Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:45])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@H:12]3[O:18][C@@H:17]([CH2:19][O:20]C(=O)C4C=CC=CC=4)[C@:15](C(=O)C4C=CC=CC=4)([OH:16])[C@:13]3(C(=O)C3C=CC=CC=3)[OH:14])[C:6]=2[N:7]=1.C[O-].[Na+]>CO>[NH2:1][C:2]1[NH:3][C:4](=[O:45])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@H:12]3[O:18][C@@H:17]([CH2:19][OH:20])[C@H:15]([OH:16])[C@@H:13]3[OH:14])[C:6]=2[N:7]=1
Reactant: Nc1nc2c(sc(=O)n2[C@H]2O[C@@H](COC(=O)c3ccccc3)[C@@](O)(C(=O)c3ccccc3)[C@@]2(O)C(=O)c2ccccc2)c(=O)[nH]1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1nc2c(sc(=O)n2[C@H]2O[C@@H](CO)[C@H](O)[C@@H]2O)c(=O)[nH]1
Reaction time: 64 h
Yield: 67.8 %

Procedure:
5-Amino-3-(2′,3′,5′-O-tribenzoyl-β-L-ribofuranosyl)thiazolo[4,5-d]pyrimidine-2,7(6H)-dione 33 (1.09 g, 1.717 mmol) was dissolved in methanol (25 mL) and sodium methoxide (5.4 M in methanol, 0.64 mL) added. The solution stood at room temperature for 64 h. Most methanol was evaporated and water (20 mL) and Amberite H-Form (1.0 g) added. The suspension was stirred gently for 20 min and the resin filtered by suction, washed with water (2×10 mL). The filtrate was concentrated and the crude product was purified by crystallization from methanol to give 368 mg of 5-Amino-3-β-L-ribofuranosylthiazolo[4,5d]pyrimidine-2,7(6H)-dione 34 as a colorless solid.
Reaction SMILES: [Sn](Cl)Cl.[Br:4][C:5]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[C:6]=1[NH2:7].[OH-].[Na+]>Cl>[NH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:5]([Br:4])[C:6]=1[NH2:7]
Reactant: Nc1c(Br)cccc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Product: Nc1cccc(Br)c1N
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirring slurry of tin(II) chloride dihyrate (11.8 g, 52.3 mmol) in conc. hydrochloric acid (55 mL) was added 2-bromo-6-nitroaniline (2.84 g, 13.1 mmol), and the resulting mixture was stirred at room temperature for 5 minutes—an exotherm was observed. The mixture was then stirred at reflux for 30 minutes. After cooling to room temperature, the slurry was poured onto crushed ice (200 mL), and the pH was adjusted to 14 by the addition of sodium hydroxide pellets. The resulting mixture was washed with diethyl ether (5×100 mL), then the combined organic layers were dried (MgSO4) and concentrated in vacuo. The crude product was purified by chromatography on a Biotage SP1 apparatus, on a 40S silica gel column, eluting with 5% to 50% ethyl acetate in dichloromethane, yielding the product as a yellow-brown oil, which solidified upon standing (2.02 g, 87%) 1H NMR (400 MHz, CDCl3): δ 6.97 (1H, dd, J=1.4, 8.0 Hz), 6.64 (1H, dd, J=1.4, 7.8 Hz), 6.56 (1H, t, J=7.9 Hz), 3.61 (3H, s); m/z (ES+) 187, 189 [MH+].
Reaction SMILES: [CH2:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([OH:10])[C:4]=2[CH2:3][CH2:2]1.C[O-].[Na+].[I-].[K+].Br[CH:17]([C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[CH:24][CH:23]=1)[C:18]([O:20][CH3:21])=[O:19]>CO.C1C=CC=CC=1.O>[CH2:1]1[C:9]2[C:4](=[C:5]([O:10][CH:17]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]4[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=4)=[CH:24][CH:23]=3)[C:18]([O:20][CH3:21])=[O:19])[CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Oc1cccc2c1CCC2
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: C[O-]
Agent: [I-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CO
Solvent: O
Product: COC(=O)C(Oc1cccc2c1CCC2)c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
To a solution of 3.36 g of 4-indanol, 1.188 g of sodium methoxide and 50 mg of potassium iodide in 40 ml of methanol is added 7.11 g of methyl α-bromo-α-[p-(p-chlorophenoxy)phenyl]acetate in 10 ml of benzene. The mixture is refluxed overnight and then poured into 100 ml of water. The mixture is extracted with 2×75 ml of ether. The combined extracts are washed with 50 ml of 5% NaOH, 50 ml of water, 50 ml saturated brine, and dried (MgSO4). Evaporation of the solvent yields a yellow oil. Chromatography on 100 g of silica gel (benzene, 400 ml) yields the product as a light yellow oil which solidifies on standing.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][C:14](OC(C)=O)=[O:15]>C1COCC1>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:14](=[O:15])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Solvent: C1CCOC1
Product: CC(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (750 mg, 3.26 mmol; Example 1, Step H), TEA (1363 μL, 9.78 mmol), and Ac2O (646 μL, 6.85 mmol) were placed in THF (15 mL) at room temperature and stirred for 30 minutes. The reaction was then filtered, and the solid product was dried to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)acetamide (595 mg, 2.19 mmol, 67% yield).
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([C:10]([O:12]CC)=[O:11])[C:5]([CH3:15])=[C:4]([CH3:16])[C:3]=1[C:17](=[O:35])[CH:18]=[CH:19][C:20]1[CH:25]=[C:24](C(C)(C)C)[C:23](O)=[C:22](C(C)(C)C)[CH:21]=1.[Cl:36]C1C=CC(C=O)=CC=1>>[OH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([C:10]([OH:12])=[O:11])[C:5]([CH3:15])=[C:4]([CH3:16])[C:3]=1[C:17](=[O:35])[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:36])=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1c(C)c(C)c(C(=O)C=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(O)c1OC
Reactant: O=Cc1ccc(Cl)cc1
Product: COc1c(O)c(C(=O)C=Cc2ccc(Cl)cc2)c(C)c(C)c1C(=O)O

