:6]1[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=1[NH:4][CH:2]=[O:3]
Reactant: C[n+]1ccccc1CCc1ccccc1NC=O
Agent: C[n+]1ccccc1C=Cc1ccccc1[N+](=O)[O-]
Agent: [I-]
Product: CN1CCCCC1CCc1ccccc1NC=O

Procedure:
Reduction of 2-(o-formamidophenethyl)-1-methylpyridinium iodide as described in Example 1 for 2-(o-nitrostyryl)-1-methylpyridinium iodide provides 2'-[2-(1-methyl-2-piperidyl)-ethyl]formanilide which is purified by crystallization from isopropyl ether, (79% yield) m.p. 81°-84.5° C. (corr.).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH2:38][NH2:39].[CH2:43]([N:47]1[C:56]2[C:51](=[CH:52][CH:53]=[C:54]([C:57]([F:60])([F:59])[F:58])[CH:55]=2)[C:50]([CH3:61])=[C:49]([C:62](O)=[O:63])[C:48]1=[O:65])[CH2:44][CH2:45][CH3:46]>CN(C=O)C.O.CCOC(C)=O.CCCCCC>[CH2:43]([N:47]1[C:56]2[C:51](=[CH:52][CH:53]=[C:54]([C:57]([F:60])([F:59])[F:58])[CH:55]=2)[C:50]([CH3:61])=[C:49]([C:62]([NH:39][CH2:38][C:37]2[CH:40]=[CH:41][CH:42]=[C:35]([F:34])[CH:36]=2)=[O:63])[C:48]1=[O:65])[CH2:44][CH2:45][CH3:46]
Reactant: CCCCn1c(=O)c(C(=O)O)c(C)c2ccc(C(F)(F)F)cc21
Reactant: NCc1cccc(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCn1c(=O)c(C(=O)NCc2cccc(F)c2)c(C)c2ccc(C(F)(F)F)cc21
Reaction time: 3 h
Yield: 50 %

Procedure:
349 mg (0.9 mmol) HATU, 550 μl (3.1 mmol) DIPEA and 90 μl (0.8 mmol) 3-fluoro-benzylamine were added to a solution of 250 mg (0.8 mmol) 1-butyl-4-methyl-2-oxo-7-(trifluoromethyl)-1H-quinoline-3-carboxylic acid in DMF (3 ml) at RT and stirring was continued for 3 h. The RS was then diluted with water (20 ml) and extracted with EtOAc (3×30 ml). The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated in vacuo. After CC (EtOAc/hexane 1:4) of the residue, 180 mg (0.4 mmol, 54%) 1-butyl-N-[(3-fluorophenyl)-methyl]-4-methyl-2-oxo-7-(trifluoromethyl)-1H-quinoline-3-carboxylic acid amide (example 2) was obtained. MS: m/z 435.2 [M+H]+.
Reaction SMILES: [C:1](O[C@H]1[C@H](OC(=O)C)[C@@H](OC(=O)C)[C@H](C2C=C(CC3C=CC(OCC)=CC=3)C(Cl)=CC=2OCC=C)O[C@@H]1COC(=O)C)(=[O:3])[CH3:2].[CH2:45]([C:52]1[C:61]([Cl:62])=[C:60]2[C:55]([CH2:56][CH2:57][CH2:58][O:59]2)=[C:54]([C@H:63]2[C@H:68]([OH:69])[C@@H:67]([OH:70])[C@H:66]([OH:71])[C@@H:65]([CH2:72][OH:73])[O:64]2)[CH:53]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>>[C:58]([O:71][C@H:66]1[C@H:67]([O:70][C:63](=[O:64])[CH3:54])[C@@H:68]([O:69][C:68](=[O:69])[CH3:67])[C@H:63]([C:54]2[CH:53]=[C:52]([CH2:45][C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:61]([Cl:62])=[C:60]3[C:55]=2[CH2:56][CH2:57][CH2:58][O:59]3)[O:64][C@@H:65]1[CH2:72][O:73][C:1](=[O:3])[CH3:2])(=[O:59])[CH3:57]
Reactant: C=CCOc1cc(Cl)c(Cc2ccc(OCC)cc2)cc1[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: OC[C@H]1O[C@@H](c2cc(Cc3ccccc3)c(Cl)c3c2CCCO3)[C@H](O)[C@@H](O)[C@@H]1O
Product: CC(=O)OC[C@H]1O[C@@H](c2cc(Cc3ccccc3)c(Cl)c3c2CCCO3)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
Similar procedure with preparation of 25 proceeded except for using compound 175 to obtain the compound 176.
Reaction SMILES: [Cl:1][CH:2]([CH3:8])[CH2:3][CH2:4][C:5](Cl)=[O:6].[C:9]1([C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:16][NH2:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1C=CC=CC=1.C(OCC)(=O)C>ClCCl>[Cl:1][CH:2]([CH3:8])[CH2:3][CH2:4][C:5]([NH:17][N:16]=[C:15]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:6]
Reactant: NN=C(c1ccccc1)c1ccccc1
Reactant: CC(Cl)CCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(Cl)CCC(=O)NN=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.6 %

