Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[Cl:7][S:8]([OH:11])(=O)=[O:9]>>[Cl:1][C:2]1[S:3][C:4]([S:8]([Cl:7])(=[O:11])=[O:9])=[CH:5][C:6]=1[S:8]([Cl:7])(=[O:11])=[O:9]
Reactant: O=S(=O)(O)Cl
Reactant: Clc1cccs1
Product: O=S(=O)(Cl)c1cc(S(=O)(=O)Cl)c(Cl)s1
Temperature: 30 °C

Procedure:
2-Chlorothiophene (40 g) was added to stirred chlorosulphonic acid (400 ml) over a five minute period. The solution was then heated at 80°-90° C. for four hours, cooled to 30° C., and added to ice-water with stirring. The product was filtered off, washed with water and dried. The yield was 84 g.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].C[Al](C)C.[NH2:13][C:14]1[C:15]2[N:16]([C:20]([CH:27]3[CH2:30][CH2:29][CH2:28]3)=[N:21][C:22]=2[C:23](OC)=[O:24])[CH:17]=[CH:18][N:19]=1>C1(C)C=CC=CC=1>[NH2:13][C:14]1[C:15]2[N:16]([C:20]([CH:27]3[CH2:28][CH2:29][CH2:30]3)=[N:21][C:22]=2[C:23]([NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[NH2:8])=[O:24])[CH:17]=[CH:18][N:19]=1
Reactant: COC(=O)c1nc(C2CCC2)n2ccnc(N)c12
Reactant: Nc1ccccc1N
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Nc1ccccc1NC(=O)c1nc(C2CCC2)n2ccnc(N)c12
Temperature: 120 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A suspension of 1,2-phenylenediamine (60 mg, 0.6 mmol) in toluene (2.0 mL) was treated with a 2M solution of trimethylaluminum in toluene (0.5 mL) effecting the formation of a pink solution. After 5 min this solution was treated with solid methyl 8-amino-3-cyclobutylimidazo[1,5-a]pyrazine-1-carboxylate (30 mg, 0.1 mmol) and the mixture heated at 120° C. for 30 min then stirred at rt overnight. The mixture was then partitioned between 2M NaOH (10 mL) & EtOAc (10 mL) and stirred for 15 min. The organic layer was separated and the aqueous layer extracted further with EtOAc (3×10 mL). The combined organics were washed with brine, dried and concentrated in vacuo to give ˜85% pure 8-amino-N-(2-aminophenyl)-3-cyclobutylimidazo[1,5-α]pyrazine-1-carboxamide which was used without purification.
Reaction SMILES: [CH2:1]1[CH:4]([C:5]([OH:7])=[O:6])[NH:3][CH2:2]1.[H-].[Na+].[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[C:19]([CH2:25][C:26]3[CH:27]=[CH:28][C:29](F)=[N:30][CH:31]=3)[C:18]=2[F:33])[CH:14]=[CH:15][CH:16]=1.Cl>CCOC(C)=O.O.CN(C=O)C>[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[C:19]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([N:3]4[CH2:2][CH2:1][CH:4]4[C:5]([OH:7])=[O:6])=[N:30][CH:31]=3)[C:18]=2[F:33])[CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)C1CCN1
Reactant: COc1ccc(Cc2ccc(F)nc2)c(F)c1-c1cccc(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(Cc2ccc(N3CCC3C(=O)O)nc2)c(F)c1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 6 %

Procedure:
A vial was charged with D,L-azetidine-2-carboxylic acid (56 mg, 0.56 mmol) and DMF (1 mL). Then NaH (60% dispersion in mineral oil, 33 mg, 0.84 mmol) was added slowly (gas evolution). After 2 min. of stirring at room temperature was added 5-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-fluoro-pyridine (P-456). The heterogeneous white reaction mixture was stirred and heated at 120° C. After overnight stirring the reaction mixture was cooled to rt and was diluted in EtOAc (5 mL). The mixture was poured into a reparatory funnel with 0.5M HCl (1 mL) and water (5 mL). The aqueous layer was extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (15 mL), dried over Na2SO4 and concentrated in-vacuo. The crude was purified by silica gel column chromatography, eluted with dichloromethane in methanol (9:1) to produce 7.7 mg (6% yield) of 1-[5-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-azetidine-2-carboxylic acid (P-446) as a cream solid.
Reaction SMILES: Cl[C:2]([F:32])([F:31])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([NH:18]CC2C=CC=CC=2)[C:4]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27].C(N(CC)CC)C.Cl>C(O)C.[Pd]>[F:32][CH:2]([F:31])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([NH2:18])[C:4]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OCC)c1NCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1N
Reaction time: 18 h

