Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCCO[C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([CH:22]=[N:23][NH:24]4)=[CH:20][CH:19]=3)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28].[OH:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.[I-].[Na+].C[O:41][CH2:42][CH2:43]OC>>[OH:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][N:35]([CH2:43][CH2:42][O:41][C:11]2[C:10]([C:15]#[N:16])=[C:9]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([CH:22]=[N:23][NH:24]4)=[CH:20][CH:19]=3)[C:8]3[C:13](=[CH:14][CH:5]=[C:6]([O:27][CH3:28])[CH:7]=3)[N:12]=2)[CH2:34][CH2:33]1
Reactant: OCCN1CCNCC1
Reactant: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCCl
Reactant: COCCOC
Agent: [I-]
Agent: [Na+]
Product: COc1ccc2nc(OCCN3CCN(CCO)CC3)c(C#N)c(Nc3ccc4cn[nH]c4c3)c2c1
Temperature: 135 °C

Procedure:
Using an analogous procedure to that described in Example 157, 196.5 mg (0.5 mmol) of the 7-(2-chloro-ethoxy)-4-(1H-indazol-6-ylamino)-6-methoxy-quinoline-3-carbonitrile, 651.0 mg (5.0 mmol) of 1-(2-hydroxyethyl)piperazine and 75.0 mg (0.5 mmol) of sodium iodide in 5 mL of DME was heated at 135° C. for 16 hr. The work up gave 90.5 mg (37.1%) of the product as a yellow solid, m.p. 174° C. (dec.), mass (electrospray, m/e): M+H 488.0.
Reaction SMILES: [Li+].[OH-].[N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]=1[CH2:12][NH:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]2[NH:25][CH:24]([CH2:26][C:27]([O:29]C)=[O:28])[C:23](=[O:31])[N:22]([CH3:32])[CH2:21][C:20]=2[CH:33]=1)=[O:15].CC#N.O>C1COCC1.O>[N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]=1[CH2:12][NH:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]2[NH:25][CH:24]([CH2:26][C:27]([OH:29])=[O:28])[C:23](=[O:31])[N:22]([CH3:32])[CH2:21][C:20]=2[CH:33]=1)=[O:15]
Reactant: COC(=O)CC1Nc2ccc(C(=O)NCc3nc4ccccc4[nH]3)cc2CN(C)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: O
Product: CN1Cc2cc(C(=O)NCc3nc4ccccc4[nH]3)ccc2NC(CC(=O)O)C1=O
Reaction time: 21.5 h

Procedure:
1.0 N LiOH (0.57 mL, 0.57 mmol) was added dropwise at RT to a mixture of methyl (±)-7-[[[(2-benzimidazolyl)methyl]amino]carbonyl]4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (0.11 g, 0.26 mmol) in THF (4 mL) and H2O (5 mL). The resulting light brownish-yellow solution was stirred for 21.5 h, then was concentrated on the rotavap. The resulting residue was lyophilized to give the crude product (0.11 g, 100%) as a yellowish powder. Preparative HPLC. (PRP-1® column, step gradient, 10-20% CH3CN/H2O-0.1% TFA) afforded the title compound: 1H NMR (250 MHz, DMSO-d6) δ 6.45-9.06 (m, 9H), 5.53 (d, J=16 Hz, 1H), 5.13 (m, 1H), 4.86 (d, J=5 Hz, 2H), 3.87 (d, J=17 Hz, 1H), 2.95 (s, 3H), 2.80 (dd, J=17, 9 Hz, 1H), 2.57 (dd, J=17, 5 Hz, 1H); MS (ES) m/e 408.2 (M+H)+. Anal. Calcd for C21H21N5O4.4/3 CF3CO2H.H2O: C, 49.22; H, 4.25; N, 12.13. Found: C, 49.24; H, 4.22; N, 12.11.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:6]=[C:5]2[CH2:22]Br.[CH2:24]([N:26]([C@H:34]([CH2:37][NH:38][CH3:39])[CH2:35][OH:36])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])C.C(N(CC)C(C)C)(C)C>C1COCC1.O>[C:29]([O:28][C:27]([N:26]1[CH2:24][CH2:39][N:38]([CH2:22][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=3)[C:8](=[O:12])[N:7]([S:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)(=[O:14])=[O:15])[CH:6]=2)[CH2:37][C@@H:34]1[CH2:35][OH:36])=[O:33])([CH3:30])([CH3:31])[CH3:32]
Reactant: CCN(C(=O)OC(C)(C)C)[C@@H](CO)CNC
Reactant: O=c1c2ccc(Br)cc2c(CBr)cn1S(=O)(=O)c1ccccc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2cn(S(=O)(=O)c3ccccc3)c(=O)c3ccc(Br)cc23)C[C@@H]1CO
Temperature: 50 °C
Reaction time: 1 h
Yield: 101.4 %

