Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[C:10]([NH:24][C:25]3[CH:26]=[CH:27][C:28]4[S:32][CH:31]=[N:30][C:29]=4[CH:33]=3)=[N:11][CH:12]=[C:13]([C@H:15]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][C@@H:18]3[CH3:23])[CH3:16])[CH:14]=2)[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[C:10]([NH:24][C:25]3[CH:26]=[CH:27][C:28]4[S:32][CH:31]=[N:30][C:29]=4[CH:33]=3)=[N:11][CH:12]=[C:13]([C@H:15]([N:17]3[CH2:22][CH2:21][N:20]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:19][C@@H:18]3[CH3:23])[CH3:16])[CH:14]=2)[N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc(N)nc(-c2cc([C@@H](C)N3CCNC[C@@H]3C)cnc2Nc2ccc3scnc3c2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(N)nc(-c2cc([C@@H](C)N3CCN(S(C)(=O)=O)C[C@@H]3C)cnc2Nc2ccc3scnc3c2)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 10.1 %

Procedure:
A mixture of N-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-((R)-1-((S)-2-methylpiperazin-1-yl)ethyl)pyridin-2-yl)benzo[d]thiazol-5-amine (0.100 g, 0.217 mmol) in THF (5 mL) was chilled to 0° C. in an ice bath, then sodium carbonate (0.115 g, 1.083 mmol) was added to the mixture while stirring. After 10 min, methanesulfonyl chloride (0.051 mL, 0.650 mmol) was added into the mixture slowly via syringe. After the addition, the ice bath was removed and the mixture was allowed to stir under inert atmosphere overnight. The mixture was diluted with chloroform (20 mL) and water (10 mL). The organic layer was extracted with chloroform (3×10 mL). The combined organic extracts were dried (magnesium sulfate), filtered and concentrated in vacuo. The crude material was adsorbed onto silica gel and purified by chromatography through a silica-gel column (25 g), eluting with a 20% mixture of 10:1 methanol/ammonium hydroxide in dichloromethane to give N-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-((R)-1-((S)-2-methyl-4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-2-yl)benzo[d]thiazol-5-amine (0.012 g, 0.022 mmol, 10.26% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 12.02 (s, 1H) 8.92 (s, 1H) 8.65 (s, 1H) 8.60 (s, 1H) 8.26 (d, J=2.35 Hz, 1H) 7.79-7.83 (m, 1H) 7.72 (dd, J=8.61, 1.56 Hz, 1H) 5.55 (s, 2H) 4.05 (q, J=7.04 Hz, 1H) 3.21 (s, 2H) 3.11 (s, 1H) 2.87 (s, 2H) 2.61-2.73 (m, 4H) 2.47-2.60 (m, 4H) 1.34-1.46 (m, 3H) 1.02-1.22 (m, 3H). m/z (ESI, +ve ion) 540.0 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH:4]1[CH2:8][CH2:7][N:6](CC2C=CC=CC=2)[CH2:5]1.[H][H]>[Pd].CO>[CH3:1][N:2]([CH3:16])[CH2:3][CH:4]1[CH2:8][CH2:7][NH:6][CH2:5]1
Reactant: [H][H]
Reactant: CN(C)CC1CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CN(C)CC1CCNC1
Yield: 96.8 %

Procedure:
A mixture of 1.25 g (5.72 mmol) of N,N-dimethyl-1-(phenylmethyl)-3-pyrrolidinemethanamine, 100 ml of methyl alcohol, 0.2 g of 20% palladium on carbon and hydrogen were shaken at a pressure of 55.1 psi. After 16.8 hours the catalyst was filtered and the filtrate evaporated under reduced pressure. The residue was bulb to bulb distilled yielding 0.71 g (97%) N,N-dimethyl-3-pyrrolidinemethanamine as a clear yellow oil.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([S:8][CH3:9])=[CH:6][CH:7]=1.Cl.[CH3:11][C:12]1[CH:13]=[C:14]([C:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH:23]=2)[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[CH3:11][C:12]1[CH:13]=[C:14]([C:18]2[CH2:23][CH2:22][N:21]([C:2]3[N:3]=[N:4][C:5]([S:8][CH3:9])=[CH:6][CH:7]=3)[CH2:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: Cc1cccc(C2=CCNCC2)c1
Reactant: CSc1ccc(Cl)nn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: CSc1ccc(N2CC=C(c3cccc(C)c3)CC2)nn1
Yield: 18 %