Procedure:
A mixture of 340 g (0.722 mol) of product from Example 99, 87.67 g (0.866 mol) of triethylamine and 10.00 g of 5% Pd/C (50% water coated) in 700 ml of ethanol was hydrogenated at 50° C. under 446 kPa of H2 pressure for 18 hours. Then 150 ml of 18% HCl (0.722 mol) was added, and the mixture was hydrogenated at 50° C. under 446 kPa of H2 pressure for 2 hours. The reaction mixture was filtered through celite, and concentrated in vacuo to remove the ethanol. The residue was caken up in H2O, and extracted with diethyl ether. The ether phase was dried (MgSO4) and concentrated in vacuo to 161.7 g (65%) of a brown oil, 90pure by GC analysis. Then 5.0 g were urified by HPLC in 5ethyl acetate/cyclohexane affording 3.9 g of product as a yellow solid; mp 29-30° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](N1C=CN=C1)(N1C=CN=C1)=[O:17].[CH3:28][O:29][CH:30]([O:46][CH3:47])[CH2:31][NH:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:35][CH:34]=1>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:13][C:16](=[O:17])[N:32]([CH2:31][CH:30]([O:46][CH3:47])[O:29][CH3:28])[C:33]2[CH:38]=[CH:37][C:36]([O:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:35][CH:34]=2)=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: COC(CNc1ccc(Oc2ccccc2)cc1)OC
Solvent: CN(C)C=O
Product: COC(CN(C(=O)Nc1ccc(OCc2ccccc2)cc1)c1ccc(Oc2ccccc2)cc1)OC
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
A solution of 4-benzyloxyaniline (199 mg) in dimethylformamide (1 ml) was added dropwise to a solution of carbonyldiimidazole (162 mg) in dimethylformamide (1 ml) at 0° C. After a reaction time at 0° C. of 10 minutes, the reaction was allowed to continue at room temperature for 20 minutes. Then (2,2-dimethoxyethyl)-(4-phenoxyphenyl)amine (273 mg) was added, and the mixture was heated at 80° C. for 1.5 hours. Cooling was followed by dilution with water and extraction with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The product with the molecular weight of 498.58 (C30H30N2O5); MS (ESI): 499 ([M+H]+), was obtained in this way.
Reaction SMILES: [OH-:1].[Na+].[CH:3]1([C:6]2[N:15]([CH2:16][C:17]3[CH:22]=C[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4C(OC)=O)=[CH:19][CH:18]=3)[C:9]3=[N:10][CH:11]=[CH:12][C:13]([CH3:14])=[C:8]3[N:7]=2)[CH2:5][CH2:4]1.[CH2:33]([OH:35])[CH3:34]>>[CH:3]1([C:6]2[N:15]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[C:34]([C:33]([OH:1])=[O:35])[CH:22]=3)[C:9]3=[N:10][CH:11]=[CH:12][C:13]([CH3:14])=[C:8]3[N:7]=2)[CH2:5][CH2:4]1
Reactant: COC(=O)c1ccccc1-c1ccc(Cn2c(C3CC3)nc3c(C)ccnc32)cc1
Reactant: CCO
Reactant: [OH-]
Agent: [Na+]
Product: Cc1ccnc2c1nc(C1CC1)n2Cc1ccc(-c2ccccc2)c(C(=O)O)c1
Yield: 81 %