Procedure:
A solution of 6-bromo-4-(bromomethyl)-2-(phenylsulfonyl)isoquinolin-1(2H)-one (Example 11d, 1.75 g) in THF (20 mL) was treated with (R)-tert-butyl ethyl(1-hydroxy-3-(methylamino)propan-2-yl)carbamate (0.98 g) and N,N-diisopropylethylamine (0.80 mL) under nitrogen. The resulting solution was stirred at 50° C. for 1 h. The reaction mixture was diluted with water (300 mL), and extracted with ethyl acetate (250 mL×2). The combined organics were dried (MgSO4), filtered and evaporated. Triturated with diethyl ether/isohexane (1:1) afforded the subtitle compound (2.30 g) as a solid.
Reaction SMILES: [OH:1][C:2]1[NH:3][C:4]2C=CC=C[C:5]=2[N:6]=1.[C:11]([CH2:15][CH2:16][C:17](Cl)=[O:18])([O:13]C)=[O:12].[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[C:11]([CH2:15][CH2:16][C:17]([C:5]1[NH:6][C:2]([OH:1])=[N:3][CH:4]=1)=[O:18])([OH:13])=[O:12]
Reactant: COC(=O)CCC(=O)Cl
Reactant: Oc1nc2ccccc2[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: O=C(O)CCC(=O)c1cnc(O)[nH]1

Procedure:
Carbon disulfide (110 ml), 2-hydroxybenzimidazole (5 g) and 3-carbomethoxypropionyl chloride (5.6 g) are added to a flask containing aluminum chloride (25 g) under an atmosphere of nitrogen. The resulting suspension is refluxed for about 20 hours, quenched with ice cold hydrochloric acid (6N), stirred and filtered. The filtered solid is washed with water and dried in a vacuum oven, affording the desired compound as a solid, which is used in the next step without further purification, M.P. 295° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:17]3[C:18]([CH3:28])=[N:19][N:20]4[CH:25]=[CH:24][C:23]([CH:26]=O)=[CH:22][C:21]=34)[S:10][C:11]=2[C:12]2[NH:16][CH:15]=[N:14][N:13]=2)=[CH:4][CH:3]=1.[N:31]1([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:17]3[C:18]([CH3:28])=[N:19][N:20]4[CH:25]=[CH:24][C:23]([CH2:26][N:34]5[CH2:35][CH2:36][N:31]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:32][CH2:33]5)=[CH:22][C:21]=34)[S:10][C:11]=2[C:12]2[NH:16][CH:15]=[N:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1nn2ccc(C=O)cc2c1-c1nc(Cc2ccc(Cl)cc2)c(-c2nnc[nH]2)s1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1nn2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)cc2c1-c1nc(Cc2ccc(Cl)cc2)c(-c2nnc[nH]2)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70.3 %

Procedure:
A mixture of 3-[4-(4-chlorobenzyl)-5-(4H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-2-methylpyrazolo[1,5-a]pyridine-5-carbaldehyde (0.0563 g, 0.109 mmol), tert-butyl 1-piperazinecarboxylate (60.8 mg, 0.326 mmol) and acetic acid (0.0800 mL, 1.41 mmol) in dry methylene chloride (10 mL) was stirred at rt for 15 min. Sodium triacetoxyborohydride (69.1 mg, 0.326 mmol) was added and the mixture was stirred at rt for 15 hours. The mixture was washed with saturated NaHCO3 solution and the aqueous layer was extracted with DCM. The DCM extract was washed with water, brine, dried over Na2SO4, filtered and evaporated to give a crude product which was purified by column chromatography on silica gel column using MeOH/DCM (0/100 to 5/95) to give solid product (0.0464 g, yield 70.5%). LCMS: (FA) ES+ 605, 607; ES− 603, 605. 1H NMR (400 MHz, CDCl3 and d4-methanol) δ: 8.23-8.25 (d, J=7.03 Hz, 1H), 8.20 (s, 1H), 7.94 (s, 1H), 7.29-7.31 (d, J=8.28 Hz, 2H), 7.15-7.17 (d, J=8.53 Hz, 2H), 6.86-6.89 (dd, J=7.28, 1.76 Hz, 1H), 4.53 (s, 2H), 3.45 (s, 2H), 3.33-3.36 (m, 4H), 2.62 (s, 3H), 2.35 (s, br, 4H), 1.37 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:16]1[C:21]([C:22]2[CH:23]=[N:24][N:25]([C:27]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:26]=2)=[CH:20][CH:19]=[CH:18][N:17]=1>CN1CCCC1=O>[C:27]([N:25]1[CH:26]=[C:22]([C:21]2[C:16]([O:8][C:5]3[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=3)=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:23]=[N:24]1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Clc1ncccc1-c1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: Nc1ccc(Oc2ncccc2-c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)cc1
Temperature: 20 °C
Reaction time: 0.08 h