Procedure:
A mixture of 3.2 parts of 3-chloro-6-(methylthio)pyridazine, 3.14 parts of 1,2,3,6-tetrahydro-4-(3-methylphenyl)pyridine hydrochloride. 5.3 parts of sodium carbonate and 80 parts of 1-butanol was stirred for 48 hours at reflux temperature. The reaction mixture was evaporated. Water was added. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 0.8 parts (18%) of 3-[3.6-dihydro-4-(3-methylphenyl)-1(2H)-pyridinyl]-6-(methylthio)pyridazine: mp. 129.8° C. (compound 214).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[C:16]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30])[CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:11][C:12]([O:14][CH3:15])=[O:13].CCN(CC)CC.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:38][S:39]([O:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:16](=[C:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:1][S:39]([CH3:38])(=[O:41])=[O:40])[CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH2:17][C:18]([O:20][CH3:21])=[O:19])(=[O:41])=[O:40]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)CC(CCCCCCCCO)=C(CCCCCCCCO)CC(=O)OC
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CC(CCCCCCCCOS(C)(=O)=O)=C(CCCCCCCCOS(C)(=O)=O)CC(=O)OC
Temperature: 0 °C
Reaction time: 14 h
Yield: 81.9 %

Procedure:
To a flamed-dried 20 mL vial fitted with a screw-cap septa was added Dimethyl 3,4-bis(8-hydroxyoctyl)hex-3-enedioate (1 equiv, 0.642 mmol, 275 mg), CH2Cl2 (6 mL), and Et3N (4 equiv, 2.57 mmol, 0.36 mL). The mixture was cooled to 0° C. and DMAP (0.1 equiv, 0.064 mmol, ˜8 mg) was added followed by the dropwise addition of MsCl (3 equiv, 1.93 mmol, 0.15 mL). The reaction was allowed to come to ambient temperature over 14 h at which time the reaction was quenched with sat. aq. NaHCO3 (10 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×15 mL). The combined organic layers were washed with H2O (20 mL), dried with Na2SO4, concentrated in vacuo, and purified by flash column chromatography (45% EtOAc/Hex) to afford Dimethyl 3,4-bis(8-((methylsulfonyl)oxy)octyl)hex-3-enedioate (309 mg, 0.526 mmol, 82%) as an inseparable 2:1 mixture of isomers. TLC Rf=0.24 (45% EtOAc/Hex); 1HNMR (500 MHz): δ 4.20-4.25 (ovlp. t's, 4H), 3.68 (s, 4H), 3.66 (s, 2H), 2.13 (s, 2.7H), 3.11 (s, 1.3H), 3.02 (s, 6H), 2.07-2.17 (4H), 1.71-1.79 (4H), 1.25-1.45 (20H); 13CNMR (125 MHz): δ 172.3, 172.2, 130.7, 130.6, 70.20, 70.18, 51.8, 37.6, 37.4, 37.2, 33.2, 32.8, 31.6, 29.58, 29.55, 29.33, 29.29, 29.1, 29.00, 28.97, 28.3, 28.0, 25.4; FTIR: 2929, 2855, 1732, 1435, 1350, 1170, 972, 935, 833, 721 cm−1; HRMS-ESI: calc. for C36H48NaO10S2 (M+Na)+: 607.2587. found: 607.2570.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:17]#[N:18])=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][O:11]3)[C:6]=2[CH:16]=1>N.CO.[Ni]>[CH3:1][C:2]1[C:3]([CH2:17][NH2:18])=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][O:11]3)[C:6]=2[CH:16]=1
Reactant: Cc1cc2c(cc1C#N)ncn2C1CCCCO1
Agent: [Ni]
Agent: N
Solvent: CO
Product: Cc1cc2c(cc1CN)ncn2C1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.7 %

