Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH2:14]([N:21]1[C:25]2[CH:26]=[CH:27][C:28]3[CH2:29][CH2:30][C:31](=O)[C:32]=3[C:24]=2[N:23]=[C:22]1[CH3:34])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1.O>[CH2:14]([N:21]1[C:25]2[CH:26]=[CH:27][C:28]3[CH2:29][CH2:30][C:31](=[CH:5][C:3]#[N:4])[C:32]=3[C:24]=2[N:23]=[C:22]1[CH3:34])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: Cc1nc2c3c(ccc2n1Cc1ccccc1)CCC3=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2c3c(ccc2n1Cc1ccccc1)CCC3=CC#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
To a suspension of 60% sodium hydride (32 mg, 0.80 mmol) in tetrahydrofuran (5 mL) was added diethyl cyanomethylphosphonate (142 μL, 0.88 mmol), and the mixture was stirred at room temperature for 30 min. A solution of 3-benzyl-2-methyl-6,7-dihydroindeno[4,5-d]imidazol-8(3H)-one (73.4 mg, 0.27 mmol) in tetrahydrofuran (2 mL) was added thereto, and the mixture was stirred at room temperature for 30 min. The reaction solution was diluted with water, extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=30/70→80/20) to give the title compound (53.3 mg, yield 67%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17](=[S:19])[NH2:18])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[CH2:20](N(CC)CC)[CH3:21].ClCC=O.O>C(O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:17]4[S:19][CH:20]=[CH:21][N:18]=4)=[CH:15][CH:16]=3)[N:10]=2)[CH:7]=1
Reactant: CCN(CC)CC
Reactant: NC(=S)c1ccc(-c2cn3cc(I)ccc3n2)cc1
Agent: O=CCCl
Solvent: O
Solvent: CCO
Product: Ic1ccc2nc(-c3ccc(-c4nccs4)cc3)cn2c1

Procedure:
4-(6-Iodoimidazo[1,2-a]pyridin-2-yl)-1-benzenecarbothioamide (249 mg) was dissolved in ethanol (10 mL). Triethylamine (91 μL) and chloroacetaldehyde (155 μL) were added to the solution, and the mixture was refluxed for 18 hours. Water was added to the reaction mixture, followed by extraction with dichloromethane-methanol. The solvent was evaporated, and the residue was purified through silica gel column chromatography (dichloromethane:methanol=100:5), followed by concentration under reduced pressure, to thereby yield the title compound (103 mg).
Reaction SMILES: [N:1]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][NH:9][C:10](=[O:18])[C@@H:11]([NH:14][C:15](=[O:17])[CH3:16])[CH2:12][OH:13])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[CH3:21]I>>[N:1]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][NH:9][C:10](=[O:18])[C@@H:11]([NH:14][C:15](=[O:17])[CH3:16])[CH2:12][O:13][CH3:21])=[CH:6][CH:5]=1)=[N+:2]=[N-:3]
Reactant: CC(=O)N[C@@H](CO)C(=O)NCc1ccc(N=[N+]=[N-])cc1
Reactant: CI
Product: COC[C@H](NC(C)=O)C(=O)NCc1ccc(N=[N+]=[N-])cc1
Yield: 81.3 %