Procedure:
This compound was synthesized from 2′-hydroxy-4′-(ethoxycarbonyldimethylmethyloxy)acetophenone (starting material 1) and 4-chlorobenzaldehyde according to general method 2 described earlier.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:27]2[CH:28]=[N:29][C:30]([O:33]C)=[CH:31][CH:32]=2)=[N:5][C:6]([NH:10][C:11]([C:13]2([C:16]3[CH:26]=[CH:25][C:19]4[O:20][C:21]([F:24])([F:23])[O:22][C:18]=4[CH:17]=3)[CH2:15][CH2:14]2)=[O:12])=[CH:7][C:8]=1[CH3:9])#[N:2].I[Si](C)(C)C>C(#N)C>[C:1]([C:3]1[C:8]([CH3:9])=[CH:7][C:6]([NH:10][C:11]([C:13]2([C:16]3[CH:26]=[CH:25][C:19]4[O:20][C:21]([F:24])([F:23])[O:22][C:18]=4[CH:17]=3)[CH2:14][CH2:15]2)=[O:12])=[N:5][C:4]=1[C:27]1[CH:32]=[CH:31][C:30](=[O:33])[NH:29][CH:28]=1)#[N:2]
Reactant: COc1ccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc(C)c2C#N)cn1
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: Cc1cc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc(-c2ccc(=O)[nH]c2)c1C#N
Temperature: 55 °C

Procedure:
N-(3-cyano-6′-methoxy-4-methyl-2,3′-bipyridin-6-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (0.150 g, 0.323 mmol) was dissolved in acetonitrile (7.2 mL). Iodotrimethylsilane (129.3 mg, 92 μL, 0.65 mmol) was added and the reaction mixture was heated to 55° C. for 5 hours. The crude reaction mixture was then evaporated to dryness, re-dissolved in a minimum of dichloromethane and purified on 12 g of silica gel utilizing a gradient of 0-100% ethyl acetate in hexanes (0.125 g, 86%). ESI-MS m/z calc. 450.1. found 451.1 (M+1)+. Retention time 1.60 minutes. 1H NMR (400 MHz, CDCl3) 8.17 (s, 1H), 8.07-8.03 (m, 2H), 7.82 (s, 1H), 7.26 (dd, J=1.7, 8.2 Hz, 1H), 7.19-7.16 (m, 2H), 6.69 (d, J=10.4 Hz, 1H), 2.58 (s, 3H), 1.80-1.75 (m, 2H), 1.27-1.22 (m, 2H).
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:4]=2[N:3]=1.Cl.[Cl:13][C:14]1[C:15]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:16][CH:17]=[CH:18][CH:19]=1.C(N(CC)C(C)C)(C)C>>[Cl:13][C:14]1[C:15]([N:20]2[CH2:21][CH2:22][N:23]([C:2]3[NH:6][C:5]4[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:4]=4[N:3]=3)[CH2:24][CH2:25]2)=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: Clc1cccnc1N1CCNCC1
Reactant: Cc1ccc2nc(Cl)[nH]c2c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2nc(N3CCN(c4ncccc4Cl)CC3)[nH]c2c1