Procedure:
A suspension of 176 (4.6 g, 19 mmol) Raney-Ni (>15 eq) in 7N NH3 solution in MeOH (10 mL) was stirred under hydrogen at 25° C. for 2 h. The mixture was filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with a MeOH/DCM gradient (3 to 5% MeOH) to afford 3.2 g (69%) of (6-methyl-1-tetrahydropyran-2-yl-benzimidazol-5-yl)methanamine (178) as a yellow oil: MS (ESI) m/z=246 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]1.[CH2:19]=O.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([CH3:19])[CH2:14]1
Reactant: C=O
Reactant: COc1ccc2[nH]cc(CC3CCCNC3)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2[nH]cc(CC3CCCN(C)C3)c2c1
Temperature: 10 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of compound of Description 6 [5-methoxy-3-(piperidin-3-ylmethyl)-1H-indole] (2 g, 0.0082 mol) in methanol (50 ml) was added dropwise aqueous formaldehyde (40%) (5.63 ml; 0.082 mol). The mixture was heated at reflux for 2 hours. The reaction mixture was cooled at 10° C. and then sodium borohydride (0.93 g; 0.025 mol) was added. The resulting mixture was stirred at room temperature for 1.5 hours. The reaction was then quenched with water and the solvent (methanol) was evaporated under vacuum. The product was extracted with ethyl acetate, the organic extract was dried (Mg SO4) and evaporated under vacuum, then the compound was triturated with diethyl ether and dried under vacuum giving the title compound as a solid (1.8 g)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12][NH2:13]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[S:9]([CH3:11])([NH:13][CH3:12])=[O:10])=[CH:4][CH:3]=1
Reactant: CS(=O)Nc1ccc(Br)cc1
Reactant: CN
Product: CNS(C)(=O)=Nc1ccc(Br)cc1

Procedure:
The title compound is prepared from N-(4-bromophenyl)methanesulfinamide and methylamine following a procedure analogous to that described for Intermediate 3 (Step 2). LC (method 1): tR=0.85 min; Mass spectrum (ESI+): m/z=263, 265 [M+H]+.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[Cl:16].C1CCCCC1.C([Li])CCC.[F:28][C:29]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:30]=1[CH:31]=[O:32]>O1CCCC1>[Cl:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[C:3]1[C:4]([CH3:8])=[N:5][N:6]([CH3:7])[C:2]=1[CH:31]([C:30]1[CH:33]=[CH:34][C:35]([F:37])=[CH:36][C:29]=1[F:28])[OH:32]
Reactant: Cc1nn(C)c(Br)c1-c1ccc(F)cc1Cl
Reactant: O=Cc1ccc(F)cc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: Cc1nn(C)c(C(O)c2ccc(F)cc2F)c1-c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5-Bromo-4-(2-chloro-4-fluorophenyl)-1,3-dimethyl-1H-pyrazole (i.e. the product of Synthesis Example 2, Step A) (0.25 g, 0.82 mmol) was dissolved in anhydrous tetrahydrofuran (12 mL), and the mixture was cooled in a dry ice/acetone bath under a nitrogen atmosphere. A cyclohexane solution of n-butyllithium (2.0 M, 0.49 mL, 0.98 mmol) was added dropwise over 5 minutes. After 15 minutes, a solution of 2,4-difluorobenzaldehyde (0.09 mL, 0.82 mmol) in anhydrous tetrahydrofuran (3 mL) was added slowly dropwise, causing the dark red-colored solution to lighten to a yellow color. After 45 minutes, the reaction mixture was quenched by the addition of saturated aqueous NH4Cl solution (˜20 mL) and allowed to warm to ambient temperature. This mixture was extracted with ethyl acetate, and the organic phase was washed with saturated aqueous NH4Cl solution (25 mL) and with brine, dried over Na2SO4, and concentrated to leave a viscous residue. This residue was purified by column chromatography through silica gel eluted with a gradient of ethyl acetate in hexane (7% to 10%) to give the title product, a compound of the present invention, as a white semi-solid (109 mg).
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH:7]=[CH:8][N:9]=1.[H-].[Na+].Cl[CH2:24][C:25]1[N:26]=[C:27](/[CH:30]=[CH:31]/[C:32]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=2[F:39])[O:28][CH:29]=1>>[F:38][C:37]1[CH:36]=[CH:35][CH:34]=[C:33]([F:39])[C:32]=1/[CH:31]=[CH:30]/[C:27]1[O:28][CH:29]=[C:25]([CH2:24][O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][CH2:11][CH2:10][N:6]3[CH:7]=[CH:8][N:9]=[C:5]3[CH2:4][CH2:3][S:2][CH3:1])=[CH:15][CH:16]=2)[N:26]=1
Reactant: Fc1cccc(F)c1/C=C/c1nc(CCl)co1
Reactant: CSCCc1nccn1CCCCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Product: CSCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3c(F)cccc3F)n2)cc1
Yield: 72.4 %