Procedure:
At 0° C., a solution of 0.16 g (1.0 mmol) of 4-chloropentanoyl chloride in 15 ml dichloromethane is added to a solution of 0.20 g (1.0 mmol) of diphenylmethanone hydrazone and 0.08 ml of pyridine in 15 ml of dichloromethane. The reaction mixture is stirred at room temperature for 16 h. Ethyl acetate/saturated aqueous NH4Cl solution is added to the reaction mixture, the organic phase is separated off and the aqueous phase is extracted with 3×100 ml of ethyl acetate. The combined organic phases are dried over Na2SO4 and freed from the solvent under reduced pressure. Purification by column chromatography on silica gel (cyclohexane/ethyl acetate) gives 0.32 g (100%) of the desired product; log P(HCOOH): 3.76; 1H-NMR (ppm): δ (DMSO-d6)=1.45 (d, 0.9H), 1.52 (d, 2.1H), 1.81-2.12 (m, 1H), 2.30-2.42 (m, 1H), 2.88-3.00 (m, 2H), 4.13-4.20 (m, 0.3H), 4.28-4.34 (m, 0.7H), 7.26-7.61 (m, 10H), 9.19 (s, 1H); LC-MS: m/z=315 [M+H]+
Reaction SMILES: Cl.C(O[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[NH:6])C.C(N(CC)CC)C.[C:30]1([CH2:36][C:37]([NH:39][NH2:40])=O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:5]4[NH:6][C:37]([CH2:36][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)=[N:39][N:40]=4)[CH:8]=3)[NH:12][N:11]=2)=[CH:17][CH:18]=1
Reactant: NNC(=O)Cc1ccccc1
Reactant: CCOC(=N)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Agent: Cl
Solvent: CCN(CC)CC
Product: Fc1ccc(-c2n[nH]c3ccc(-c4nnc(Cc5ccccc5)[nH]4)cc23)cc1
Yield: 44.1 %