Procedure:
Utilizing Method B, (S)—N-(4-Azidobenzyl)-2-acetamido-3-hydroxypropanamide (2.40 g, 8.66 mmol), Ag2O (10.04 g, 43.30 mmol), and MeI (5.40 mL, 86.60 mmol) gave crude (S)-5 after 4 d. The product was purified by column chromatography (SiO2; 1/9 MeOH/CHCl3) to obtain 2.05 g (81%) of (S)-5 as a white solid: mp 149-150° C.; [α]26D +15.4° (c 1.0, MeOH); Rf=0.5 (1/9 MeOH/CHCl3); IR (nujol mull) 3285, 2927, 2112, 1635, 1565, 1457 cm−1; 1H NMR (CDCl3) δ 2.03 (s, CH3C(O)), 3.38 (s, OCH3), 3.43 (dd, J=7.5, 9.0 Hz, CHH′OCH3), 3.81 (dd, J=4.2, 9.0 Hz, CHH′OCH3), 4.40 (½HH′q, J=6.0, 15.0 Hz, CHH′Ar), 4.46 (½HH′q, J=6.0, 15.0 Hz, CHH′Ar), 4.51-4.57 (m, CH), 6.43 (br d, J=6.3 Hz, NHCH), 6.78-6.83 (br m, NHCH2), 6.96-7.01 (m, 2 ArH), 7.23-7.27 (m, 2 ArH), addition of excess (R)-(−)-mandelic acid to a CDCl3 solution of (R)-5 gave only a single signal for the acetyl methyl protons and the ether methyl protons, addition of excess (R)-(−)-mandelic acid to a CDCl3 solution of (R)-5 and (S)-5 (1:2 ratio) gave two signals for the acetyl methyl protons (δ 1.995 (R) and 2.010 (S) (Δppm=0.015)), and the ether methyl protons (δ 3.302 (S) and 3.342 (R) (Δppm=0.040)); 13C NMR (CDCl3) δ 23.3 (CH3C(O)), 43.1 (CH2Ph), 52.7 (CH), 59.2 (CH2OCH3), 72.0 (CH2OCH3), 119.4, 129.1, 135.0, 139.4 (C6H5), 170.3, 170.6 (2 C(O)); HRMS (ESI) 292.1405 [M+H+] (calcd. for C13H18N5O3 292.1410); Anal. (C13H17N5O3) Calcd.: C, 53.60%; H, 5.88%; N, 24.04%. Found: C, 53.76%; H, 5.97%; N, 24.22%.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[O:34])[NH:21][C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:24][CH:23]=3)[CH:15]=2)=[C:10]([CH3:35])[CH:9]=1)(C)(C)C.Cl>CO>[N:28]1([C:25]2[CH:24]=[CH:23][C:22]([NH:21][C:20]([C:16]3[CH:15]=[C:14]([C:11]4[CH:12]=[CH:13][C:8]([NH2:7])=[CH:9][C:10]=4[CH3:35])[CH:19]=[CH:18][CH:17]=3)=[O:34])=[CH:27][CH:26]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)ccc1-c1cccc(C(=O)Nc2ccc(N3CCOCC3)cc2)c1
Agent: Cl
Solvent: CO
Product: Cc1cc(N)ccc1-c1cccc(C(=O)Nc2ccc(N3CCOCC3)cc2)c1

Procedure:
[2-Methyl-3′-(4-morpholin-4-yl-phenylcarbamoyl)-biphenyl-4-yl]-carbamic acid tert-butyl ester (670 mg) was stirred in methanol (15 ml) and 5M HCl (5 ml) at 20 C for 2 days. TLC indicated that the reaction was progressing slowly and so the mixture was heated to reflux for 6 h. The reaction was allowed to cool and was then basified and extracted with dichloromethane. The dried extract was evaporated and the residue purified on silica gel. Elution with dichloromethane:ethanol:0.880 ammonia; 400:8:1 gave a colourless foam which crystallized on standing (354 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:33]3[CH:38]=[CH:37][C:36]([CH:39]=O)=[CH:35][CH:34]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12.[OH:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:33]3[CH:34]=[CH:35][C:36]([CH2:39][N:47]4[CH2:48][CH2:49][N:44]([CH2:43][CH2:42][OH:41])[CH2:45][CH2:46]4)=[CH:37][CH:38]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12
Reactant: OCCN1CCNCC1
Reactant: COc1cc(-c2nn(-c3ccc(C=O)cc3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: COc1cc(-c2nn(-c3ccc(CN4CCN(CCO)CC4)cc3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 36.4 %

