Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[N:10]([CH2:11][CH2:12][CH2:13][C:14](OC(C)(C)C)=[O:15])[C:9](=[O:21])[CH:8]([CH3:22])[N:7]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:6]1)=[O:4].Cl.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH2:59]1[C:61]2([CH2:66][CH2:65][NH:64][CH2:63][C@H:62]2[OH:67])[CH2:60]1.C(N(CC)CC)C>C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3]([C@H:5]1[N:10]([CH2:11][CH2:12][CH2:13][C:14]([N:64]2[CH2:65][CH2:66][C:61]3([CH2:59][CH2:60]3)[C@H:62]([OH:67])[CH2:63]2)=[O:15])[C:9](=[O:21])[CH:8]([CH3:22])[N:7]([C:23]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24])[CH2:6]1)=[O:4]
Reactant: O[C@@H]1CNCCC12CC2
Reactant: COC(=O)[C@@H]1CN(C(=O)OCc2ccccc2)C(C)C(=O)N1CCCC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CN(C(=O)OCc2ccccc2)C(C)C(=O)N1CCCC(=O)N1CCC2(CC2)[C@H](O)C1
Reaction time: 2 h

Procedure:
To 0.15 g (0.3 mmol) of (S)-4-(3-tert-butoxycarbonyl-propyl)-6-methyl-5-oxo-piperazine-1,3-dicarboxylic acid 1-benzyl ester 3-methyl ester in 5 ml of THF was added 1.5 ml of 37% hydrochloric acid. The reaction was stirred for 2 h after which time it was evaporated to dryness. The residue was redissolved in 2 m of DMF, 0.14 g (0.4 mmol) of HATU and 0.06 g (0.4 mmol) of (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (intermediate 2) were added followed by 0.2 ml (1.2 mmol) of triethylamine. The reaction was stirred for 1 h after which time the solvent was evaporated, the residue redissolved in EtOAc, washed with water, brine, dried (Na2SO4) and concentrated to give after flash silica gel column (CH2Cl2/MeOH 95:5) the title compound in quantitative yield as a colorless foam. MS: 502.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]4[O:32][C:31]([CH:33]=O)=[CH:30][CH:29]=4)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[NH2:35][CH2:36][CH2:37][S:38]([CH3:41])(=[O:40])=[O:39].O.[C:43]1([CH3:53])[CH:48]=[CH:47][C:46]([S:49]([OH:52])(=[O:51])=[O:50])=[CH:45][CH:44]=1>CO.ClCCl.[Pd]>[CH3:53][C:43]1[CH:44]=[CH:45][C:46]([S:49]([O-:52])(=[O:51])=[O:50])=[CH:47][CH:48]=1.[CH3:41][S:38]([CH2:37][CH2:36][NH:35][CH2:33][C:31]1[O:32][C:28]([C:25]2[CH:24]=[CH:23][C:22]3[N:21]=[CH:20][N:19]=[C:18]([NH:17][C:4]4[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]5[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=5)=[C:2]([Cl:1])[CH:3]=4)[C:27]=3[CH:26]=2)=[CH:29][CH:30]=1)(=[O:40])=[O:39]
Reactant: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CS(=O)(=O)CCN
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CS(=O)(=O)CCNCc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 25 °C
Yield: 106 %

Procedure:
The suspension of 5-[4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)quinazolin-6-yl]-2-furaldehyde (5 g, 10.6 mmoL) in methanol (25 mL) and dichloromethane (25 mL) was charged with 2-aminoethylmethylsulfone (1.4 g, 11.2 mmoL) slowly under constant stirring at room temperature. The reaction mixture was stirred for 2-4 hours until reaction completion and then the reaction mixture was charged with 5% Pd—C (500 mg) and stirred under hydrogen atmosphere (after evacuation) for 16-24 hours until reaction completion. The reaction mixture was further charged with methanol (25 mL) and dichloromethane (25 mL) and stirred for 12-16 hours. The obtained mixture was filtered, washed with 1:1 mixture of methanol (20 mL) and dichloromethane (20 mL). The yellow filtrate thus obtained was slowly charged with a solution of p-toluenesulfonic acid monohydrate (2.2 g, 11.2 mmoL) in methanol (5 mL). The yellow solid which precipitated out was filtered and washed with 1:1 mixture of methanol (20 mL) and dichloromethane (20 mL). The solid obtained was dried under vacuum at 40-45° C. to provide the monotosylate salt of Lapatinib (6.5 g, Yield=81%, HPLC purity>99%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[P:6](=O)([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)[C:7]1[O:8][CH:9]=[CH:10][CH:11]=1.II.C(P(CCCC)CCCC)CCC>C(#N)C.C1COCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[P:6]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=P(c1ccco1)(c1ccco1)c1ccco1
Agent: CCCCP(CCCC)CCCC
Agent: II
Solvent: CC#N
Solvent: C1CCOC1
Product: c1coc(P(c2ccco2)c2ccco2)c1