Procedure:
The reaction of 2-chloro-6-methyl-1H-benzoimidazole (0.202 g, 1.59 mmol, Example 14b), 1-(3-chloropyridin-2-yl)piperazine hydrochloride (0.373 g, 1.22 mmol, Example 3b) and N,N-diisopropylethylamine (0.56 mL, 3.2 mmol, Aldrich) under the conditions of Example 3c afforded the title compound as a white solid. M.p. 258-259° C. MS (ESI, pos. ion) m/z: 328 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C@@H:9]2[C:18]3[C:13](=[C:14]([F:20])[CH:15]=[CH:16][C:17]=3[F:19])[O:12][CH2:11][C@H:10]2[CH:21]=O)=[CH:4][CH:3]=1.[CH2:23]([CH2:25][NH2:26])[OH:24].[BH4-].[Na+].CO>C1COCC1.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH:9]([NH:26][CH2:25][CH2:23][OH:24])[CH:10]2[CH2:21][C:18]3[C:13](=[C:14]([F:20])[CH:15]=[CH:16][C:17]=3[F:19])[O:12][CH2:11]2)=[CH:6][CH:7]=1
Reactant: O=C[C@@H]1COc2c(F)ccc(F)c2[C@H]1Sc1ccc(Cl)cc1
Reactant: NCCO
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: OCCNC(Sc1ccc(Cl)cc1)C1COc2c(F)ccc(F)c2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trans-4-(4-chloro-phenylsulfanyl)-5,8-difluoro-chroman-3-carbaldehyde (2.2 g, 5.9 mmole) and ethanolamine (1.1 g, 18 mmole) were dissolved in 20 ml THF. The reaction was stirred at room temperature overnight. 2 g Sodium borohydride and 10 ml MeOH were added and the reaction was stirred for three hours. 100 ml water and 100 ml EtOAc were added. The organic layer was washed with water, dried over sodium sulfate and concentrated. The product was purified by column chromatography (EtOAc/hexane from 25/75 to 100/0 in 45 minutes). Yield, 0.40 g, 17.5%. 1H NMR (CDCl3 400 MHz) δ 7.45 (d, J=8.1 Hz, 2H), 7.31 (d, J=8.1 Hz, 2H), 6.92-7.00 (m, 1H), 6.54-6.60 (m, 1H), 4.62 (dd, J=8.8 and 2.2 Hz, 1H), 4.48 (br, 1H), 4.38 (dt, J=11.7 and 2.2 Hz, 1H), 3.55 (t, J=5.1 Hz, 2H), 2.67 (dd, J=12.4 and 7.3 Hz, 1H), 2.62 (t, J=5.1 Hz, 2H), 2.48 (dd, J=12.4 and 8.1 Hz, 1H), 2.09 (m, 1H).
Reaction SMILES: [OH-].[Na+].[CH:3]1([O:9][N:10]2[C:15]([CH3:17])([CH3:16])[CH2:14][CH:13]([OH:18])[CH2:12][C:11]2([CH3:20])[CH3:19])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH2:21]([CH:23]1[O:25][CH2:24]1)Cl>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH:3]1([O:9][N:10]2[C:11]([CH3:20])([CH3:19])[CH2:12][CH:13]([O:18][CH2:21][CH:23]3[O:25][CH2:24]3)[CH2:14][C:15]2([CH3:16])[CH3:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: CC1(C)CC(O)CC(C)(C)N1OC1CCCCC1
Reactant: ClCC1CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)CC(OCC2CO2)CC(C)(C)N1OC1CCCCC1
Temperature: 0 °C