Procedure:
In 4 separate microwave vessels were added equal amounts of the following (total/4): dissolved 4-aminophenol (0.054 g, 0.498 mmol) in 1-methyl-2-pyrrolidinone (4.7 mL), added cesium carbonate (0.309 g, 0.948 mmol). Each mixture was stirred at 20° C. for 5 minutes, after which was added 2-chloro-3-(1-trityl-1H-pyrazol-4-yl)pyridine (0.200 g, 0.474 mmol) and heated to 200° C. in the microwave for 6 minutes. The solutions were combined and extracted into EtOAc, washed 1×H2O, 1×NaCl, dried with Mg2SO4, filtered through fritted funnel, and concentrated. The crude residue was purified by silica gel chromatography using 25-70% EtOAc/Hexanes. The product fraction were concentrated to yield 4-(3-(1-trityl-1H-pyrazol-4-yl)pyridin-2-yloxy)benzenamine as brown oil. MS m/z=495 [M+1]+. Calc'd for C33H26N4O: 494.59.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([S:15]([C:18]2[C:19]3[C:20]([Cl:28])=[CH:21][N:22]=[CH:23][C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:17])=[O:16])[CH2:10]1)=O)(C)(C)C.C(OC(NC1CCCNC1)=O)(C)(C)C.C(OC(N[C@H]1CCCNC1)=O)(C)(C)C>>[NH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([S:15]([C:18]2[C:19]3[C:20]([Cl:28])=[CH:21][N:22]=[CH:23][C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:17])=[O:16])[CH2:10]1.[ClH:28]
Reactant: CC(C)(C)OC(=O)NC1CCCN(S(=O)(=O)c2cccc3cncc(Cl)c23)C1
Agent: CC(C)(C)OC(=O)NC1CCCNC1
Agent: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Product: Cl
Product: NC1CCCN(S(=O)(=O)c2cccc3cncc(Cl)c23)C1

Procedure:
3-(tert-Butoxycarbonylamino)-1-(4-chloro-5-isoquinolinesulfonyl)piperidine (Intermediate 18) can be prepared by using 3-(tert-butoxycarbonylamino)piperidine in the method of Example 21-1, Step A instead of (S)-3-(tert-butoxycarbonylamino)piperidine, and then used in the method of Step B in a similar manner to obtain the title compound as hydrochloride.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[CH3:12][O-:13].[Na+].Cl>CO>[CH3:12][O:13][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc([N+](=O)[O-])c(O)c1
Temperature: 60 °C
Yield: 93 %