Procedure:
100 mg (0.431 mmol) of tri(2-furyl)phosphine oxide (31P NMR, s, −15.4) were treated with I2 11 mg (43 μmol) and tributylphosphine 180 μL (0.70 mmol) in acetonitrile/THF (1:1 v/v) 2 mL for 19 hours at room temperature, which gave 31P NMR integrated conversion of tri(2-furyl)phosphine (31P NMR, s, −76.5) in ca. 50%.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][P:9]([O:12][CH2:13][CH:14]1[CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]1)([CH3:11])=[O:10]>ClCCl>[OH:5][C:3]([C:2]([F:7])([F:6])[F:1])=[O:4].[CH3:8][P:9]([CH3:11])(=[O:10])[O:12][CH2:13][CH:14]1[CH2:17][NH:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CC(COP(C)(C)=O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CP(C)(=O)OCC1CNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (120 mL) was added dropwise to the product of Step 1 (80 g) in dichloromethane (120 mL) at 0° C. over a period of 30 min. The reaction mixture was stirred at room temperature for 2 h. After completion of reaction, reaction mixture was concentrated to remove excess trifluoroacetic acid under vacuum to afford azetidin-3-ylmethyl dimethylphosphinate TFA salt (90 g) as brown liquid. LC ESI: [M+H]+ m/z 164.2; HPLC purity; >97%. 1H NMR (400 MHz, CD3OD) S: 1.62 (s, 3H), 1.65 (s, 3H), 3.23-3.27 (m, 1H), 4.02 (dd, J=7.7, 11.1 Hz, 2H), 4.11-4.19 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][CH:9]([OH:11])[CH3:10])=[CH:5][CH:4]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19](O)=[CH:18][CH:17]=1.[OH-].[Na+].O>C(#N)C>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][CH:9]([O:11][C:19]2[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)[CH3:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(O)cc1
Reactant: COc1ccc(OCC(C)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: COc1ccc(OCC(C)Oc2ccc(OC)cc2)cc1
Yield: 76.4 %

Procedure:
In 500 ml of acetonitrile were dissolved 168 g of 1-p-methoxyphenoxy-2-propanol and 62 g of p-methoxyphenol. To the solution was added 50 g of a 48% sodium hydroxide aqueous solution, and the mixture was allowed to react at 80° C for 3 hours while stirring. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration and recrystallized from methanol to obtain 110 g of 1,2-bis(4-methoxyphenoxy)propane having a melting point of 84 to 84.5° C.
Reaction SMILES: N[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:20])=[CH:4][CH:3]=1.[CH:21]([N:24](CC)C(C)C)(C)[CH3:22].C(Cl)(=[O:32])C>C1COCC1>[O:20]=[C:12]1[C:11](=[C:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([CH2:22][C:21]([NH2:24])=[O:32])[CH:10]=3)[CH2:6][O:7]2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13]1
Reactant: CC(=O)Cl
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1ccc2c(c1)C(=C1C(=O)Nc3ccccc31)OC2
Solvent: C1CCOC1
Product: NC(=O)Cc1ccc2c(c1)C(=C1C(=O)Nc3ccccc31)OC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
To a solution of 3-(6-Amino-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one (50.0 mg, 0.189 mmol) and N,N-diisopropylethylamine (98.8 μL, 0.567 mmol) in 2.0 mL THF was added acetyl chloride (13.4 μL, 0.189 mmol). After stirring at room temperature for 1 h, the slurry was partitioned between NaHCO3 solution and EtOAc (warmed to dissolve solid). The organic phase was washed with H2O, 4% aqueous HCl solution, H2O, saturated NaHCO3, brine and dried with Na2SO4. After concentrating in vacuo the residue was triturated with EtOAc to give the title compound (47.4 mg, 82%) as a yellow solid.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[C:11]1[NH:12][CH:13]=[CH:14][N:15]=1>>[C:1]([C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ncc[nH]1
Reactant: O=C(Cl)c1ccccc1
Product: O=C(c1ccccc1)c1ncc[nH]1
Yield: 60 %