Procedure:
78.4 g (1.96 mol) of sodium hydroxide are dissolved in 80 ml of water under argon in a 750 ml sulfonation flask fitted with a stirrer, thermometer and dropping funnel. 100 g (392 mmol) of 1-cyclohexyloxy-2,2,6,6-tetramethyl-4-hydroxypiperidine and 12.6 g (39.2 mmol) of tetrabutylammonium bromide, dissolved in 250 ml of toluene, are added. The mixture is heated to 50°-55° C., and 90.7 g (980 mmol) of epichlorohydrin are added dropwise in the course of 45 minutes. During this operation, the mixture is stirred vigorously. The reaction mixture is stirred at 55° C. for a further 3 hours. It is then poured onto 1 liter of ice-water and the organic phase is separated off and washed once with water. The organic phase is dried over sodium sulfate, decolorized with active charcoal, filtered and evaporated. The residue is distilled over a Vigreux column: boiling point 116°-117° C./0.06 mmHg.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[N+:9]([C:12]1[CH:13]=[C:14]([C:18]2[N:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[O:20][N:19]=2)[CH:15]=[CH:16][CH:17]=1)([O-])=O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.O>[F:25][C:23]([F:24])([F:26])[C:21]1[O:20][N:19]=[C:18]([C:14]2[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=2)[NH2:9])[N:22]=1
Reactant: O=[N+]([O-])c1cccc(-c2noc(C(F)(F)F)n2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S([O-])S(=O)[O-]
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1cccc(-c2noc(C(F)(F)F)n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.2 %

Procedure:
Sodium dithionite (1.61 g, 9.2 mmol) and a catalytic amount of tetra-n-butylammonium bromide (20 mg) were added to a solution of 3-(3-nitrophenyl)-5-(trifluoromethyl)-1,2,4-oxadiazole (1.6 g, 6.1 mmol) in THF—H2O (30 mL, 1:1 v/v), and the reaction mixture was stirred at room temperature for 2 h and monitored by TLC (petroleum ether/EtOAc 1:1). Solvent was removed under reduced pressure and the product was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 30-35% EtOAc in petroleum ether) to afford 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)aniline (0.8 g, yield 57%). 1H NMR (300 MHz, CDCl3) δ 7.52-7.49 (dt, J=7.7 Hz, 1.2 Hz, 1H), 7.42 (m, 1H), 7.30 (t, J=8.0 Hz, 1H), 6.89-6.86 (ddd, J=7.9 Hz, 2.4 Hz, 0.9 Hz, 1H), 3.87 (br s, 2H). MS (ESI) m/z: Calculated for C9H6F3N3O: 229.05. found: 230.0 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH2:15]O)[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2].C(Br)(Br)(Br)[Br:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:18][CH2:15][C:13]1[CH:12]=[C:7]([CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cc(CO)cc(C(C)(C)C)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc(CBr)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 98.6 %

Procedure:
To a solution of methyl 3-tert-butyl-5-hydroxymethylbenzoate VII (9.50 g, 42.7 mmol) and carbon tetrabromide (17.25 g, 52.0 mmol) in dichloromethane (50 mL) was slowly added triphenylphosphine (13.6 g, 52.0 mmol) over the period of 20 minutes, and the mixture was stirred at room temperature for 25 minutes. The reaction mixture was concentrated under reduced pressure and the residue was suspended in ethyl acetate. The precipitate was removed by filtration and the filtrate was concentrated. The crude material was purified by a silica gel chromatography (hexanes/ethyl acetate, 4:1), and the product was re-crystallized form ethyl acetate/hexanes to afford methyl 3-bromomethyl-5-tert-butylbenzoate VIII (12.0 g, 42.1 mmol, 99%) as a white solid: 1H NMR (CDCl3) δ 1.45 (s, 9H), 3.7 (s, 3H), 4.4 (s, 2H), 7.6 (s, 1H), 7.8 (s, 1H), 8.0 (s, 1H); 13C NMR (CDCl3) δ 31.3 (3C), 33.2, 36.0, 52.3, 126.9, 127.5, 130.6, 130.7, 137.9, 152.4, 167.0.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:3]=1.[I-:13].[Na+].II.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[I:13][C:3]1[C:2]([CH3:1])=[N:6][NH:5][C:4]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: [I-]
Reactant: Cc1cc(-c2ccccc2)n[nH]1
Agent: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1n[nH]c(-c2ccccc2)c1I
Temperature: 100 °C
Reaction time: 10 h
Yield: 70.5 %