Procedure:
Ethanol (40 ml) and a 10% aqueous solution (20 ml) of sodium hydroxide were added to 1.32 g (3.3 mmol) of 2-cyclopropyl-3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-7-methyl-3H-imidazo[4,5-b]pyridine, followed by heating under reflux for 2 hours. After the reaction liquid was cooled, it was concentrated to about one-half the initial volume, and neutralized with 2N hydrochloric acid and acetic acid. The crystal thus precipitated was recovered by filtration and recrystallized from aqueous ethanol to give 1.03 of the title compound (yield 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]3[N:15]=[CH:16][C:17](I)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:30])([CH3:29])[CH3:28])=[CH:23][CH:22]=1)#[CH:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]3[N:15]=[CH:16][C:17]([C:20]#[C:19][C:21]4[CH:26]=[CH:25][C:24]([C:27]([OH:30])([CH3:28])[CH3:29])=[CH:23][CH:22]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc2c(I)cnn12
Reactant: C#Cc1ccc(C(C)(C)O)cc1
Product: Cc1cc(-c2ccc(Cl)cc2)nc2c(C#Cc3ccc(C(C)(C)O)cc3)cnn12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-3-iodo-7-methyl-pyrazolo[1,5-a]pyrimidine (example 292) (185 mg, 0.5 mmol) and 2-(4-ethynyl-phenyl)-propan-2-ol (example D.4) (80 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (94 mg, 47%). MS (ISP) 402.3 [(M+H)+]; mp 112-115° C.
Reaction SMILES: [CH2:1]([N:5]([CH2:43][CH2:44][CH2:45][CH3:46])[C:6]([C:8]1[N:9]=[C:10]([C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=2[C:31]([N:33]2[CH2:42][CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:34]2)=[O:32])[N:11](COCC[Si](C)(C)C)[CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:43]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([C:8]1[N:9]=[C:10]([C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=2[C:31]([N:33]2[CH2:42][CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:34]2)=[O:32])[NH:11][CH:12]=1)=[O:7])[CH2:44][CH2:45][CH3:46]
Reactant: CCCCN(CCCC)C(=O)c1cn(COCC[Si](C)(C)C)c(-c2ccc(C(=O)OC)cc2C(=O)N2CCc3ccccc3C2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCN(CCCC)C(=O)c1c[nH]c(-c2ccc(C(=O)OC)cc2C(=O)N2CCc3ccccc3C2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.9 %

Procedure:
To a solution methyl 4-(4-(dibutylcarbamoyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (180 mg, 0.28 mmol) in DCM (4 mL) was added trifluoroacetic acid (4 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and stirring was continued for 4 h. The reaction mixture was concentrated in vacuo. The resulting residue was dissolved in DCM and washed with sat. NaHCO3 solution. The organic layer was dried over Na2SO4 and concentrated to give crude product. The crude material was purified by flash chromatography (gradient from 0 to 5% methanol/CHCl3) to provide the title compound (130 mg, 91%). 1H NMR (CD3OD) δ 8.25-8.06 (m, 2H), 8.00-7.50 (m, 2H), 7.28-6.83 (m, 4H), 4.36 (br s, 1H), 4.01 (br s, 4H), 3.60-3.24 (m, 6H), 2.88-2.69 (m, 2H), 1.60-1.52 (m, 4H), 1.36-1.30 (m, 4H), 1.05-0.90 (m, 6H); MS(ESI−) m/z 515.2 (M−H)−.
Reaction SMILES: [CH2:1]([C@@H:3]1[O:5][CH2:4]1)[Cl:2].[N:6]1([S:12](N)(=[O:14])=[O:13])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[C:16](O)(C(F)(F)F)=O.C(N(C(C)C)CC)(C)C>C(O)C>[Cl:2][CH2:1][C@H:3]([OH:5])[CH2:4][N:9]1[CH2:10][CH2:11][N:6]([S:12]([CH3:16])(=[O:14])=[O:13])[CH2:7][CH2:8]1
Reactant: NS(=O)(=O)N1CCNCC1
Reactant: O=C(O)C(F)(F)F
Reactant: ClC[C@H]1CO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CS(=O)(=O)N1CCN(C[C@@H](O)CCl)CC1
Reaction time: 18 h