Procedure:
Using 4-[4-[2-[2-(methylsulfanyl)ethyl]-1H-imidazol-1-yl]butyl]phenol (300 mg), 65% sodium hydride (63.1 mg) and 4-chloromethyl-2-[(E)-2-(2,6-difluorophenyl)ethenyl]-1,3-oxazole (290 mg), the same reaction as Example 11-(i) was carried out to yield the titled compound (381 mg) as a colorless amorphous form.
Reaction SMILES: C(=[N:14][C:15]1[CH:20]=[C:19]([C:21]2[N:25]3[N:26]=[C:27]([N:30]4[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]4)[CH:28]=[CH:29][C:24]3=[N:23][C:22]=2[C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=2)[CH:18]=[CH:17][N:16]=1)(C1C=CC=CC=1)C1C=CC=CC=1>Cl>[F:49][C:46]1[CH:47]=[CH:48][C:43]([C:22]2[N:23]=[C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]4)=[N:26][N:25]3[C:21]=2[C:19]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:14])[CH:20]=2)=[CH:44][CH:45]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3nc(-c4ccc(F)cc4)c(-c4ccnc(N=C(c5ccccc5)c5ccccc5)c4)n3n2)CC1
Agent: Cl
Product: Nc1cc(-c2c(-c3ccc(F)cc3)nc3ccc(N4CCNCC4)nn23)ccn1
Temperature: 80 °C

Procedure:
A suspension of 0.80 (1.22 mmol) of tert-butyl 4-[3-[2-(benzhydrylideneamino)pyrid-4-yl]-2-(4-fluorophenyl)imidazo[1,2-b]pyridazin-6-yl]piperazine-1-carboxylate in 70 mL of aqueous hydrochloric acid is maintained at 80° C. for about 1 hour 30 minutes. After cooling, the aqueous phase is washed twice with diethyl ether and then basified by addition of ice-cold aqueous ammonia. The product is extracted with chloroform and the organic phase obtained is washed with water, dried over sodium sulfate and filtered, and the filtrate is concentrated under reduced pressure. The brown solid obtained is purified by chromatography on silica gel (35 g), eluting with a mixture of dichloromethane, methanol and aqueous ammonia (90/10/1). The product obtained is crystallized from 20 mL of refluxing acetonitrile to give 0.38 g of a white powder after cooling, filtering off and drying.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[CH2:13]([CH2:15][NH2:16])[OH:14]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([S:8]([NH:16][CH2:15][CH2:13][OH:14])(=[O:10])=[O:9])[CH:7]=1
Reactant: NCCO
Reactant: Cc1ccc(Br)cc1S(=O)(=O)Cl
Product: Cc1ccc(Br)cc1S(=O)(=O)NCCO
Yield: 57.8 %

