Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[C:11]([CH3:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][CH2:19][O-:20].[Na+].[Na].[CH2:23]([OH:25])[CH3:24]>>[CH2:19]([O:20][C:23](=[O:25])/[CH:24]=[CH:13]/[C:12]1[CH:15]=[CH:16][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][C:11]=1[CH3:17])[CH3:18]
Reactant: CCO
Reactant: Cc1cc(OCc2ccccc2)ccc1C=O
Reactant: CC[O-]
Agent: [Na+]
Agent: [Na]
Product: CCOC(=O)/C=C/c1ccc(OCc2ccccc2)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 11.2 g (50 mmol) of 4-benzyloxy-2-methyl-benzaldehyde [PCT Int. Appl. (2002), WO 2002/092084/A1] and of 12.33 g (55 mmol) of triethyl phosphonoacetate in 25 ml of absolute ethanol was added to a cooled solution (0° C.) of sodium ethylate (freshly prepared from 1.38 g (60 mmol) of sodium and 25 ml of absolute ethanol). Subsequently, the mixture was stirred at ambient temperature for 2 hours. Then, the solvent was evaporated and the residue was partioned between tert.-butyl methyl ether and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate and finally evaporated. After crystallization from a mixture of dichloromethane and n-heptane, 12.9 g of (E)-3-(4-benzyloxy-2-methyl-phenyl)-acrylic acid ethyl ester was obtained as beige crystals (87% of theory).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[OH-].[Na+].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>O>[C:13]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1cccc(C(=O)O)c1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cccc(NC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 79.7 %

Procedure:
To a solution of 1.37 g of 3-aminobenzoic acid and 0.4 g of sodium hydroxide added to 50 ml of water was added dropwise a solution of 1.41 g of benzoyl chloride and 0.4 g of sodium hydroxide dissolved in 5 ml of water under an ice bath at the same time, and the resulting mixture was stirred at room temperature for 6 hours. 1N hydrochloric acid was added to the reaction solution which was adjusted to pH 1, and then the precipitated solid was filtered off and collected to obtain 1.92 g of the desired product (Yield: 80%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:38]1[N:39]=[N:40][C:41]([CH3:44])=[CH:42][CH:43]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]2([CH2:32][C:33]([OH:36])([CH3:34])[CH3:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:38]4[N:39]=[N:40][C:41]([CH3:44])=[CH:42][CH:43]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(Cl)nn1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O
Product: Cc1ccc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccc(F)cc4)OC3=O)cc2)nn1

Procedure:
The title compound was prepared from (S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 3-chloro-6-methylpyridazine following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.163 min, m/z=464; 1H NMR (CDCl3) 1.12 (d, 6H), 1.55 (d, 3H), 2.18 (s, 2H), 2.19-2.28 (m, 2H), 2.40 (m, 1H), 2.74 (s, 3H), 2.90 (m, 1H), 5.71 (m, 1H), 6.96-7.05 (t, 2H), 7.10 (d, 2H), 7.29 (m, 2H), 7.38 (d, 2H), 7.69 (d, 1H), 7.82 (d, 2H).
Reaction SMILES: ClC(O[C:6](=[O:12])OC(Cl)(Cl)Cl)(Cl)Cl.N1C=CC=CC=1.Cl.[F:20][C:21]([F:40])([F:39])[C:22]1[CH:27]=[CH:26][C:25]2[C:28]3[C:32]([C:35]([O:37][CH3:38])=[O:36])([CH2:33][O:34][C:24]=2[CH:23]=1)[CH2:31][NH:30][N:29]=3.[NH2:41][C:42]1[CH:43]=[CH:44][C:45]([Cl:48])=[N:46][CH:47]=1>C(O)C.C(Cl)Cl>[Cl:48][C:45]1[N:46]=[CH:47][C:42]([NH:41][C:6]([N:30]2[CH2:31][C:32]3([C:35]([O:37][CH3:38])=[O:36])[CH2:33][O:34][C:24]4[CH:23]=[C:22]([C:21]([F:39])([F:20])[F:40])[CH:27]=[CH:26][C:25]=4[C:28]3=[N:29]2)=[O:12])=[CH:43][CH:44]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)C12CNN=C1c1ccc(C(F)(F)F)cc1OC2
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C12COc3cc(C(F)(F)F)ccc3C1=NN(C(=O)Nc1ccc(Cl)nc1)C2
Temperature: 0 °C
Reaction time: 2 h
Yield: 123.1 %