Procedure:
A mixture of N1-{4-[4-amino-1-(4-formylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamide (Intermediate 2) (0.075 g, 0.14 mmol), N-(2-hydroxyethyl)piperazine (0.035 g, 0.27 mmol), and sodium triacetoxyborohydride (0.087 g, 0.41 mmol) in dichloroethane (1.4 mL) was shaken at room temperature for 14 h. Additional portions of N-(2-hydroxyethyl)piperazine (0.010 g, 0.077 mmol) and sodium triacetoxyborohydride (0.020 g, 0.094 mmol) were added and the reaction mixture was shaken for 16 h. 1N NaOH (1.5 mL) was added and the precipitate was collected by filtration and purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 A, 25 cm; 10-60% acetonitrile—0.05 M ammonium acetate over 25 min, 21 mL/min); the fraction eluting from 21.9-22.9 min was collected, concentrated, and lyopholized to afford N1-{4-[4-amino-1-(4-{[4-(2-hydroxyethyl)piperazino]methyl}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamide as a white solid (0.034 g, 0.051 mmol): 1H NMR (d6-DMSO, 400 MHz): δH 9.94 (1H, s), 8.35-8.37 (2H, m), 8.15 (2H, d, J=8.8 Hz), 8.00 (1H, t, J=8.0 Hz), 7.90 (1H, d, J=10.4 Hz), 7.75 (1H, d, J=8.0 Hz), 7.49 (1H, s), 7.46 (2H, d, J=7.2 Hz), 7.40 (1H, d, J=8.4 Hz), 3.96 (3H, s), 3.51 (2H, s), 3.46-3.49 (4H, m), and 2.35-2.44 (8H, m); RP-HPLC (Hypersil C18, 5 μm, 100 Å, 15 cm; 5%-100% acetonitrile—0.1 M ammonium acetate over 15 min, 1 mL/min). Rt 10.92 min. MS: MH+ 664.7.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:16]4[C:17]([NH2:21])=[N:18][CH:19]=[CH:20][C:15]=4[O:14][CH:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[CH2:30][C:31](O)=[O:32].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>CN(C)C=O.O>[F:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[CH2:30][C:31]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:16]4[C:17]([NH2:21])=[N:18][CH:19]=[CH:20][C:15]=4[O:14][CH:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)=[O:32]
Reactant: Nc1nccc2occ(-c3ccc4c(c3)CCN4)c12
Reactant: O=C(O)Cc1cc(F)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nccc2occ(-c3ccc4c(c3)CCN4C(=O)Cc3cc(F)ccc3F)c12
Temperature: 25 °C
Reaction time: 17 h
Yield: 102 %

Procedure:
A mixture of 3-(2,3-dihydro-1H-indol-5-yl)furo[3,2-c]pyridin-4-amine 2HCl (688 mg, 2.016 mmol), 2,5-difluorophenylacetic acid (354 mg, 2.057 mmol), HATU (844 mg, 2.220 mmol), and Hunig's base (1.4 mL, 8.02 mmol) in N,N-Dimethylformamide (DMF) (15 mL) was stirred at room temperature for 17 hr. HPLC indicated complete conversion, so the mixture was poured into water (75 mL), the suspension was stirred for about 10 minutes, and the precipitate was collected by vacuum filtration and dried by suction to give 3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}furo[3,2-c]pyridin-4-amine (834 mg, 2.057 mmol, 102% yield) as a tan solid. LC/MS (ES) m/z=406 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.29 (t, J=8.34 Hz, 2H), 3.96 (s, 2H), 4.31 (t, J=8.46 Hz, 2H), 5.52 (s, 2H), 6.93 (d, J=5.81 Hz, 1H), 7.14-7.34 (m, 4H), 7.41 (s, 1H), 7.87 (d, J=5.81 Hz, 1H), 7.92 (s, 1H), 8.13 (d, J=8.08 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:3]=1[O:4][CH:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].[Br:21]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:19]=[C:18]([CH2:20][Br:21])[CH:17]=[CH:16][C:3]=1[O:4][CH:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)C(Oc1ccc(C)cc1Cl)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Oc1ccc(CBr)cc1Cl)c1ccccc1
Yield: 33.7 %

Procedure:
To a solution of 1.70 g (5.86 mmol) of the product from Step A dissolved in 20 mL of CCl4 was added 1.04 g (5.86 mmol) of N-bromosuccinimide and 50 mg (catalytic amount) of AIBN. The reaction mixture was stirred and heated at reflux for 7 hours, then an additional 0.20 g of NBS was added. The reaction was refluxed for 48 hours, then cooled and concentrated in vacuo. The residue was purified on a silica gel flash chromatography column eluted with 10% ethyl acetate/hexane to afford 0.730 g (34%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:22]([F:25])([F:24])[F:23])[CH2:6][CH:5]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([N+:19]([O-])=O)[CH:13]=3)[N:8]=2)[CH2:4]1.O.O.[Sn](Cl)Cl.C(=O)(O)[O-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1([C:22]([F:24])([F:25])[F:23])[CH2:4][CH:5]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH:13]=3)[NH2:19])[N:8]=2)[CH2:6]1
Reactant: COC1(C(F)(F)F)CC(c2nc(-c3ccc(C)c([N+](=O)[O-])c3)no2)C1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC1(C(F)(F)F)CC(c2nc(-c3ccc(C)c(N)c3)no2)C1
Temperature: 65 °C