Procedure:
Benzoyl imidazole was prepared by the above procedure using benzoyl chloride (28.1 grams, 200 mmole) and 2-methylimidazole (16.4 grams, 210 mmole), in an amount of 22.4 grams (60% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[CH3:22][N:23]([CH3:35])[C@@H:24]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:25](O)=[O:26].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C)C=O>[CH3:35][N:23]([CH3:22])[C@@H:24]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:25]([NH:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23)=[O:26]
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reactant: CN(C)[C@@H](Cc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)[C@@H](Cc1ccccc1)C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 78.1 %

Procedure:
Preparation from the title compound of Example 7 (hydrochloride) (40 mg, 0.128 mmol), (S)-2-Dimethylamino-3-phenyl-propionic acid (30 mg, 0.154 mmol), triethylamine (0.071 mL, 0.512 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (59 mg, 0.154 mmol) in CH2Cl2 (0.4 mL) and N,N-dimethylformamide (0.4 mL) was carried out analogously to Example 11. Silica gel chromatography (elute with 1.5% triethylamine in CH2Cl2 followed by 1.5% triethylamine in 9:1 CH2Cl2:methanol), also in an analogous manner, afforded the freebase of the title compound (46 mg, 0.10 mmol) in three separate batches for a combined 80% yield. Two of the batches were carried on to Examples 71b and 71c respectively. To the third batch (8 mg, 0.018 mmol) was added tetrahydrofuran and 1.2 equivalents of HCl in dioxane (from a 4M stock solution). After evaporation, trituration with diethyl ether and 1:1 CH2Cl2:hexane gave the title compound (6 mg, 0.012 mmol) as a yellow powder in 67% yield for the salt formation.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:7])=[CH:4][CH:3]=1.Cl[C:17]1C=CC(C=O)=C[CH:18]=1.C(OC)(=O)C=CCC.[C-]#N.[Na+]>CN(C)C=O.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]([CH2:17][CH3:18])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:7])=[CH:14][CH:15]=1
Reactant: COC(=O)CCC(=O)c1ccc(Cl)cc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: CCC=CC(=O)OC
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCC(CC(=O)OC)C(=O)c1ccc(Cl)cc1
Yield: 21 %

Procedure:
By the procedure described for the preparation of methyl 3-(4-chlorobenzoyl)propanoate (see Example 1), 4-chlorobenzaldehyde (22.48 g), methyl pent-2-enoate (13.65 g), and sodium cyanide (3.92 g) in dry dimethylformamide (DMF: 250 ml), followed by column chromatography on silica gel using dichloromethane: 40°-60° petrol (1:2) as eluent, gave methyl 3-(4-chlorobenzoyl)pentanoate (6.5 g, 21%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[N+](C1C=CC([O:39][C:40]([NH:42][C@@H:43]([CH2:61][CH:62]2[CH2:67][CH2:66][CH2:65][CH2:64][CH2:63]2)[C@@H:44]([O:56][Si](C)(C)C)[CH2:45][NH:46][C:47](=[O:55])[O:48][CH2:49][CH2:50][Si:51]([CH3:54])([CH3:53])[CH3:52])=O)=CC=1)([O-])=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:22])=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:40]([NH:42][C@@H:43]([CH2:61][CH:62]3[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67]3)[C@@H:44]([OH:56])[CH2:45][NH:46][C:47](=[O:55])[O:48][CH2:49][CH2:50][Si:51]([CH3:52])([CH3:54])[CH3:53])=[O:39])[CH2:17]2)([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOC(=O)NC[C@H](O[Si](C)(C)C)[C@H](CC1CCCCC1)NC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: COCCCC[C@@](O)(c1cccc(Cl)c1F)[C@@H]1CCCNC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCCC[C@@](O)(c1cccc(Cl)c1F)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)[C@@H](O)CNC(=O)OCC[Si](C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
To a solution of (S)-1-(3-chloro-2-fluorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol (33.0 mg, 0.10 mmol) in CH2Cl2 (2 mL), DIEA (39 mg, 0.30 mmol) was added, followed by the solution of 2-(trimethylsilyl)ethyl (2S,3S)-3-(4-nitrophenoxycarbonylamino)-4-cyclohexyl-2-(trimethylsilyloxy)butylcarbamate in CH2Cl2 (0.8 mL, 0.2 mmol) prepared in the previous step. The resulting yellow solution was stirred at rt for 30 min, and completion of reaction was confirmed by LC-MS. Solvent was removed under vacuum, and the residue was purified by preparative HPLC to give 2-(trimethylsilyl)ethyl (2S,3S)-3-((R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamido)-4-cyclohexyl-2-hydroxybutylcarbamate (25.8 mg, 38%); MS m/z 686 (M+H+).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][C:12]([O:21][CH3:22])=[CH:13][C:14]=3[O:19][CH3:20])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.C1(P([C:63]2[CH:68]=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:69](=[O:72])([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:72][CH2:69][CH2:2][N:7]1[CH2:63][CH2:68][N:9]([C:2]2[N:7]=[C:6]([C:8]3[NH:17][C:16](=[O:18])[C:15]4[C:10](=[CH:11][C:12]([O:21][CH3:22])=[CH:13][C:14]=4[O:19][CH3:20])[N:9]=3)[CH:5]=[CH:4][CH:3]=2)[CH2:8][CH2:6]1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cccc(Br)n3)nc2c1
Reactant: O=C([O-])[O-]
Reactant: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cccc(N4CCN(CCO)CC4)n3)nc2c1
Temperature: 25 °C
Yield: 197.2 %