Procedure:
To a solution of 0.15 g (0.0005 mol) of bis(trichloromethyl)carbonate, 20 mL of methylene chloride and 0.39 mL (0.0048 mol) of pyridine was added 0.5 g (0.0015 mol) of the product from Step H at 0° C. The resulting mixture was stirred at 0° C. for 2 hours and then 0.21 g (0.0016 mol) of 5-amino-2-chloro pyridine was added. The resulting mixture was stirred at room temperature for 12 hours and then 10 mL of ethanol followed by 3 g of silica gel were added and the solvent was removed. Flash chromatography of the residue on silica gel using 2:1 hexanes-EtOAc gave 0.28 g of an off-white solid that melted at 236°-238° C. 1H NMR (CDCl3, 200 MHz) δ3.77 (s, 3H), 3.85 (d, 1H), 4.24 (d, 1H), 4.53 (d, 1H), 5.07 (d, 1H), 7.20-7.35 (m, 3H), 7.98 (d, 1H), 8.02 (s, 1H), 8.12 (dd, 1H), 8.42 (d, 1H).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[C:7]1([CH:13]2[CH2:19][NH:18][C:17](=[O:20])[CH2:16][CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.II.[Br:23]Br>C(Cl)Cl>[Br:23][CH:16]1[CH2:15][CH2:14][CH:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:19][NH:18][C:17]1=[O:20]
Reactant: BrBr
Reactant: O=C1CCCC(c2ccccc2)CN1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: II
Solvent: ClCCl
Product: O=C1NCC(c2ccccc2)CCC1Br
Reaction time: 0.33 h

Procedure:
4.4 g of phosphorus pentachloride were added slowly to 60 ml of methylene chloride containing 4.0 g of 6-phenylperhydroazepin-2-one [prepared as described in step (d) above], under a stream of nitrogen, keeping the temperature of the reaction solution at 0° to 5° C. After this addition, the reaction mixture was stirred for 20 minutes, and then 40 mg of iodine, followed by 21.1 ml of a 1M methylene chloride solution of bromine, were dropped into it at 0°-5° C. When this addition was complete, the reaction mixture was stirred for 1 hour. The volume of reaction mixture was reduced by half by evaporation under reduced pressure, to separate the title compound as crystals. After the addition of water, the separated crystals were collected by filtration and washed with ethyl acetate, to give 1.8 g of an isomer of the title compound, melting at 218°-219.5° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)=[N:2]1.CN1CCOCC1.[ClH:28].C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[CH:51]([NH:54][C:55](=[O:63])[CH2:56][N:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1)([CH3:53])[CH3:52]>>[ClH:28].[ClH:28].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([C:16]([N:60]3[CH2:59][CH2:58][N:57]([CH2:56][C:55](=[O:63])[NH:54][CH:51]([CH3:52])[CH3:53])[CH2:62][CH2:61]3)=[O:18])=[CH:19][CH:20]=2)=[N:2]1
Reactant: CC(C)NC(=O)CN1CCNCC1
Reactant: O=C(O)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Product: CC(C)NC(=O)CN1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)CC1
Yield: 37.3 %

Procedure:
The crude product obtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (200 mg, 0.757 mmol) obtained in Step 6 of Example 1, N-methylmorpholine (0.166 mL, 1.51 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (203 mg, 1.06 mmol), 1-hydroxybenzotriazole monohydrate (133 mg, 0.984 mmol) and N-isopropyl-2-(piperazin-1-yl)acetamide (210 mg, 1.14 mmol) in a similar manner to Step 7 of Example 1, was purified by silica gel column chromatography (chloroform/methanol=80/20), followed by treating with 4 mol/L hydrogen chloride-ethyl acetate solution (0.665 mL) to obtain Compound 135 (99.7 mg, 26%).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Br[CH2:21][CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl.CO>CC(O)C.Cl>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21][CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Reactant: BrCCCc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: CO
Solvent: ClCCl
Product: CC1(C)C(=O)N(CCCc2cccnc2)c2cc([N+](=O)[O-])c(N)cc21
Yield: 24.7 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (1 g) is alkylated using 3-(3-bromo-propyl)-pyridine (3.04 g; 15.2 mmol) and K2CO3 (2.1 g; 15.2 mmol) at RT for 4 days. After aqueous work-up and flash chromatography on silica gel eluting with CH2Cl2/MeOH (30:1), the pure alkylated acetamide (425 mg; 1.11 mmol) is de-acetylated under reflux conditions in 2-propanol (1.2 ml) and hydrochloric acid (6 N; 3.7 ml). 5-Amino-3,3-dimethyl-6-nitro-1-(3-pyridin-3-yl-propyl)-1,3-dihydro-indol-2-one (319 mg) is obtained by aqueous work-up and used without further purification.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[N:5][N:4]=[CH:3]1.[CH2:7]([Br:9])[CH3:8]>C(#N)C>[Br-:9].[CH2:7]([N+:5]1[N:4]=[CH:3][N:2]([NH2:1])[CH:6]=1)[CH3:8]
Reactant: Nn1cnnc1
Reactant: CCBr
Solvent: CC#N
Product: CC[n+]1cn(N)cn1
Product: [Br-]
Temperature: 25 °C
Reaction time: 192 h