Procedure:
Part A: 5-Fluoro-2-nitrophenol (5.00 g, 31.8 mmol) and methanol (120 mL) were combined and the mixture was treated with sodium methoxide (4.6 mL, 190.8 mmol, 25% w/w solution in MeOH). The reaction mixture was heated at 60° C. for 40 h. The mixture was transferred to a separatory funnel containing cold 1 N HCl and the aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to afford 5-methoxy-2-nitrophenol (5.0 g, 93% yield) as a yellow solid: mp 93.0-94.0° C., 1H NMR (300 MHz, CDCl3): δ 11.05 (s, 1H), 8.03 (d, J=10.3 Hz, 1H), 6.55-6.51 (m, 2H), 3.89 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]2[C:19](=[O:34])[N:20]([CH2:22][CH2:23][CH2:24][N:25]([C:27](OC(C)(C)C)=[O:28])[CH3:26])[N:21]=[C:8]2[N:7]([C:35]2[CH:40]=CC=[C:37]([C:41](F)(F)F)[CH:36]=2)[C:6]=1[CH3:45])=[O:4].[C:46](O)([C:48]([F:51])([F:50])[F:49])=O.[CH2:53](N(CC)CC)C.C(OC(=O)C)(=O)C>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]2[C:19](=[O:34])[N:20]([CH2:22][CH2:23][CH2:24][N:25]([C:27](=[O:28])[CH3:53])[CH3:26])[N:21]=[C:8]2[N:7]([C:35]2[CH:36]=[CH:37][CH:41]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:40]=2)[C:6]=1[CH3:45])=[O:4]
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nn(CCCN(C)C(=O)OC(C)(C)C)c(=O)n2C1c1ccc(C#N)cc1
Reactant: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nn(CCCN(C)C(C)=O)c(=O)n2C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Intermediate 18 (0.12 g, 0.19 mmol) in DCM (2.5 mL), was added TFA (0.25 mL). The resulting mixture was stirred at RT for 1 hour, and then evaporated in vacuo. The resulting residue was taken up in DCM (4 mL), and triethylamine (86 μL, 0.62 mmol) was added, followed by acetic anhydride (47 μL, 0.50 mmol). The reaction mixture was stirred at RT for 30 mins and was then partitioned between EtOAc and water. The organic layer was separated, and the aqueous layer further extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and evaporated in vacuo. The resulting residue was purified by silica gel chromatography eluting with a gradient 0-10% MeOH in DCM to yield the title compound as a white solid (80 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.O.ON1C2C=CC=CC=2N=N1.O/[N:53]=[C:54](\[NH2:62])/[CH2:55][C:56]1[CH:61]=[CH:60][N:59]=[CH:58][CH:57]=1>ClCCl.O>[NH2:62]/[C:54](=[N:53]\[O:10][C:9]([C@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:21])=[O:11])/[CH2:55][C:56]1[CH:61]=[CH:60][N:59]=[CH:58][CH:57]=1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O
Reactant: N/C(Cc1ccncc1)=N\O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O/N=C(\N)Cc1ccncc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 116.6 %

Procedure:
A solution of (2R)-2-(2-tert-butoxy-2-oxoethyl)-5-cyclohexylpentanoic acid (Preparation 1) (500 mg, 1.67 mmol) in dichloromethane (20 ml) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (354 mg, 1.85 mmol), N-methylmorpholine (203 μl, 1.85 mmol) and 1-hydroxybenzotriazole hydrate (227 mg, 1.67 mmol). (1Z)-N′-hydroxy-2-(4-pyridinyl)ethanimidamide (WO 9600720) (374 mg, 1.67 mmol) followed by N-methylmorpholine (369 μl, 3.34 mmol) were added to the reaction mixture which was stirred at room temperature for 18 hours. The reaction mixture was diluted with water (10 ml) and stirred for 20 minutes. The layers were separated via a 5 micron filter cartridge. The organic solvent was removed under reduced pressure to afford the title compound as a yellow oil (840 mg). This was used without further purification in the following step.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][NH2:13]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:13][CH3:12])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CN
Solvent: C1CCOC1
Product: CNc1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 99.3 %

Procedure:
A solution of 2,4-dichloro-5-nitropyrimidine (7.26 g, 37.4 mmol) in THF (100 ml) is cooled to −78° C. A solution of methyl amine (8 M in methanol, 9.35 mL, 74.8 mmol) is added dropwise. The mixture is allowed to warm to room temperature, and concentrated. The residue is partitioned between ethyl acetate and water. The layer is separated and the aqueous layer is extracted with ethyl acetate. The combined organic extracts are washed with brine, dried over Na2SO4, filtered and concentrated to afford the title product (7.0 g). (Note: the product contains 5% regio-isomer, 4-chloro-2-(methylamino)-5-nitropyrimidine). The residue is used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:11](=[O:14])[CH2:12][CH3:13].[F:15]OC(F)(F)F>>[F:15][C:8]1[C:3]([O:2][CH3:1])=[C:4]([C:11](=[O:14])[CH2:12][CH3:13])[C:5]([O:9][CH3:10])=[CH:6][CH:7]=1
Reactant: CCC(=O)c1c(OC)cccc1OC
Reactant: FOC(F)(F)F
Product: CCC(=O)c1c(OC)ccc(F)c1OC