Procedure:
To a suspension of 2-(6-bromopyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.193 g, 0.533 mmol) in dioxane (3 mL) was added palladium(II)acetate (0.012 g, 0.053 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.0332 g, 0.053 mmol) and cesium carbonate (0.261 g, 0.800 mmol) under nitrogen. The reaction mixture was refluxed under nitrogen for 6.5 h. After that time the reaction was cooled to rt, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 95:5 dichloromethane/methanol and trace amount of ammonium hydroxide) followed by trituration with diethyl ether to give 2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.043 g, 20%) as a light yellow solid: mp 175-177° C.; 1H NMR (400 MHz, DMSO-d) δ 11.05 (br s, 1H), 7.65-7.79 (m, 2H), 7.06 (d, J=8.20 Hz, 1H), 6.78 (s, 1H), 6.58 (s, 1H), 4.48 (br s, 1H), 3.91 (s, 3H), 3.86 (s, 3H), 3.64 (br s, 4H), 3.55 (br s, 2H), 2.54 (br s, 4H), 2.45 (t, 2H); ESI MS m/z 412 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[C:14]([OH:25])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:23])[F:22])[C:12]#[N:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:26](=[O:29])([O-])[O-].[Na+].[Na+].ClC1C=C[S:35][C:34]=1C(OC)=O>CC(C)=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[C:14]([O:25][C:26]([S:35][CH3:34])=[O:29])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:23])([F:24])[F:22])[C:12]#[N:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1sccc1Cl
Reactant: CC(C)(C)c1ccc(C(C#N)=C(O)c2ccccc2C(F)(F)F)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: CSC(=O)OC(=C(C#N)c1ccc(C(C)(C)C)cc1)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
A mixture comprising 5.0 g of α-(4-tert-butylphenyl)-β-hydroxy-β-(2-trifluoromethylphenyl)acrylonitrile, 2.0 g of sodium carbonate and 30 ml of acetone, was heated, and a mixture comprising 2.1 g of methyl chlorothiolformate and 10 ml of acetone, was dropwise added over a period of 10 minutes under reflux. After completion of the dropwise addition, the reaction was carried out for 60 minutes under reflux. The reaction mixture was cooled, and then, an inorganic salt was filtered off. The cake was washed with 20 ml of acetone. Acetone in the filtrate was distilled off, and 50 ml of ISOPAR G (tradename) was added to the residue, followed by heating and dissolution. Then, the solution was left to cool to room temperature. Precipitated crystals were collected by filtration, and the cake was washed with 10 ml of ISOPAR G (tradename) and then dried at 45° C. for 12 hours to obtain 4.8 g of the desired product (isomer ratio 0:100). The HPLC conditions for the analysis of this product were the same as in Preparation Example 5. Further, the NMR spectrum data of this product were the same as the geometrical isomer having a longer retention time of Preparation Example 4.
Reaction SMILES: C1(C)C=CC=CC=1.[Br:8][CH2:9][C:10]([OH:12])=[O:11].[CH2:13](O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:11]
Reactant: CCCCCCCCO
Reactant: O=C(O)CBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCOC(=O)CBr
Reaction time: 1.5 h
Yield: 113.4 %