Procedure:
A 500 ml round bottom flask equipped with an overhead stirrer was charged with 10.00 grams of 4-amino-1,2,4-triazole and 200 ml of acetonitrile. Ethyl bromide, 45 ml, 65.0 grams, was added to the vigorously stirred acetonitrile reaction mixture. The reaction was stirred for 8 days at ambient temperature at which time, thin layer chromatography showed that all of the 4-amino-1,2,4-triazole had been consumed. The resultant solution was then rotary evaporated down to leave a colorless oil which slowly crystallized. Solid material was heated to 60 C. for 5 hours under high vacuum, whereupon it melted and lost the remaining solvent and resolidified. Crystalline 1-ethyl-4-amino-1,2,4-triazolium bromide was recovered in essentially quantitative yield and high purity, 22.94 g, 117 mmoles. Melting point: 63-67° C.; DSC onset: 150° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].[Cl:32][CH2:33][C:34](Cl)=[O:35].C(O)(=O)C>C(Cl)Cl.O>[Cl:32][CH2:33][C:34]([N:20]1[CH2:21][CH2:22][CH:17]([N:15]2[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]3[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=3)=[N:16]2)[CH2:18][CH2:19]1)=[O:35]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(C2=NN(C3CCN(C(=O)CCl)CC3)C(=O)C2(C)C)cc1OC
Temperature: 20 °C

Procedure:
430 g 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one (compound B1; synthesis alternative 2) and 215 g potassium carbonate are suspended in 6.5 l of DCM. The mixture is heated to reflux and 162 g chloroacetylchlorid is added drop wise during 1 h. The mixture is stirred at reflux temperature for 5 h, then 30 g of potassium carbonate and further 36 g of chloroacetylchlorid are added. After 1 h additional reaction time at reflux the reaction is complete. 116 g of acetic acid is added to the mixture during 10 min, then the mixture is cooled to 20° C. and during cooling 3 l of water is added. The organic layer is separated from the aqueous layer; the organic layer is washed twice with 1.5 l of water. The combined aqueous layers are extracted twice with 0.5 l of DCM. The organic layers are combined and 6 l is distilled off in vacuum. Then 2.5 l of tert. butylmethylether is added and the solution is concentrated in vacuum until crystallization starts (about 0.8 liter is distilled off). The suspension is cooled down and stirred overnight. The suspension is filtered, the solid dried in vacuum by 50° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[C:5]([F:25])=[CH:4][C:3]=1[F:26].[NH2:27][CH:28]([CH3:31])[CH2:29][OH:30].Cl>N1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:27][CH:28]([CH3:31])[CH2:29][OH:30])[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[C:5]([F:25])=[CH:4][C:3]=1[F:26]
Reactant: CC(N)CO
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Agent: Cl
Solvent: c1ccncc1
Product: CC(CO)Nc1c(F)cc2c(=O)c(C(=O)O)cn(-c3nc(N)c(F)cc3F)c2c1Cl
Temperature: 45 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
1-(6-Amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (300 mg) and 2-amino-1-propanol (400 mg) were added to pyridine (1,200 mg), and the mixture was stirred at 45° C. for 16 hours. Concentrated hydrochloric acid (600 mg) was added to the reaction mixture, and the resultant mixture was concentrated under reduced pressure. Ethanol (2 ml) was added to the residue, and deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (168 mg) as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C@@H:22]([NH:24]C(=O)OC(C)(C)C)[CH3:23])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[S:18]([CH3:21])(=[O:20])=[O:19])=[N:9]2)=[CH:4][CH:3]=1.Cl.FC1C=C2C(C=C([C@@H](N)C)C(C3C=CC=CC=3S(C)(=O)=O)=N2)=CC=1.[NH2:57][C:58]1[C:63]([C:64]#[N:65])=[C:62](Cl)[N:61]=[CH:60][N:59]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:57][C:58]1[C:63]([C:64]#[N:65])=[C:62]([NH:24][C@H:22]([C:7]2[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[S:18]([CH3:21])(=[O:20])=[O:19])=[N:9][C:10]3[C:5]([CH:6]=2)=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH3:23])[N:61]=[CH:60][N:59]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cc2ccc(F)cc2nc1-c1ccccc1S(C)(=O)=O
Agent: C[C@H](N)c1cc2ccc(F)cc2nc1-c1ccccc1S(C)(=O)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1cc2ccc(F)cc2nc1-c1ccccc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.1 %