Procedure:
The procedure described in example 123 using ethoxy[3-(4-fluorophenyl)(1H-indazol-5-yl)]methanimine hydrochloride (200 mg, 0.62 mmol), triethylamine (0.25 mL, 1.86 mmol) and phenyl acetic hydrazide (187 mg, 1.25 mmol) was used to prepare the title compound (101 mg, 44% yield). 1H NMR (DMSO-d6) δ 8.7 (s, 1H), 8.05 (m, 3H), 7.5 (d, 1H), 7.2–7.5 (m, 7H), 4.15 (s, 2H), ES-MS(m/z) 370 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12](O)=[O:13])[N:9]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[C:6]2=[N:7][CH:8]=1.[Cl:25][C:26]1[N:31]=[CH:30][C:29]([NH2:32])=[CH:28][N:27]=1>>[Cl:25][C:26]1[N:31]=[CH:30][C:29]([NH:32][C:12]([C:10]2[N:9]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[C:6]3=[N:7][CH:8]=[C:3]([C:2]([F:24])([F:1])[F:23])[CH:4]=[C:5]3[CH:11]=2)=[O:13])=[CH:28][N:27]=1
Reactant: Nc1cnc(Cl)nc1
Reactant: O=C(O)c1cc2cc(C(F)(F)F)cnc2n1Cc1cccc(F)c1
Product: O=C(Nc1cnc(Cl)nc1)c1cc2cc(C(F)(F)F)cnc2n1Cc1cccc(F)c1
Yield: 22.9 %

Procedure:
According to a method similar to that described in Stage 1.4, starting from 1.08 g (3.2 mmol) of 5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid, described in Stage 1.3, and 0.46 g (3.52 mmol) of 2-chloro-5-aminopyrimidine, we obtain 0.33 g of the expected product.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[N:11][CH:12]=[C:13]([CH:17]=2)[C:14]([OH:16])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][S@@:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[NH:21])=[O:20]>>[CH3:18][S@@:19](=[O:20])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[N:21][C:14](=[O:16])[C:13]1[CH:17]=[C:9]([C:8]#[C:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:10]=[N:11][CH:12]=1
Reactant: O=C(O)c1cncc(C#Cc2ccccc2)c1
Reactant: C[S@@](=N)(=O)c1ccccc1
Product: C[S@](=O)(=NC(=O)c1cncc(C#Cc2ccccc2)c1)c1ccccc1
Yield: 25 %

Procedure:
In a manner similar to that described in Example 423, 5-(2-phenyleth-1-ynyl)nicotinic acid and (R)-(−)-S-methyl-S-phenylsulfoximine were reacted to give the title compound as a white foam (54 mg, 25%).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[NH2:21][C:22]1[C:27]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)=[O:29])=[C:26](Cl)[N:25]=[CH:24][N:23]=1.CCN(C(C)C)C(C)C.[F-].[Cs+]>C(O)(C)(C)C>[NH2:21][C:22]1[C:27]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)=[O:29])=[C:26]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[N:25]=[CH:24][N:23]=1
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Reactant: COc1ccc(COC(=O)c2c(N)ncnc2Cl)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(COC(=O)c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)cc1
Temperature: 80 °C
Yield: 323.5 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (515 mg, 0.27 mmol), 4-methoxybenzyl 4-amino-6-chloropyrimidine-5-carboxylate (691 mg, 1.86 mmol), DIEA (1.77 ml, 10.16 mmol) and cesium fluoride (770 mg, 5.07 mmol) were suspended in tert-butanol (50 ml) and the mixture was heated at 80° C. in a sealed tube for 24 h. The solvent was evaporated under reduced pressure and the reaction mixture was diluted with ethyl acetate and washed with saturated ammonium chloride solution and brine. After evaporation of the solvent, the residue was purified by flash chromatography (0 to 50%, hexane-ethyl acetate) using SP1® Purification System to give 459 mg (51% yield) of the title compound as a solid. Purity 99%.
Reaction SMILES: [H-].[Na+].[N:3]1([C:8]2[N:13]=[CH:12][C:11]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:10][N:9]=2)[CH:7]=[N:6][N:5]=[N:4]1.[CH3:19]I>CN(C=O)C.C(OCC)(=O)C>[N:3]1([C:8]2[N:9]=[CH:10][C:11]([CH:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16])=[CH:12][N:13]=2)[CH:7]=[N:6][N:5]=[N:4]1
Reactant: CI
Reactant: COC(=O)Cc1cnc(-n2cnnn2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(C)c1cnc(-n2cnnn2)nc1
Reaction time: 0.17 h