Procedure:
Prepared by general procedure III from 5-Bromo-2-methyl-benzenesulfonyl chloride (1.6 g, 6 mmol, synthesized according to J. Am. Chem. Soc., 1940, 62, 511–514) and ethanolamine (1.0 mL, 17 mmol) to give the title compound (1.02 g, 58%) as a pale-yellow solid. MS (ISP) 294.1[(M+H)+], 296.2[(M+2+H)+].
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:21][CH3:22])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[Cl:23][C:24]1[CH:25]=[N:26][CH:27]=[C:28]([Cl:37])[C:29]=1[C:30](=O)[C:31]([O:33]CC)=O.CC(O)=O>COCCO>[Cl:37][C:28]1[CH:27]=[N:26][CH:25]=[C:24]([Cl:23])[C:29]=1[C:30]1[C:31](=[O:33])[N:21]([CH3:22])[C:3]2[N:4]=[C:5]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[CH:11][CH:10]=3)[N:6]=[CH:7][C:2]=2[N:1]=1
Reactant: CNc1nc(Nc2ccc(N3CCOCC3)cc2)ncc1N
Reactant: CCOC(=O)C(=O)c1c(Cl)cncc1Cl
Solvent: COCCO
Solvent: CC(=O)O
Product: Cn1c(=O)c(-c2c(Cl)cncc2Cl)nc2cnc(Nc3ccc(N4CCOCC4)cc3)nc21
Yield: 17.5 %

Procedure:
A mixture of 0.30 g (1 mmol) of 5-amino-4-(methylamino)-2-[[4-(morpholin-4-yl)phenyl]amino]pyrimidine, 0.37 g (1.5 mmol) of ethyl 2-(3,5-dichloropyridin-4-yl)-2-oxoacetate, and 0.3 mL HOAc in 15 mL 2-methoxyethanol as heated under reflux for 16 hours, and worked up as above in 2. Chromatography on alumina, eluting with CH2Cl2/EtOAc (4:1), gives 85 mg (18%) of the title compound (Compound 12 in Tables 1 and 2): mp (MeOH) 243–245° C.
Reaction SMILES: [F:1][CH:2]([F:13])[C:3]1[N:8]=[CH:7][C:6]([C@@H:9]([OH:12])[CH2:10][OH:11])=[CH:5][CH:4]=1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].N1C=CN=C1.O>C(Cl)Cl>[Si:14]([O:11][CH2:10][C@@H:9]([C:6]1[CH:7]=[N:8][C:3]([CH:2]([F:1])[F:13])=[CH:4][CH:5]=1)[OH:12])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC[C@H](O)c1ccc(C(F)F)nc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H](O)c1ccc(C(F)F)nc1
Reaction time: 16 h
Yield: 75 %

Procedure:
To a stirred solution of (R)-1-(6-(difluoromethyl)pyridin-3-yl)ethane-1,2-diol (2.5 g, 13.2 mmol) in dry CH2Cl2 at room temperature were added tert-butyldimethylsilyl chloride (2.19 g, 14.5 mmol) and imidazole (0.99 g, 14.5 mmol). The resulting reaction mixture was stirred for 16 h. After completion of the reaction, the reaction mixture was treated with water and extracted with CH2Cl2. The organic layer was dried over anhydrous Na2SO4 and the solvents were evaporated in vacuo. The residue was purified by column chromatography (SiO2, 20% EtOAc/pet. ether) to afford the title compound (3g, 75% yield). MS: 304 [M+1]+; 1H-NMR (300 MHz, CDCl3): 8.63 (s, 1H), 7.89 (d, 1H, J=8.2 Hz), 7.63 (d, 1H, J=8.2 Hz), 6.64 (t, 1H, J=55.4 Hz), 4.82-4.86 (m, 1H), 3.82 (dd, 1H, J=10.1, 3.7 Hz), 3.58 (dd, 1H, J=10.1, 7.8 Hz), 0.9 (s, 9H), 0.06 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:20])=[C:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:5]=[C:6]([O:8][CH:9]([F:11])[F:10])[CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Cl)=[CH:35][CH:34]=1.CCOC(C)=O>CN(C=O)C>[Br:1][C:2]1[C:3]([Cl:20])=[C:4]([N:12]([CH2:37][C:36]2[CH:39]=[CH:40][C:33]([O:32][CH3:31])=[CH:34][CH:35]=2)[C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])[CH:5]=[C:6]([O:8][CH:9]([F:11])[F:10])[CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(OC(F)F)cc(Br)c1Cl
Reactant: COc1ccc(CCl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2cc(OC(F)F)cc(Br)c2Cl)cc1
Reaction time: 8 h
Yield: 72.9 %