Procedure:
To (S)-tert-butyl (1-(7-fluoro-2-(2-(methylsulfonyl)phenyl)quinolin-3-yl)ethyl)-carbamate (440 mg, 1.0 mmol) was added HCl, 4M (1 mL). The resulting mixture was stirred at rt for 1 h. Solvent was removed and the crude (S)-1-(7-fluoro-2-(2-(methylsulfonyl)phenyl)quinolin-3-yl)ethanamine was used without further workup. A solution of (1S)-1-(7-fluoro-2-(2-(methylsulfonyl)phenyl)-quinolin-3-yl)ethanamine (100 mg, 290 μmol), 4-amino-6-chloropyrimidine-5-carbonitrile (45 mg, 290 μmol) and DIEA (101 μl, 581 μmol) in DMF (4 mL) was heated to 100° C. overnight. Solvent was removed under reduce pressure and purified via preparatory. TLC using 3% of MeOH/DCM to afford a white powder of (S)-4-amino-6-((1-(7-fluoro-2-(2-(methylsulfonyl)phenyl)quinolin-3-yl)ethyl)-amino)pyrimidine-5-carbonitrile (6.9 mg, 5.1%). 1H NMR (500 MHz, CD3OD) δ ppm 1.51 (d, J=7.09 Hz, 3H) 3.17 (s, 3H) 5.43 (d, J=6.85 Hz, 1H) 7.48 (d, J=2.45 Hz, 1H) 7.60-7.63 (m, 1H) 7.66-7.69 (m, 2H) 7.73 (d, J=1.47 Hz, 1H) 7.81 (s, 1H) 8.07 (dd, J=9.05, 6.11 Hz, 1H) 8.13-8.17 (m, 1H) 8.49 (s, 1H). Mass Spectrum (ESI) m/e=463 (M+1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.[C:10](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(O)C1CCOCC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COC(=O)C1CCOCC1
Yield: 99.3 %

Procedure:
Tetrahydro-2H-pyran-4-carboxylic acid (1.00 g, 7.68 mmol) was slowly added to a stirred suspension of anhydrous potassium carbonate (1.17 g, 8.45 mmol) in acetone (40 mL), followed by dimethyl sulfate (0.8 mL, 8.45 mmol). The mixture was stirred and heated for 3 h. The inorganic salts were then removed by filtration and washed with acetone, and the filtrate was dried and concentrated to give methyl tetrahydro-2H-pyran-4-carboxylate (1.1 g, 99%), which was used in the next step without further purification. GC-MS m/z 145 (MH+); 1H NMR (300 MHz, CDCl3) δ 11.70-1.80 (m, 4H), 2.47-2.52 (m, 1H), 3.34-3.43 (m, 2H), 3.65 (s, 3H), 3.88-3.95 (m, 2H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[NH:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][OH:33])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[C:1]1([CH2:7][CH2:8][C:9]2[N:13]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([CH2:32][OH:33])=[CH:28][CH:27]=3)[N:12]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=3)[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCc1ccc(CCl)cc1
Reactant: FC(F)(F)c1ccc(-c2cc(CCc3ccccc3)[nH]n2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCc1ccc(Cn2nc(-c3ccc(C(F)(F)F)cc3)cc2CCc2ccccc2)cc1
Temperature: 120 °C
Reaction time: 1 h
Yield: 49.9 %