Procedure:
The electrophilic fluorination of compound IV can be performed by passing trifluoromethyl hypofluorite into a stirred mixture of the compound in Freon at -78° C. The reaction is monitored frequently by thin layer chromatography to avoid over-fluorination. The crude product from the reaction is purified by column chromatography to provide 1-(3-fluoro-2,6-dimethoxyphenyl)propan-1-one V which is then reduced with borane in the presence of boron trifluoride in boiling tetrahydrofuran to give 1-fluoro-2,4-dimethoxy-3-propylbenzene VI in excellent yield. Acylation of V with an alkanoyl chloride under conventional Friedel-Crafts, conditions provides a compound of general structure VII which on treatment with boron tribromide in methylene chloride at -78° C. is demethylated to yield the afore-mentioned 1-(2,4-dihydroxy-5-fluoro-3-propylphenyl)alkan-1-one of general formula VIII.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20](Cl)(=[O:22])=[O:21]>>[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:22])=[O:21]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccccc2C)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 2-methylbenzenesulfonyl chloride according to METHOD A, giving 0.22 g (32%) of a pink powder: 1H NMR (CDCl3) δ: 1.3 (3H, t), 2.5 (3H, s), 3.9 (2H, s), 4.2 (2H, q), 6.4 (1H, s), 7.8-7.2 (3H, m), 8.1 (1H, t).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:12]=[C:11]2[C:6]([N:7]=[C:8]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[C:9]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[C:10]2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[N:5]1.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[N:36][CH:35]=1>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:10]2[C:11]3[C:6](=[N:5][N:4]([CH2:3][CH2:2][NH:1][C:33](=[O:40])[C:34]4[CH:39]=[CH:38][CH:37]=[N:36][CH:35]=4)[CH:12]=3)[N:7]=[C:8]([C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[CH:14][CH:15]=1
Reactant: NCCn1cc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1
Reactant: O=C(Cl)c1cccnc1
Product: O=C(NCCn1cc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1)c1cccnc1

Procedure:
Following a similar procedure to that described in example 245, but starting from 2-(2-aminoethyl)-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine (obtained in example 90) and nicotinoyl chloride hydrichloride (obtained in section a), the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][C:11]([OH:13])=O.S(Cl)([Cl:16])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][C:11]([Cl:16])=[O:13]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CC(=O)O)c(Cl)c1
Solvent: Cc1ccccc1
Product: COc1ccc(CC(=O)Cl)c(Cl)c1

Procedure:
160 g of 2-chloro-4-methoxyphenylacetic acid are suspended in 210 ml of toluene, and the suspension is stirred together with 96 ml of thionyl chloride at 80° C. until the evolution of gas has ceased. The volatile components are stripped off, and the residue is distilled. 90 g of an orange oil are obtained (thin-film evaporator 170° C., 0.08 mbar).
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O+:7]([CH3:9])C.[C:10]([NH:14][C:15]1[C:16]([CH3:35])=[N:17][C:18]2[C:23]([N:24]=1)=[C:22]([C:25]1[NH:33][C:32]3[CH2:31][CH2:30][NH:29]C(=O)[C:27]=3[CH:26]=1)[CH:21]=[CH:20][CH:19]=2)([CH3:13])([CH3:12])[CH3:11].CO>C(Cl)Cl>[C:10]([NH:14][C:15]1[C:16]([CH3:35])=[N:17][C:18]2[C:23](=[C:22]([C:25]3[NH:33][C:32]4[CH2:31][CH2:30][N:29]=[C:6]([O:7][CH3:9])[C:27]=4[CH:26]=3)[CH:21]=[CH:20][CH:19]=2)[N:24]=1)([CH3:11])([CH3:13])[CH3:12]
Reactant: C[O+](C)C
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)(C)C
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: ClCCl
Product: COC1=NCCc2[nH]c(-c3cccc4nc(C)c(NC(C)(C)C)nc34)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.8 %