Procedure:
There were added to 150 ml of toluene, 20 g of bromoacetic acid, 20 g of n-octyl alcohol and 2.5 g of p-toluenesulfonic acid, and azeotropical dehydration was carried out for 1.5 hours. After cooling, toluene was distilled off at reduced pressure, and 41 g of n-octyl bromoacetate were obtained by vacuum distillation (110° C., 11 mm Hg).
Reaction SMILES: ClC[CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=1)[N:9]=[C:8]2[NH:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35](C(OC(C)(C)C)=O)[N:34]=[CH:33]2.[CH3:46][N:47]([CH3:53])[C:48](=[O:52])[CH2:49][NH:50][CH3:51].[CH3:54]S(C)=O>>[NH:35]1[C:36]2[C:32](=[CH:31][C:30]([NH:29][C:8]3[C:7]4[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([O:4][CH2:3][CH2:51][N:50]([CH3:54])[CH2:49][C:48]([N:47]([CH3:53])[CH3:46])=[O:52])[CH:6]=4)[N:11]=[C:10]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:18]=4)[N:9]=3)=[CH:38][CH:37]=2)[CH:33]=[N:34]1
Reactant: CS(C)=O
Reactant: CNCC(=O)N(C)C
Reactant: COc1cc2nc(-c3cccc(-c4ccccc4)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OCCCl
Product: COc1cc2nc(-c3cccc(-c4ccccc4)c3)nc(Nc3ccc4[nH]ncc4c3)c2cc1OCCN(C)CC(=O)N(C)C
Temperature: 85 °C
Reaction time: 4 h
Yield: 74 %

Procedure:
To a mixture of tert-butyl 5-(6-(2-chloroethoxy)-2-[(3-phenyl)phenyl)-7-methoxyquinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.25 g, 0.40 mmole) in DMSO (2 mL) was added N,N-dimethyl-2-(methylamino)acetamide (0.232 g, 2.00 mmole) and the reaction was stirred at 85° C. for 4 h. The mixture was poured onto ice-water and the crude product was filtered. The product was then dissolved in a mixture of CH2Cl2 and CH3OH and the solution was concentrated in vacuo. The residue was purified via preparative TLC (SiO2, 10% CH2Cl2/CH3OH). To the product was added TFA (4 mL) and the reaction was stirred at RT for 2 h. The solution was concentrated in vacuo and the residue was triturated with ether, filtered and dried under vacuum to give 2-((2-(4-(1H-indazol-5-ylamino)-2-[(3-phenyl)phenyl)-7-methoxyquinazolin-6-yloxy)ethyl)(methyl)amino)-N,N-dimethylacetamide (0.178 g, 0.30 mmole, 74%). MS 602.6 (M+1). HPLC retention time 5.24 mins.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[C:5]([NH2:6])=[C:4]([Cl:14])[CH:3]=1.C(N(CC)CC)C.[C:22]([CH2:26][C:27](Cl)=[O:28])([CH3:25])([CH3:24])[CH3:23]>ClCCl>[Br:1][C:2]1[CH:8]=[C:7]([O:9][C:10]([F:12])([F:11])[F:13])[C:5]([NH:6][C:27](=[O:28])[CH2:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[C:4]([Cl:14])[CH:3]=1
Reactant: Nc1c(Cl)cc(Br)cc1OC(F)(F)F
Reactant: CC(C)(C)CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CC(=O)Nc1c(Cl)cc(Br)cc1OC(F)(F)F
Temperature: 25 °C
Yield: 92.6 %