Procedure:
A stirring mixture of 5-(3-methoxy-3-(trifluoromethyl)cyclobutyl)-3-(4-methyl-3-nitrophenyl)-1,2,4-oxadiazole (124) (40 mg, 0.112 mmol) and tin (II) chloride dihydrate (101 mg, 0.448 mmol) in ethanol (2 mL) was heated at 65° C. for 2 hours. The reaction was cooled to room temperature and the pH was adjusted between 8-10 with saturated sodium bicarbonate. The slurry was filtered and washed with aqueous ethanol. The solvent was partially reduced and the crude product was extracted with ethyl acetate. The organic was washed with 1× water and dried over anhydrous sodium sulfate. The crude product was purified by silica chromatography to yield 5-(5-(3-methoxy-3-(trifluoromethyl)cyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylaniline (125). 1H NMR (400 MHz, d6-DMSO) δ 10.24 (s, 1H), 10.13 (s, 1H), 8.70 (s, 1H), 8.08 (d, J=1.6 Hz, 1H), 7.95 (dd, J=2.0, 9.6 Hz, 1H), 7.88-7.84 (m, 2H), 7.52 (d, J=8.4 Hz, 1H), 3.92-3.84 (m, 1H), 3.24-3.02 (m, 4H), 2.64 (s, 3H), 2.38 (s, 3H). MS m/z 433.16 (M+1)+.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].[F:5][C:6]([F:17])([F:16])[C:7]1[CH:8]=[C:9]([N:13]=[C:14]=[O:15])[CH:10]=[CH:11][CH:12]=1>CC#N>[CH2:1]([NH:4][C:14]([NH:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:6]([F:5])([F:16])[F:17])[CH:8]=1)=[O:15])[C:2]#[CH:3]
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: C#CCN
Solvent: CC#N
Product: C#CCNC(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85.9 %

Procedure:
A solution of propargyl amine (4.41 g, 5.13 mL, 80 mmol) in MeCN (30 mL) was added to a stirred solution of 3-(trifluoromethyl)phenyl isocyanate (15.0 g, 12.12 mL, 80 mmol) in MeCN (60 mL) under a nitrogen atmosphere. The reaction mixture was cooled with a RT cooling bath and the rate of addition was such that the internal temperature did not exceed 35° C. After 1.5 h the mixture was concentrated in vacuo. EtOAc (10 ml) was added to the residue and the mixture was sonicated for 2 minutes. The resultant slurry was diluted with cyclohexane (40 ml). The mixture was stirred for 10 minutes and the solid was then recovered by filtration. The mother liquors were concentrated in vacuo and the residue dissolved in EtOAc (10 mL). Dilution with cyclohexane (90 ml) precipitated a second batch of product which was recovered by filtration. The two batches were combined as an ethyl acetate solution and concentrated in vacuo to afford the title compound as a fawn solid (16.65 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:14]([O:18][CH3:19])(=[O:17])[CH:15]=[CH2:16]>>[CH3:19][O:18][C:14](=[O:17])[CH2:15][CH2:16][NH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(=O)OC
Reactant: Nc1cccc(-c2ccccc2)c1
Product: COC(=O)CCNc1cccc(-c2ccccc2)c1
Temperature: 90 °C
Reaction time: 5 h
Yield: 41 %

Procedure:
In a round bottom flask was added 3-aminobiphenyl 2.6 g (15.3 mmol), methyl acrylate 1.5 g (16.9 mmol) and cupric acetate 0.1 g, the reaction mixture was stirred 5 hour at 90° C., another 5 equivalent of methyl acrylate 7 g (75 mmol), and 0.25 g of cupric acetate was added, and the reaction mixture was heated for another 5 hours. The crude was purified using silica gel chromatography using 15% of ethyl acetate and petroleum ether. Yield to 1.6 g of oil.
Reaction SMILES: [OH:1][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].II.[Cl:24]Cl>C(Cl)(Cl)(Cl)Cl>[OH:1][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:12]([Cl:24])[CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: ClCl
Reactant: CCOC(=O)C(O)CCc1ccc(C2CCCCC2)cc1
Agent: II
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(O)CCc1ccc(C2CCCCC2)c(Cl)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Ethyl α-hydroxy-γ-(4-cyclohexylphenyl)butyrate 0.38 mole and 6.1 g. of iodine (0.048 mole) and dissolved in 100 ml. of carbon tetrachloride. To this solution is added a solution of 40.4 g. (0.57 mole) of chlorine dissolved in 365 ml. of carbon tetrachloride over a period of 2 hours. During the addition, the temperature of the reaction mixture is maintained at 0°C. The mixture is stirred for 3 hours and allowed to stand with gradual warming to room temperature over 15 hours. The solvent is removed by distillation under reduced pressure. The residue is fractionally distilled to obtain ethyl α-hydroxy-γ-(3-chloro-4-cyclohexylphenyl)butyrate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[NH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>CO>[CH3:17][O:16][C:14]([C:13]1[CH:18]=[CH:19][C:10]([NH:9][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:11][CH:12]=1)=[O:15]
Reactant: O=Cc1cccnc1
Reactant: COC(=O)c1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(NCc2cccnc2)cc1
Temperature: 0 °C