Procedure:
Trimethyloxonium tetrafluoroborate (239 mg, 1.617 mmol, Sigma-Aldrich) was added to a red slurry of 2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (193, 113 mg, 0.32 mmol) in DCM (10 mL) and the resulting mixture was stirred at RT for 1 h when the solid had begun to stick to the side of the flask; MeOH (2 mL) was added to bring all the solid into solution and stir at RT for 16 h when a mixture of product and starting material was observed via lcms. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 100% DCM to 4% 2 M NH3 in MeOH/DCM to give N-(tert-butyl)-8-(4-methoxy-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-2-yl)-3-methylquinoxalin-2-amine (351, 16 mg, 14% yield) as a rust colored solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.66 (s, 9H) 2.55 (s, 3H) 2.82 (t, J=7.73 Hz, 2H) 3.84 (t, J=7.73 Hz, 2H) 3.88 (s, 3H) 4.84 (s, 1H) 6.80 (d, J=1.96 Hz, 1H) 7.36 (t, J=7.82 Hz, 1H) 7.63 (dd, J=8.12, 1.27 Hz, 1H) 7.91 (dd, J=7.63, 1.37 Hz, 1H) 12.54 (br. s., 1H). 13C NMR (101 MHz, CDCl3) δ ppm 21.30, 21.51, 28.68, 46.23, 51.32, 52.37, 100.94, 110.83, 124.51, 124.72, 125.43, 126.11, 131.26, 135.55, 136.41, 136.91, 145.19, 148.40, 161.58. MS (ESI, pos. ion) m/z: 364.4 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:30])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:14]([CH3:15])[C:13]3[CH:16]=[CH:17][C:18]([O:20][C:21]4([C:27](O)=O)[CH:26]=[CH:25][CH:24]=[CH:23][NH:22]4)=[CH:19][C:12]=3[N:11]=2)=[CH:5][CH:4]=1.[N:31]1([CH2:36][CH2:37][NH2:38])[CH2:35][CH2:34]C[CH2:32]1.CN([C:42]([O:46]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH3:30][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[N:14]([CH3:15])[C:13]3[CH:16]=[CH:17][C:18]([O:20][C:21]4([CH:27]5[CH2:32][N:31]([CH2:36][CH2:37][NH:38][CH:42]=[O:46])[CH2:35][CH2:34]5)[CH:26]=[CH:25][CH:24]=[CH:23][NH:22]4)=[CH:19][C:12]=3[N:11]=2)=[CH:7][CH:8]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: NCCN1CCCC1
Reactant: CN(C)c1ccc(Nc2nc3cc(OC4(C(=O)O)C=CC=CN4)ccc3n2C)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)c1ccc(Nc2nc3cc(OC4(C5CCN(CCNC=O)C5)C=CC=CN4)ccc3n2C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 4-(2-{[4-(dimethylamino)phenylamino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylic acid (1 eq) in tetrahydrofuran was added 2-pyrrolidinylethylamine (2 eq), HBTU (2 eq) and N,N-diisopropylethylamine (4 eq) and stir at ambient temperature for 16 h. The mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was concentrated and preparative chromatography yielded [4-(2-{[4-(dimethylamino)phenyl]amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-pyrrolidinylethyl)carboxamide. MS: MH+=498.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=2)[CH2:4][C:3]1([CH3:22])[CH3:21].[Cl:23][C:24]1[C:25]([C:33]([F:36])([F:35])[F:34])=[C:26]([CH2:30][CH2:31][NH2:32])[CH:27]=[CH:28][CH:29]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:23][C:24]1[C:25]([C:33]([F:34])([F:35])[F:36])=[C:26]([CH:27]=[CH:28][CH:29]=1)[CH2:30][CH2:31][NH:32][C:11]1[N:10]=[C:9]([NH:8][C@@H:5]2[CH2:6][CH2:7][C@H:2]([OH:1])[C:3]([CH3:22])([CH3:21])[CH2:4]2)[C:14]([C:15]#[N:16])=[CH:13][N:12]=1
Reactant: CC1(C)C[C@H](Nc2nc(S(C)(=O)=O)ncc2C#N)CC[C@@H]1O
Reactant: NCCc1cccc(Cl)c1C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1(C)C[C@H](Nc2nc(NCCc3cccc(Cl)c3C(F)(F)F)ncc2C#N)CC[C@@H]1O
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 39.1 %

Procedure:
A mixture of 4-(((1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl)amino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (75 mg, 0.23 mmol), 2-(3-chloro-2-(trifluoromethyl)phenyl)ethanamine (100 mg, crude) and DIEA (85 mg, 0.66 mmol) in THF (2 mL) was stirred at 100° C. in a microwave reactor for 1.5 h. After cooling to room temperature, the reaction mixture was concentrated and the residue was purified by standard methods to afford the title compound (42.2 mg, 0.090 mmol, 39% yield). 1H NMR (400 MHz, CD3OD) δ (ppm) 8.10-8.03 (m, 1H), 7.48-4.41 (m, 2H), 7.30 (m, 1H), 4.31-4.28 (m, 1H), 3.73-3.69 (m, 1H), 3.63-3.56 (m, 1H), 3.39-3.37 (m, 1H), 3.17-3.14 (m, 2H), 1.88-1.44 (m, 6H), 0.97 (s, 3H), 0.96 (s, 3H). MS (ESI) m/z 468.1 [M+H]+.