Procedure:
To a solution of 5-methyl-3-phenyl-1H-pyrazole (1.5 g, 9.48 mmol) in THF (20 mL) and water (20 mL), were added sodium iodide (1.42 g, 9.48 mmol), iodine (3.61 g, 14.22 mmol), and K2CO3 (1.96 g, 14.22 mmol) at room temperature. The reaction was warmed to 100° C. and stirred for 10 h. After cooling to room temperature, the reaction was poured into water and extracted with ethyl acetate, which was washed with 2.0 M aq. sodium thiosulfite and saturated. NaHCO3 successively. The extract was dried over MgSO4 and concentrated under reduced pressure to give a semi-solid, which was recrystallized from 10% ethyl acetate in hexane to give the title compound (1.9 g). LCMS m/z=285.5 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([F:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13]C)[CH:8]=2)[N:3]=1.[C:15]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[C:20]([Cl:27])[CH:19]=1)([OH:17])=[O:16]>>[Cl:27][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[C:2]1[CH:11]=[C:10]([F:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:13])[CH:8]=2)[N:3]=1)[C:15]([OH:17])=[O:16]
Reactant: COc1ccc2nc(Cl)cc(F)c2c1
Reactant: O=C(O)c1ccc(B(O)O)c(Cl)c1
Product: O=C(O)c1ccc(-c2cc(F)c3cc(O)ccc3n2)c(Cl)c1

Procedure:
Followed Scheme 2, B conditions starting with 2-chloro-4-fluoro-6-methoxyquinoline (Intermediate 7) and 4-carboxy-2-chlorophenylboronic acid. 1H NMR (MeOD 400 MHz): δ 8.20 (d, J=1.2 Hz, 1H), 8.10 (dd, J=8.0, 1.6 Hz, 1H), 8.02 (d, J=9.2, 1.2 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.52-7.45 (m, 2H), 7.47 (d, J=2.4 Hz, 1H). MS (ESI): m/z 317.9 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]2[N:13]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)(=[O:16])=[O:15])[CH:12]=[C:11]([CH2:25][N:26](C)[C:27](=O)OC(C)(C)C)[C:10]=2[F:35])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].C(OCC)(=O)C.[ClH:42]>C(OCC)(=O)C.CC(O)C>[ClH:42].[F:35][C:10]1[C:11]([CH2:25][NH:26][CH3:27])=[CH:12][N:13]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)(=[O:16])=[O:15])[C:9]=1[C:8]1[C:3]([C:1]#[N:2])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2C#N)c1
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)c2cccc(OC)c2)c(-c2cccnc2C#N)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
To a solution of tert-butyl ({5-(2-cyanopyridin-3-yl)-4-fluoro-1-[(3-methoxyphenyl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (476 mg) in ethyl acetate (3 mL) and 2-propanol (2 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (6 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a white solid (yield 265 mg, 64%).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]3([CH2:19][CH2:18]3)[CH2:9][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:22][C:23]1[C:37]([O:38][CH3:39])=[CH:36][C:26]([C:27]([NH:29][C@@H:30]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31]2)=[O:28])=[C:25]([F:40])[CH:24]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)CC(O)C>[CH:13]1([N:10]2[CH2:9][C:8]3([CH2:19][CH2:18]3)[C:7](=[O:20])[N:6]([CH3:21])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[C:37]([O:38][CH3:39])=[CH:36][C:26]([C:27]([NH:29][C@@H:30]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31]5)=[O:28])=[C:25]([F:40])[CH:24]=4)=[N:12][C:11]2=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COc1cc(C(=O)N[C@@H]2CCN(C)C2)c(F)cc1N
Reactant: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)CC(C)O
Product: COc1cc(C(=O)N[C@@H]2CCN(C)C2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Yield: 46.5 %