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil) (19.1 mg, 0.477 mmol) in anhydrous DMF (3.2 mL) was added solution of methyl 2-(2-(1H-tetrazol-1-yl)pyrimidin-5-yl)acetate (100 mg, 0.454 mmol) in anhydrous DMF (1.4 mL) at room temperature. Stirred for 10 min, then added methyl iodide (42.6 μl, 0.681 mmol) dropwise. Stirred at room temperature for 1 h. Reaction mixture was diluted with ethyl acetate and washed with water (3 times). Organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by MPLC, eluting with 20-100% ethyl acetate/hexanes, 26 column volumes. LC/MS: [(M+1)]+=235.2;
Reaction SMILES: C[O:2][C:3]([C:5]1[S:13][C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[Br:14])=[O:4].O[Li].O>C1COCC1.O>[Br:14][C:6]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:12]2[S:13][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1sc2cccnc2c1Br
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1sc2cccnc2c1Br
Reaction time: 72 h

Procedure:
To a solution of compound 145-E (4.94 g, 18.2 mmol) in 5:1 THF/H2O (200 mL) was added LiOH.H2O (0.797 g, 19.0 mmol). The reaction was stirred for 3 days then concentrated in vacuo, to which was added water (100 mL) and 1N HCl (19.0 mL), and the resultant precipitate was isolated by filtration. The solid was rinsed with water and dried under vacuum to afford compound 145-F as a tan-yellow solid (4.51 g, 96%). 1H-NMR (DMSO-d6): δ 7.62 (dd, 1H), 8.62 (dd, 1H), 8.86 (dd, 1H), 14.18 (br s, 1H); MS: m/z 257.9 (MH+).
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH2:6][CH3:7])[CH2:3][OH:4].[ClH:8].[NH2:9][CH2:10][C:11](=[O:17])[CH2:12][CH2:13][C:14](O)=[O:15]>>[ClH:8].[NH2:9][CH2:10][C:11](=[O:17])[CH2:12][CH2:13][C:14]([O:4][CH2:3][CH:2]([CH3:1])[CH2:5][CH2:6][CH3:7])=[O:15]
Reactant: NCC(=O)CCC(=O)O
Reactant: CCCC(C)CO
Agent: Cl
Product: CCCC(C)COC(=O)CCC(=O)CN
Reaction time: 3.5 h

Procedure:
From 2-methyl-1-pentanol (6.0 ml) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol) at 70° C. The reaction was complete after 3.5 h. The yield was 1.43 g (95%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[C:18]([O:20][CH:21]([CH3:23])[CH3:22])[CH:19]=2)[NH:16][C:15]([C:24]2[S:25][CH:26]([CH2:29][C:30](O)=[O:31])[CH2:27][N:28]=2)=[CH:14]3)=[CH:6][CH:5]=1.Cl.[CH2:34]([N:36]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.CN>O.CN(C)C=O.C(N(CC)CC)C>[CH3:1][O:2][CH2:3][C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[C:18]([O:20][CH:21]([CH3:23])[CH3:22])[CH:19]=2)[NH:16][C:15]([C:24]2[S:25][CH:26]([CH2:29][C:30]([NH:36][CH3:34])=[O:31])[CH2:27][N:28]=2)=[CH:14]3)=[CH:6][CH:5]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: COCc1ccc(Oc2cc(OC(C)C)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cn1
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)CC1CN=C(c2cc3cc(Oc4ccc(COC)nc4)cc(OC(C)C)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 13 h
Yield: 68.1 %