Procedure:
(R)-Epichlorohydrin (3.10 mL, 39.5 mmol) was added to a stirred solution of piperazine sulfonamide.TFA (10.0 g, 35.9 mmol) and diisopropylethylamine (6.26 mL, 35.9 mmol) in ethanol (150 mL) at room temperature. The reaction mixture was stirred for 18 h and a further amount of (R)-epichlorohydrin was added (0.28 mL, 3.6 mmol) and stirred for an additional 3 h. The reaction mixture was concentrated in vacuo and the white solid was suspended in ethanol (150 mL) and stirred for 2 days. The solid was collected by filtration and washed with cold ethanol to afford the title compound (5.69 g) as a white solid which was used without further purification. (m/z): [M+H]+ calcd for C8H17ClN2O3S, 257.07; found 257.2. 1H NMR (DMSO-d6): δ (ppm) 2.37 (dd, 1H), 2.45 (dd, 1H), 2.50-2.58 (m, 4H), 2.86 (s, 3H), 3.09 (m, 4H), 3.55 (dd, 1H), 3.65 (dd, 1H), 3.84 (m, 1H), 5.09 (d, 1H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Br:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.O>CN(C=O)C>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(I)cc1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: BrCCCCOc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
To a stirring solution of 4-iodophenol (100 g, 0.5 mol) and K2CO3 (70 g, 0.5 mol) in DMF (400 mL) was added 1,4 dibromobutane (100 mL, 0.84 mol) over a period of 1 hr. The solution was stirred overnight at room temperature under Ar. H2O (1000 mL) was added and the reaction mixture was extracted with CH2Cl2. The organic layer was then washed with 1000 mL of brine, dried over MgSO4, concentrated to gave a white solid (100 g); 1H NMR (CD3Cl): δ 2.15-1.87 (m, 6H), 3.50-3.20 (m, 4H), 3.94 (t, 2H), 6.85 (d, 2H), 7.55 (d, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[CH:16]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]3[C:24](=[O:28])[NH:25][C:26](=[O:27])[C:13]=3[C:12]=2[C:11]2[CH:10]=[C:9]([OH:29])[CH:8]=[CH:7][C:6]1=2.[NH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[OH:29][C:9]1[CH:8]=[CH:7][C:6]2[N:5]([CH2:4][CH2:3][CH2:2][N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:17]3[CH:16]=[C:15]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:14]4[C:24](=[O:28])[NH:25][C:26](=[O:27])[C:13]=4[C:12]=3[C:11]=2[CH:10]=1
Reactant: O=C1NC(=O)c2c1c(-c1ccccc1)cc1c2c2cc(O)ccc2n1CCCBr
Reactant: C1CNCCN1
Product: O=C1NC(=O)c2c1c(-c1ccccc1)cc1c2c2cc(O)ccc2n1CCCN1CCNCC1
Reaction time: 20 h
Yield: 55 %

Procedure:
Bromide (204) (70 mg, 0.16 mmol) prepared as described in example 173 was reacted with piperazine according to The procedure described in example 179 except that the reaction was performed at room temperature for 20 h, to give amine (215) (40 mg, 55%) as a yellow powder, mp 178–183° C. 1H NMR δ [(CD3)2SO] 11.0 (br s, 1H), 9.35 (br s, 1H), 8.40 (d, J=2.4 Hz, 1H), 7.78 (s, 1H), 7.62 (m, 2H), 7.56 (d, J=8.8 Hz, 1H), 7.45 (m, 3H), 7.14 (dd, J=8.8, 2.4 Hz, 1H), 4.49 (t, J=6.3 Hz, 2H), 2.52 (m, 4H), 2.12 (m, 6H), 1.91 (m, 2H). Found: C, 69.31; H, 5.97; N, 11.49. C27H26N4O3.4/5H2O requires: C, 69.16; H, 5.93; N, 11.94.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2.Cl[CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28]>CN(C=O)C>[Br:3][C:4]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2[CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: C[Si](C)(C)CCOCCl
Reactant: Fc1ccc(Oc2cc(Br)c3cn[nH]c3c2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ncc2c(Br)cc(Oc3ccc(F)cc3F)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 25.8 %