Procedure:
2′-chloro-9′-cyclopentyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 130; 100 mg, 0.32 mmol), 4-amino-2-fluoro-5-methoxy-N-[(3R)-1-methylpyrrolidin-3-yl]benzamide (Intermediate 182; 87 mg, 0.32 mmol) and 4-toluenesulphonic acid monohydrate (154 mg, 0.81 mmol) were heated in 4-methyl-2-pentanol (3 mL) at 140° C. for 3 hours. The mixture was cooled and absorbed on to an SCX column, washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (80 mg, 46%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:8]=[CH:9][N:10]([CH:12]2[CH2:17][CH2:16][N:15]([C:18](OC(C)(C)C)=O)[CH2:14][CH2:13]2)[CH:11]=1.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[O:46]=[C:47]1[NH:56][CH:55]=[CH:54][C:53]2[N:52]=[C:51]([C:57]3[CH:64]=[CH:63][C:60](C=O)=[CH:59][CH:58]=3)[C:50](C3C=CC=CC=3)=[CH:49][C:48]1=2>C(Cl)Cl>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:8]=[CH:9][N:10]([CH:12]2[CH2:13][CH2:14][N:15]([CH2:18][C:60]3[CH:59]=[CH:58][C:57]([C:51]4[CH:50]=[CH:49][C:48]5[C:47](=[O:46])[NH:56][CH:55]=[CH:54][C:53]=5[N:52]=4)=[CH:64][CH:63]=3)[CH2:16][CH2:17]2)[CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cnc(-c3ccccn3)c2)CC1
Reactant: O=Cc1ccc(-c2nc3cc[nH]c(=O)c3cc2-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]ccc2nc(-c3ccc(CN4CCC(n5cnc(-c6ccccn6)c5)CC4)cc3)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-(4-pyridin-2-yl-1H-imidazol-1-yl)piperidine-1-carboxylate (300 mg, 0.9 mmol) in CH2Cl2 (4 mL) was added trifluoroacetic acid (2 mL). The resulting solution was stirred at room temperature for 1 h. The solvents were removed in vacuo and the residue was dried under vacuum for a further 2 h. The residue was dissolved in a solution of triethylamine (1 mL) in CH2Cl2 (3 mL). The reaction mixture was stirred for 1 h at room temperature and sodium triacetoxyborohydride (381 mg, 1.8 mmol), 4-(5-oxo-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)benzaldehyde (295 mg, 0.9 mmol) and molecular sieves were added. Stirring was continued at room temperature for 16 h and the reaction quenched by addition of methanol. The residue was purified by HPLC (phenomenex column, 35%-100% acetonitrile/water+0.1% TFA) to afford 3-phenyl-2-(4-{[4-(4-pyridin-2-yl-1H-imidazol-1-yl)piperidin-1-yl]methyl}phenyl-1,6-naphthyridin-5(6H)-one trifluoroacetic acid salt as a yellow oil. 1H NMR (500 MHz, CD3OD) δ 8.56 (m, 3H), 8.28 (s, 1H), 8.10 (m, 1H), 7.99 (m, 1H), 7.45 (m, 1H), 7.42 (m, 5H), 7.21 (m, 3H), 7.15 (m, 2H), 6.77 (m, 1H), 4.62 (m, 1H), 4.34 (s, 2H), 3.55 (m, 2H), 3.21 (m, 2H), 2.39 (m, 4H).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].C(O)C[OH:13]>>[CH2:4]([CH2:3][OH:13])[CH2:5][CH2:6][OH:8].[C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: OCCO
Agent: O=C(O)CCCCC(=O)O
Product: OCCCCO

Procedure:
The following were mixed with 1,6-HG (39.3 parts) to prepare homogeneous glycol components: a polyester diol (243.5 parts) having an Mn of 1000 yielded from 1, 4-BD, and adipic acid; a polyester diol (243.5 parts) having an Mn of 2600 yielded from 1,4-BD, ethylene glycol, and adipic acid; and a polyester diol (324.7 parts) having an Mn of 1500 yielded from 1,6-HG and isophthalic acid. The glycol components were mixed with HDI, and the mixture was supplied at a flow rate ratio of 100:17.5 from a hopper of a biaxial extruder, the temperature of which was adjusted to about 190° C. The mixture was kneaded, and simultaneously resinified to yield a polyurethane resin.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]=[CH:14][C:15]1[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=1)[CH2:21][N:20]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:19][CH2:18]3)[CH:7]=[CH:6]2)#[N:2].[N+](=[CH2:34])=[N-]>C1COCC1.C(OCC)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]1[CH2:34][CH:14]1[C:15]1[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=1)[CH2:21][N:20]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:19][CH2:18]3)[CH:7]=[CH:6]2)#[N:2]
Reactant: C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(C=Cc3ccc4cc(C#N)ccc4c3)ccc2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCc2cc(C3CC3c3ccc4cc(C#N)ccc4c3)ccc2C1

Procedure:
A solution of Example 42I (207 mg, 0.5 mmol) and Pd(OAc)2 (5 mg) in THF (100 mL), at 0° C. was treated with a 0° C. 2M solution of diazomethane in diethyl ether (20 mL), warmed to room temperature over 10 minutes, treated with Pd(OAc)2 (5 mg) and 2M diazomethane in diethyl ether (20 mL), and treated two more times with Pd(OAc)2 and 2M diazomethane after 10 minute stirring intervals. After the final addition, the mixture was stirred for 1 hour, filtered through diatomaceous earth (Celite®) and concentrated. The concentrate was purified by flash column chromatography on silica gel with 10% ethyl acetate/hexanes to provide the desired product.