Procedure:
Alternately, 3-pyridinecarboxaldehyde ((61.6 g, 0.575 moles, 1 eq) and methyl 4-aminobenzoate (1-03.87 g, 0.687 moles, 1.2 eq) with p-toluenesulfonic acid (2.19 g, 0.012 moles, 0.02 eq) were refluxed in methanol (25 volumes) for 2 hours. The reaction mixture was cooled to 0° C. and sodium borohydride (67.6 g, 1.787 moles, 3.5 eq) added slowly then it was allowed to warm to ambient overnight. The reaction was concentrated, dissolved with dichloromethane and washed with water then brine, and evaporated to give the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:59])([CH3:58])[C@H:3]([N:44]1[CH2:48][CH2:47][N:46]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([CH3:56])[N:51]=2)[C:45]1=[O:57])[C:4]([NH:6][C@@H:7]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:8][C@H:9]([OH:36])[C@@H:10]([NH:25]C(=O)OCC1C=CC=CC=1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=2)=[CH:14][CH:13]=1)=[O:5].Cl>C(OCC)(=O)C.CO.[OH-].[OH-].[Pd+2]>[NH2:25][C@@H:10]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=2)=[CH:14][CH:13]=1)[C@@H:9]([OH:36])[CH2:8][C@@H:7]([NH:6][C:4](=[O:5])[C@@H:3]([N:44]1[CH2:48][CH2:47][N:46]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([CH3:56])[N:51]=2)[C:45]1=[O:57])[C:2]([CH3:1])([CH3:58])[CH3:59])[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Cc1ccnc(-c2ccc(C[C@H](NC(=O)OCc3ccccc3)[C@@H](O)C[C@H](Cc3ccccc3)NC(=O)[C@@H](N3CCN(Cc4cccc(C)n4)C3=O)C(C)(C)C)cc2)c1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccnc(-c2ccc(C[C@H](N)[C@@H](O)C[C@H](Cc3ccccc3)NC(=O)[C@@H](N3CCN(Cc4cccc(C)n4)C3=O)C(C)(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution containing the product from Example 80D (0.054 g, 0.068 mmol) in a mixture of ethyl acetate (0.3 mL) and methanol (0.3 mL) was treated with Pd(OH)2 on carbon (0.014 g, 20% Pd by wt.) and HCl solution (0.068 mL, 4N in dioxane), stirred under a hydrogen atmosphere (balloon pressure) at 25° C. for 16 hours, filtered through a bed of celite® and rinsed with methanol. The solvent was concentrated to give the title compound as the hydrochloride salt, which was used without further purification.
Reaction SMILES: C([N:4]1[CH2:9][CH:8]=[C:7]([C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:27])[C:15]4[C:25](=[O:26])[NH:24][S:23][C:16]=4[N:17]3[CH:20]3[CH2:22][CH2:21]3)=[CH:12][C:11]=2[F:28])[CH2:6][CH2:5]1)(=O)C>Cl>[NH:4]1[CH2:5][CH:6]=[C:7]([C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:27])[C:15]4[C:25](=[O:26])[NH:24][S:23][C:16]=4[N:17]3[CH:20]3[CH2:22][CH2:21]3)=[CH:12][C:11]=2[F:28])[CH2:8][CH2:9]1
Reactant: CC(=O)N1CC=C(c2cc3c(cc2F)c(=O)c2c(=O)[nH]sc2n3C2CC2)CC1
Agent: Cl
Product: O=c1[nH]sc2c1c(=O)c1cc(F)c(C3=CCNCC3)cc1n2C1CC1
Temperature: 90 °C
Yield: 98 %