Procedure:
Sodium hydride (98 mg of 60% weight in mineral oil, 2.45 mmol) was washed with hexanes and added to 5 mL of dry DMF, and the mixture was placed under nitrogen atmosphere and cooled to 0° C. 4-Bromo-6-(2,4-difluoro-phenoxy)-1H-indazole (0.50 g, 1.54 mmol) dissolved in 5 mL dry DMF was added to the reaction mixture. The reaction mixture was stirred for 30 minutes at room temperature, then cooled to 0° C. again. (2-Chloromethoxy-ethyl)-trimethyl-silane (0.386 g, 2.32 mmol) was added, and the reaction mixture was stirreed for 21 hours at room temperature under nitrogen. The reaction mixture was partitioned between water and ethyl acetate, and the organic phase was separated, washed with brine and water, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was chromatographed through silica (0%-25% EtOAc in hexanes) to give 0.181 g of 4-bromo-6-(2,4-difluoro-phenoxy)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole, MS(M+H)=455.
Reaction SMILES: [N:1]1([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:24])C=1>ClCCl.C(=O)(O)[O-].[Na+]>[CH:3]12[O:24][CH:4]1[CH2:5][N:1]([C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH2:2]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(OCc1ccccc1)N1CC=CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CC2OC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To solution of benzyl 2,5-dihydro-1H-pyrrole-1-carboxylate (10.0 g, 49.2 mmol) in dichloromethane (197 mL) at 0° C. was added m-CPBA (16.98 g, 98 mmol) in several portions and the resulting mixture was allowed to warm to rt and stir overnight. The resulting white heterogeneous mixture obtained was diluted with dichloromethane (150 mL) and aq. sat. sodium bicarbonate (150 mL). The mixture was stirred and the resulting layers were separated and the organic portion was washed successively with aq. sat. sodium bicarbonate (150 mL), water, brine, before drying over anhyd. sodium sulfate, filtering and concentrating in vacuo to a colorless oil (˜14 g). This crude material was subjected to purification by preparative chromatography using Hex/EtOAc mixtures as the eluant and an 80 g silica gel cartridge. Fractions containing the major product were combined and concentrated to afford the title compound (9.60 g, 43.8 mmol, 89%) as a colorless oil. LCMS: 220.2 (M+H)+; 1H NMR (400 MHz, METHANOL-d4): δ 7.41-7.31 (m, 4H), 5.14 (d, J=1.1 Hz, 2H), 3.84-3.74 (m, 4H), 3.42 (t, J=13.8 Hz, 2H).
Reaction SMILES: Cl.Cl.Cl.[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([C:16]1[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=3)[N:17]=1)[CH:10]=[C:9]2[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.Br[CH2:39][CH2:40][CH2:41][OH:42].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:13]([CH:12]=[C:11]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=4)[N:17]=3)[CH:10]=[C:9]2[N:32]2[CH2:33][CH2:34][N:35]([CH2:39][CH2:40][CH2:41][OH:42])[CH2:36][CH2:37]2)=[CH:14][CH:15]=1
Reactant: COc1cccc(CNc2nccc(-c3cc(N4CCNCC4)c4cc(OC)ccc4c3)n2)c1
Reactant: OCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1cccc(CNc2nccc(-c3cc(N4CCN(CCCO)CC4)c4cc(OC)ccc4c3)n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.6 %

Procedure:
A mixture of 4-(6-methoxy-4-(piperazin-1-yl)naphthalen-2-yl)-N-(3-methoxybenzyl)pyrimidin-2-amine tris hydrochloride salt (1.0 g, 1.78 mmol), 3-bromopropan-1-ol (250 mg, 1.80 mmol), potassium carbonate (1.23 g, 8.91 mmol) and acetonitrile (20 ml) was stirred for 16 hours at room temperature. The mixture was diluted with water (100 ml) and extracted with dichloromethane (3×50 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (24 g) using a gradient of ethyl acetate-hexanes to afford 3-(4-(7-methoxy-3-(2-((3-methoxybenzyl)amino)pyrimidin-4-yl)naphthalen-1-yl)piperazin-1-yl)propan-1-ol 193 as a yellow solid (600 mg, 66%). 400 M Hz 1H NMR (DMSO-d6) δ: 8.35 (d, J=5.2 Hz, 1H), 8.29 (s, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.80 (bm, 2H), 7.42 (s, 1H), 7.23 (m, 3H), 6.99 (bm, 2H), 6.78 (dd, J=2.4 and 8.4 Hz, 1H), 4.55 (m, 3H), 3.91 (s, 3H), 3.71 (s, 3H), 3.50 (m, 3H), 3.06 (bm, 6H), 2.73 (bm, 3H), 1.67 (m, 2H); LCMS[M+H]: 514.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C@H:19]3[CH2:23][CH2:22][CH2:21][NH:20]3)=[CH:13][CH:12]=2)[N:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2.Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>>[C:29]([O:28][C:26](=[O:27])[CH2:25][N:20]1[CH2:21][CH2:22][CH2:23][C@@H:19]1[CH2:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([N:3]2[C:2]([Cl:1])=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[CH:9]3)=[N:4]2)=[CH:16][CH:15]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Clc1c2ccccc2nn1-c1ccc(OC[C@H]2CCCN2)cc1
Product: CC(C)(C)OC(=O)CN1CCC[C@@H]1COc1ccc(-n2nc3ccccc3c2Cl)cc1
Yield: 82.3 %