Procedure:
To a solution of 4-bromo-2-chloro-6-trifluoromethoxy-aniline (2.9 g, 10 mmol) and triethylamine (1.5 g, 15 mmol) in anhydrous dichloromethane (50 mL) was added dropwise tert-butylacetyl chloride (1.6 g, 12 mmol) with stirring at room temperature. The reaction mixture was stirred for 3 hours at room temperature, than the reaction mixture was diluted with dichloromethane and washed with water and dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column (ISCO, hexane/EtOAc, 0-40%, 40 min) to give a white solid (3.6 g, 93%).
Reaction SMILES: Cl.[CH3:2][N:3]1[C:11](=[O:12])[C:10]2[N:9]([C@@H:13]([CH3:17])[C:14]([OH:16])=O)[CH:8]=[N:7][C:6]=2[N:5]([CH3:18])[C:4]1=[O:19].[CH3:20][C@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[C:26]1[N:31]=[CH:30][C:29]([C:32]2[N:37]=[C:36]([NH2:38])[CH:35]=[N:34][CH:33]=2)=[CH:28][N:27]=1.C1C=NC2N(O)N=NC=2C=1.N1C=CC=CC=1.CC(C)N=C=NC(C)C>C(Cl)Cl>[CH3:2][N:3]1[C:11](=[O:12])[C:10]2[N:9]([C@@H:13]([CH3:17])[C:14]([NH:38][C:36]3[CH:35]=[N:34][CH:33]=[C:32]([C:29]4[CH:28]=[N:27][C:26]([N:22]5[CH2:23][CH2:24][CH2:25][C@@H:21]5[CH3:20])=[N:31][CH:30]=4)[N:37]=3)=[O:16])[CH:8]=[N:7][C:6]=2[N:5]([CH3:18])[C:4]1=[O:19]
Reactant: C[C@@H](C(=O)O)n1cnc2c1c(=O)n(C)c(=O)n2C
Reactant: C[C@H]1CCCN1c1ncc(-c2cncc(N)n2)cn1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@H]1CCCN1c1ncc(-c2cncc(NC(=O)[C@H](C)n3cnc4c3c(=O)n(C)c(=O)n4C)n2)cn1
Temperature: 25 °C
Reaction time: 7.5 h
Yield: 47 %

Procedure:
A flask was charged with (S)-2-(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propanoic acid hydrochloride (Intermediate 8) (8.96 g, 31.0 mmol), (S)-6-(2-(2-methylpyrrolidin-1-yl)pyrimidin-5-yl)pyrazin-2-amine (7.23 g, 28.2 mmol), HOAt (3.84 g, 28.2 mmol), nitrogen, DCM (141 ml) and stirred at room temperature. The suspension was cooled to 0° C. followed by addition of pyridine (4.60 ml, 56.4 mmol), then DIC (6.59 ml, 42.3 mmol). The reaction was removed from ice bath immediately after addition of DIC was complete. The reaction was complete after 7.5 hours. The reaction mixture was diluted with 100 mL DCM. The organic layer was washed with 0.5 M HCl aq. (2×20 mL). The resulting organic layer was washed with water, brine, dried over MgSO4, filtered and concentrated. The resulting DCM filtrate was slowly added dropwise to 300 mL of stirred hexanes at room temperature. The resulting solids were collected via vacuum filtration with aide of hexanes and dried on on frit filter overnight to afford off-white solids (6.5 g, 13.25 mmol, 47.0% yield, 93% ee). ESI-MS (EI+, m/z): 491.33, 1H NMR (DMSO-d6) δ: 11.35 (s, 1H), 9.10 (s, 1H), 9.05 (s, 2H), 8.91 (s, 1H), 8.36 (s, 1H), 5.85 (d, J=7.2 Hz, 1H), 4.30 (s, 1H), 3.59 (d, J=27.6 Hz, 2H), 3.46 (s, 3H), 3.19 (s, 3H), 2.08 (s, 3H), 1.95 (s, 1H), 1.88 (d, J=7.3 Hz, 3H), 1.72 (s, 1H), 1.24 (d, J=6.3 Hz, 3H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:23][C:22](=O)[O:21][C:19](=[O:20])[CH2:18]2)=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]([CH2:23][C:22]2[NH:9][C:4]3[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=3[N:8]=2)[CH2:18][C:19]([OH:21])=[O:20])=[CH:15][CH:16]=1.[ClH:10]
Reactant: O=C1CC(c2ccc(Cl)cc2)CC(=O)O1
Reactant: Nc1ccc(F)cc1N
Product: Cl
Product: O=C(O)CC(Cc1nc2ccc(F)cc2[nH]1)c1ccc(Cl)cc1

Procedure:
By a procedure similar to that of 1.4, starting from commercial 4-fluoro-1,2-phenylenediamine and 3-(4-chlorophenyl)glutaric anhydride, 3-(4-chlorophenyl)-4-(5-fluoro-2-benzimidazolyl)butanoic acid•HCl was obtained as colourless solid.