Procedure:
Compound 26 (11.1 mg, 0.028 mmol) is dissolved partially in an aqueous solution of hydrochloric acid (6 M, 3.0 mL) in air and heated at 90° C. to give an amber solution. After 22 h of heating, the solvent is removed under reduced pressure. The residue is dissolved in water (˜3 mL) and titrated to pH 7 with dilute sodium hydroxide. The precipitated solid is collected by filtration, washed with water (2×10 mL), and dried in vacuo to give 27 as a yellow solid (98% purity by HPLC). mp >241-242° C. dec. 1H NMR (DMSO-d6/acetic acid-d4 (5:1 v/v)): δ 1.19 (m, 2H, c-Pr CH2), 1.29 (m, 2H, c-Pr CH2), 2.72 (m, 2H, NCH2CH2), 3.33 (m, 2H, NCH2CH2), 3.54 (m, 1H, c-Pr CH), 3.80 (m, 2H, NCH2CH), 6.21 (m, 1H, NCH2CH), 7.87 (br, 1H, aromatic), 7.91 (br, 1H, aromatic). 19F{1H} NMR (DMSO-d6/acetic acid-d4 (5:1 v/v)): δ −121.4 (s). LCMS m/z calcd for C18H16FN3O2S ([M]+) 357. Found 358 ([M+H]+). HRMS m/z calcd for C18H16FN3NaO2S ([M+Na]+) 380.0845. Found 380.0847.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1[CH:13]=[CH:12][C:11]([N:14]=[C:15](Cl)Cl)=[CH:10][CH:9]=1.[N:18]1([CH2:24][C:25]2[CH:26]=[C:27]([CH:37]=[CH:38][CH:39]=2)[O:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]([NH:35][NH2:36])=[O:34])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C1COCC1>[C:11]1([NH:14][C:15]2[O:34][C:33]([NH:32][CH2:31][CH2:30][CH2:29][O:28][C:27]3[CH:37]=[CH:38][CH:39]=[C:25]([CH2:24][N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[CH:26]=3)=[N:35][N:36]=2)[CH:12]=[CH:13][CH:8]=[CH:9][CH:10]=1
Reactant: ClC(Cl)=Nc1ccccc1
Reactant: NNC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: c1ccc(Nc2nnc(NCCCOc3cccc(CN4CCCCC4)c3)o2)cc1
Temperature: 25 °C

Procedure:
1.4 ml (10 mmol) of triethylamine and 0.7 ml (5 mmol) of phenyl isocyanide dichloride are added to 1.5 g (5 mmol) of N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-hydrazine carboxamide in 30 ml of THF and the mixture is stirred at room temperature until the reaction is quantitative. Solid triethylammonium chloride is filtered off, the filtrate is concentrated by evaporation under vacuum, and the solid residue is recrystallised from ethanol. The analytical values are summarized in Table II.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:5]2.[OH:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[C:20]([CH3:27])[CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O.O1CCOCC1>[OH:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:5]3)=[C:20]([CH3:27])[CH:19]=1
Reactant: CCOC(=O)c1ccc2cc(Br)ccc2n1
Reactant: Cc1cc(O)ccc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2cc(-c3ccc(O)cc3C)ccc2n1
Temperature: 60 °C
Yield: 59.8 %

Procedure:
Palladium(II)acetate (3.2 mg, 14.5 μmol) was added to ethyl 6-bromo-2-quinolinecarboxylate (81.1 mg, 289.5 μmol), (4-hydroxy-2-methylphenyl)boronic acid (66.0 mg, 434.2 μmol), triphenylphosphine (7.6 mg, 29.0 μmol), and potassium phosphate (215.1 mg, 1.01 mmol). Then, dioxane (2.8 mL) was added to the mixture, followed by water (289.5 μL), and the reaction mixture was heated open to the atmosphere at 60° C. in an oil bath for 18 hours, then allowed to cool to room temperature. Water was added, followed by ethyl acetate, and the mixture was filtered through Celite®. The filtrate was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate, then filtered and concentrated. The residue was purified by silica gel chromatography eluting with 2:3 ethyl acetate:hexanes to give 53.2 mg (60%) of ethyl 6-(4-hydroxy-2-methylphenyl)-2-quinolinecarboxylate as a solid. 1H NMR (400 MHz, d6-DMSO): δ 9.51 (s, 1H), 8.56 (d, J=9 Hz, 1H), 8.16 (d, J=9 Hz, 1H), 8.13 (d, J=9 Hz, 1H), 7.98 (s, 1H), 7.82 (d, J=9 Hz, 1H), 7.16 (d, J=8 Hz, 1H), 6.74 (s, 1H), 6.71 (dd, J=8, 2 Hz, 1H), 4.43 (q, J=7 Hz, 2H), 2.23 (s, 3H), 1.39 (t, J=7 Hz, 3H). ESI-LCMS m/z 308 (M+H)+.