Procedure:
The title compound was prepared from 3-chloro-2-[4-((R)-1-pyrrolidin-2-ylmethoxy)-phenyl]-2H-indazole (0.4 g, 1.1 mmol) and t-butyl bromoacetate (0.27 g, 1.4 mmol) using the procedure of step 7 of the Example 5 to provide the title compound (0.4 g, 80%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14](=[O:23])[C:15]2[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=2[F:22])[CH:8]=1)[CH3:2].[F:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>>[CH2:1]([O:3][C:4](=[O:24])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:15]2[CH:20]=[C:19]([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]([F:25])[CH:31]=3)[CH:18]=[CH:17][C:16]=2[F:22])=[O:23])[CH:8]=1)[CH3:2]
Reactant: OB(O)c1cccc(F)c1
Reactant: CCOC(=O)C=Cc1cccc(NC(=O)c2cc(Br)ccc2F)c1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2cc(-c3cccc(F)c3)ccc2F)c1

Procedure:
The phenyl bromide (106) (100 mg, 0.25 mmol) was coupled to 3-fluoro-phenylboronic acid (39 mg, 0.28 mmol) using Method E. The crude product was purified by column chromatography eluting with 20% EtOAc in heptane to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[CH3:23].[F:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:32]([NH:31][C:28]2[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=2)=[O:33])=[CH:18][C:17]=1[CH3:23]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3C)c2cc1OC
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3C)c2cc1OC
Yield: 58 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-3-methyl-aniline (50 mg) was dissolved in chloroform (3 ml), and p-fluorophenyl isocyanate (22 μl ) was then added to the solution. The mixture was heated under reflux overnight. The precipitated crystal was collected by filtration and was washed to give 42 mg (yield 58%) of the title compound.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[C:11]([OH:20])=[CH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2>ClCCl.[Cl-].[Zr+4].[Cl-].[Cl-].[Cl-]>[Cl:1][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:19]=[C:10]([CH3:9])[C:11]=1[OH:20]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc2ccccc2cc1O
Agent: [Zr+4]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc2ccccc2c(Cl)c1O
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of N-chlorosuccinimide (8.02 g, 60.05 mmol) in dichloromethane (475 mL) at −78° C. was added zirconium(IV) chloride (2.80 g, 12.01 mmol), followed by 3-methyl-naphthalen-2-ol (CombiBlocks, 9.5 g, 60.05 mmol) under argon. The reaction mixture was stirred at −78° C. for 5 minutes, the cooling bath was removed and the reaction was stirred at room temperature for 5 h. The reaction was quenched with saturated sodium bicarbonate solution and stirred for 5 minutes. The mixture was diluted with H2O, extracted with dichloromethane (3×) and the combined organic layer was dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give 1-chloro-3-methyl-naphthalen-2-ol. 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J=8.2 Hz, 1H), 7.72 (d, J=8.2 Hz, 1H), 7.54 (s, 1H), 7.52 (dd, J=8.2, 8.2 Hz, 1H), 7.36 (dd, J=8.2, 8.2 Hz, 1H), 5.99 (s, 1H), 2.47 (s, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.Cl.[CH3:26][C@@H:27]1[CH2:31][CH2:30][C@@H:29]([CH3:32])[NH:28]1>>[CH3:26][C@@H:27]1[CH2:31][CH2:30][C@@H:29]([CH3:32])[N:28]1[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: C[C@@H]1CC[C@@H](C)N1
Reactant: CCN(CC)C(=O)c1ccc(-c2ccc(OCCCCl)cc2)cc1
Agent: Cl
Product: CCN(CC)C(=O)c1ccc(-c2ccc(OCCCN3[C@H](C)CC[C@H]3C)cc2)cc1

Procedure:
The product from Example 2A and (2R,5R)-2,5-dimethylpyrrolidine hydrochloride were processed as described in Example 10F to provide the title compound.