Procedure:
tert-Butyl (3-bromo-2-chloro-5-(difluoromethoxy)phenyl)carbamate (2.78 g, 7.46 mmol) was dissolved in DMF (37.3 ml) at room temperature. NaHMDS (8.95 ml, 8.95 mmol) was added drop wise and the reaction mixture was stirred for 30 min before the addition of 4-methoxybenzyl chloride (1.321 ml, 9.70 mmol). The reaction was allowed to stir overnight. EtOAc (250 mL) was added and the organic layer was washed with 10% LiCl solution (2×, dried over Na2SO4 and concentrated. Column chromatography (120 g SiO2, 0 to 10% EtOAc-hexane gradient elution) afforded tert-butyl (3-bromo-2-chloro-5-(difluoromethoxy)phenyl)(4-methoxybenzyl)carbamate as a clear oil (2.68 g)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[O:26][C@@H:27]([CH3:32])[C:28]([O:30]C)=O)[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:36][NH:37][CH3:38]>>[F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[O:26][C@@H:27]([CH3:32])[C:28]([N:37]([CH3:38])[CH3:36])=[O:30])[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CNC
Reactant: COC(=O)[C@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12
Product: C[C@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12)C(=O)N(C)C
Yield: 56 %

Procedure:
A solution of methyl (2S)-2-[(4-{[1-(3-fluorobenzyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (200 mg, 0.42 mmol) in 6N methanolic dimethylamine (10 ml) was stirred for 18 hours. After evaporation of the solvents, the residue was purified by chromatography on silica gel (eluant: 2% methanol in dichloromethane) to give the title compound as a beige solid (115 mg, 56%); NMR Spectrum 1.59 (d, 3H), 2.94 (s, 3H), 3.15 (s, 3H), 5.71 (s, 2H), 5.86 (q, 1H), 7.07 (m, 3H), 7.30 (d, 1H), 7.36 (m, 2H), 7.74 (m, 2H), 7.84 (m, 1H), 8.17 (s, 1H), 8.51 (s, 1H), 8.55 (s, 1H); Mass spectrum 485.
Reaction SMILES: C1(O)C=CC=CC=1.[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1.[OH:14][C:15]1[CH:31]=[CH:30][C:18]([CH:19]=[C:20]2[C:25](=[O:26])[O:24][C:23]([CH3:28])([CH3:27])[O:22][C:21]2=[O:29])=[CH:17][CH:16]=1>ClCCl.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>[CH3:27][C:23]1([CH3:28])[O:24][C:25](=[O:26])[C:20](=[CH:19][C:18]2[CH:30]=[CH:31][C:15]([O:14][CH:13]3[CH2:12][CH2:11][CH2:10][CH2:9][O:8]3)=[CH:16][CH:17]=2)[C:21](=[O:29])[O:22]1
Reactant: CC1(C)OC(=O)C(=Cc2ccc(O)cc2)C(=O)O1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: Oc1ccccc1
Product: CC1(C)OC(=O)C(=Cc2ccc(OC3CCCCO3)cc2)C(=O)O1