Procedure:
A mixture of {2-[5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-7-(1-methylethoxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (300 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (190 mg), 1-hydroxybenzotriazole (130 mg), methylamine hydrochloride (90 mg), triethylamine (150 mg) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 13 h. Water was added to the mixture and the resultant was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:methanol=100:0 to 95:5, volume ratio) to give the title compound (210 mg, 68%) as a yellow amorphous solid. MS 469 (MH+).
Reaction SMILES: C1(O[C:8](=[O:26])[NH:9][C:10]2[N:11]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[N:12]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:14]=2)C=CC=CC=1.[NH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([N:38]2[C:46]3[CH:45]=[CH:44][N:43]=[CH:42][C:41]=3[CH:40]=[CH:39]2)=[CH:30][CH:29]=1.CO>CS(C)=O.ClCCl>[C:15]([C:13]1[CH:14]=[C:10]([NH:9][C:8]([NH:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]([N:38]3[C:46]4[CH:45]=[CH:44][N:43]=[CH:42][C:41]=4[CH:40]=[CH:39]3)=[CH:30][CH:29]=2)=[O:26])[N:11]([C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)[N:12]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)cc1
Reactant: Nc1ccc(-n2ccc3cnccc32)c2ccccc12
Solvent: CO
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(-n3ccc4cnccc43)c3ccccc23)cc1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 83.7 %

Procedure:
(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid phenyl ester (144 mg, 0.411 mmol, 1.1 equiv.) and 1-(4-aminonaphthalen-1-yl)pyrrolo[3,2-c]pyridine (Example 1) (97 mg, 0.374 mmol, 1 equiv.) were combined in 2 mL anhydrous DMSO. The mixture was stirred under inert atmosphere for 1.5 h, then heated to 60° C. for 0.5 h. The reaction was allowed to cool, quenched with 5% aqueous NaOH and extracted with EtOAc three times. The combined organic extracts were washed with water, then brine. They were then dried (MgSO4), filtered, and the solvents were removed in vacuo. The residue was purified by column chromatography using 3-4% MeOH in dichloromethane providing 161 mg title compound (0.313 mmol, 84%) as a glassy solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:17]=[CH:16][S:15][CH:14]=1)=[O:12]>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11](=[O:12])[C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH:7]=1
Reactant: O=C(CBr)c1ccsc1
Reactant: O=c1ncc(Cl)c[nH]1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(Cn1cc(Cl)cnc1=O)c1ccsc1
Temperature: 25 °C
Yield: 45.2 %

Procedure:
A mixture of 5-chloropyrimidin-2-one (522 mg) and 3-bromoacetylthiophene (1.025 g) in triethylamine (0.84 ml) and ethanol (25 ml) was stirred at room temperature. After 1 h. the mixture was cooled to 3° C., the resulting precipitate was collected, then dried and recrystallised twice from ethanol to give the title pyrimidinone (460 mg), m.p. 227°-230° C., λmax (EtOH) 250 nm (ε 15,770), 333 nm (ε 2,690).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([F:19])[CH:18]=1)[O:5][C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12]O)=[CH:8][CH:7]=1.P(Br)(Br)[Br:21]>CCCCCC>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([F:19])[CH:18]=1)[O:5][C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][Br:21])=[CH:8][CH:7]=1
Reactant: OCCOc1ccc(Oc2cc(F)cc(F)c2)cc1
Reactant: BrP(Br)Br
Solvent: CCCCCC
Product: Fc1cc(F)cc(Oc2ccc(OCCBr)cc2)c1
Reaction time: 0.5 h
Yield: 105.7 %

Procedure:
To a mixture of 2-[4-(3,5-difluorophenoxy)phenoxy]ethanol (1.00 g, 3.76 mmol) and n-hexane (50 ml), phosphorus tribromide (0.71 g, 2.63 mmol) was gradually added with stirring under ice-cooling. After completion of the addition, the temperature was elevated to room temperature and stirring was continued at the same temperature for 30 minutes, followed by stirring under reflux for 1 hour. After allowed to cool, the upper n-hexane layer was collected by decantation, and the n-hexane layer was washed with water two times, an aqueous sodium carbonate solution three times and a saturated aqueous sodium chloride solution once in order and dried over anhydrous magnesium sulfate. Removal of the solvent gave 2-[4-(3,5-difluorophenoxy)phenoxy]ethyl bromide (915 mg).