Procedure:
Protection of the phenol with dihydropyran was carried out based on the method given in Miyashita et al. (1977) J. Org. Coed. 42: 3772. Compound 1.1 (500 g, 2 mol) was dissolved in dichloromethane (4 L). 3,4-Dihydro-2H-pyran (250 g, 3 mol) was added to the suspension followed by PPTS (5 g, 20 mmol). The reaction mixture heated to a gentle reflux (3.5 h). HPLC showed ˜90% completion of the reaction. The reaction was concentrated under reduced pressure to ˜2 L of volume. 1 L of acetone was added, and 2 L of solvent was removed under reduced pressure. 1 L of acetone was added, and 1 L of solvent was removed under reduced pressure. 0.5 L of acetone was added, and 0.5 L of solvent was removed under reduced pressure. The resulting slurry of very fine, light yellow crystals was filtered and rinsed sequentially with two 500 mL portions of acetone. The product was dried in a vacuum oven at 50° C. until no further solvent collected in the traps. Compound 52.1 (528 g) was obtained as fine, light yellow crystals. 1H NMR(400 MHz)(DMSO-d6) δ 8.29 (s, 1H); 8.18 (d, 2H, J=8.9 Hz); 7.13 (d, 2H, J=8.9 Hz); 5.67 (m, 1H); 3.70 (m, 1H); 3.60 (m, 1H). 1.9-1.5 (m, 12H). MS ESI (pos.) m/e: 355.1 (M+Na).
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[F:15])[C:8]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23](Cl)(=[O:26])[CH2:24][CH3:25].C(N(CC)C(C)C)(C)C>>[C:23]([O:22][C:19]1[CH:18]=[CH:17][C:16]([C:8]2[C:9]3[C:14](=[C:13]([F:15])[CH:12]=[CH:11][CH:10]=3)[N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:7]=2)=[CH:21][CH:20]=1)(=[O:26])[CH2:24][CH3:25]
Reactant: CCC(=O)Cl
Reactant: Oc1ccc(-c2nn(C3CCCC3)c3c(F)cccc23)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)Oc1ccc(-c2nn(C3CCCC3)c3c(F)cccc23)cc1

Procedure:
Prepared according to Method E from 4-(1-cyclopentyl-7-fluoro-1H-indazol-3-yl)phenol (0.30 g, 1.0 mmol), propanoyl chloride (0.105 mL, 1.2 mmol) and N,N-diisopropylethylamine (0.21 mL, 1.2 mmol) to give 0.284 g to the title compound as a white solid, mp 60–61° C.;
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[O:18][CH3:19]>>[C:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[O:18][CH3:19])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(C(=O)O)ccc1O
Product: COc1cc(C(=O)O)ccc1OC(C)=O
Temperature: 25 °C

Procedure:
Acetic anhydride (72.9 g, 67.4 mL) is added under nitrogen at room temperature to 4-hydroxy-3-methoxybenzoic acid (97.7 g) in xylenes (817 g, 950 mL) while stirring. The stirred mixture is heated to 115°-125° C. and heated at 120°-125° C. for 4 to 20 hours under nitrogen. Part of the liquid is then removed by distillation at about 150° bath temperature to a volume of about 700 ml and the mixture is cooled to room temperature to obtain a slurry of 4-acetoxy-3-methoxybenzoic acid which is again diluted with additional xylenes (224 g, 226 mL). N,N-dimethylformamide (DMF, 1.9 g, 2.0 mL) is added followed by dropwise addition, over 2.5 hours, of oxalyl chloride (90.6 g, 62.2 mL). The reaction mixture is stirred at room temperature for 24 hours to obtain a solution of 4-acetoxy-3-methoxybenzoyl chloride which is used as such in the next step. The xylenes solution is cooled to -14° to -20° C. with a brine solution and diisopropylamine (169 g, 234 mL) is added dropwise over a 45 minute period, at a rate so that the temperature does not exceed 0° C. The reaction mixture is allowed to warm to room temperature and is stirred at room temperatue (17°-20° C.) for 21 hours. The resulting slurry is filtered under vacuum, and the filter cake is further slurried with xylenes (430 mL) and filtered.