Procedure:
A mixture of 5-(2-phenylethyl)-3-[4-(trifluoromethyl)phenyl]-1H-pyrazole (318 mg, 1.01 mmol), [4-(chloromethyl)phenyl]methanol (240 mg, 1.53 mmol), potassium carbonate (276 mg, 2.0 mmol) and N,N-dimethylformamide (10 mL) was stirred at 120° C. for 1 hr. The reaction mixture was poured into 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried using a Presep Dehydration tube (manufactured by Wako Pure Chemical Industries, Ltd.) and concentrated. The residue was purified by silica gel column chromatography (10%-80% ethyl acetate/hexane) to give the title compound (220 mg, yield 50%) as a yellow oil.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:38])[C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])[N:12]=[CH:11][N:10]=[C:9]2[NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)=[C:24]([Cl:37])[CH:23]=1)=[O:4].[C:39](Cl)(=[O:42])[CH:40]=[CH2:41].C(=O)(O)[O-].[Na+]>C1COCC1.O>[Cl:37][C:24]1[CH:23]=[C:22]([NH:21][C:9]2[C:8]3[C:13](=[CH:14][C:15]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[C:6]([NH:5][C:3]([C@@H:2]([NH:1][C:39](=[O:42])[CH:40]=[CH2:41])[CH3:38])=[O:4])[CH:7]=3)[N:12]=[CH:11][N:10]=2)[CH:27]=[CH:26][C:25]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=1
Reactant: C=CC(=O)Cl
Reactant: COCCOc1cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2cc1NC(=O)[C@H](C)N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CC(=O)N[C@@H](C)C(=O)Nc1cc2c(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)ncnc2cc1OCCOC
Yield: 24 %

Procedure:
205 mg of (2S)-amino-N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-7-(2-methoxyethoxy)-quinazolin-6-yl}-propionamide as a starting material was dissolved in 10 ml of a mixture of THF and water (3:1), and reacted with 0.047 ml of acryloylchloride at room temperature for 1 hour after adding 97 mg of sodium bicarbonate. The reacted solution was extracted with a mixture of chloroform and isopropanol after adding water, washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure, and the resulting residue was subjected to column chromatography (eluent-ethylacetate:methanol=30:1) to obtain the title compound (55 mg, 24%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7]([O:22][CH:23]3[CH2:40][CH:39]4[CH:25]([C:26](=[O:46])[N:27]([CH3:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=[CH:33][CH:34]5[C:36]([C:42](O)=[O:43])([NH:37][C:38]4=[O:41])[CH2:35]5)[CH2:24]3)=[N:8][C:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:10]2)=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C1CCN2C(=NCCC2)CC1.[CH:70]1([S:73]([NH2:76])(=[O:75])=[O:74])[CH2:72][CH2:71]1>C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7]([O:22][CH:23]3[CH2:40][CH:39]4[CH:25]([C:26](=[O:46])[N:27]([CH3:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=[CH:33][CH:34]5[C:36]([C:42]([NH:76][S:73]([CH:70]6[CH2:72][CH2:71]6)(=[O:75])=[O:74])=[O:43])([NH:37][C:38]4=[O:41])[CH2:35]5)[CH2:24]3)=[N:8][C:9]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2nc(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)c3ccc(OC)c(C)c3n2)cc1
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1ccc(-c2nc(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)c3ccc(OC)c(C)c3n2)cc1
Temperature: 60 °C

Procedure:
The acid 137 (130 mg, 0.207 mmol) and N,N,-carbonyldiimidazole (43 mg, 0.26 mmol) in THF (7 mL) were heated to reflux for 2 hours. DBU (29 μl), and cyclopropanesulfonamide, prepared as described in WO03/053349, (28 mg, 0.23 mmol) was then added and the mixture was stirred at 60° C. over-night. The reaction mixture was diluted with ethyl acetate (25 mL) and washed with 0.5 M citric acid. Purification by HPLC gave 30 mg of the title compound. MS (M+H)+ 732.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:7])=[N:4][O:5][N:6]=1.C(OCC)C.[Cl-].[CH:14]1([C:17](O)=[O:18])[CH2:16][CH2:15]1>N1C=CC=CC=1>[CH3:1][C:2]1[C:3]([NH:7][C:17]([CH:14]2[CH2:16][CH2:15]2)=[O:18])=[N:4][O:5][N:6]=1
Reactant: O=C(O)C1CC1
Reactant: Cc1nonc1N
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: CCOCC
Product: Cc1nonc1NC(=O)C1CC1
Reaction time: 0.5 h

Procedure:
5 g (about 0.05 moles) of 4-methyl-3-aminofurazan, 50 ml of ethyl ether and 4 ml of pyridine are then loaded into a 100 ml glass reactor. This is cooled to a temperature of from 0° to 10° C. and 5 ml (0.06 moles) of the chloride of cyclopropanecarboxylic acid are added under agitation. Heating is then carried out under reflux for about one hour. After cooling of the reaction mass, the ether is evaporated and the residual solid is transferred into about 100 ml of water. Slight heating is effected for about 30 minutes and then the mass is cooled and filtered, the solid being washed with water. The solid obtained is dried in an oven at 90° C.
Reaction SMILES: C([C:3]1[C:11]([O:12][CH2:13][C@H:14]([NH:16][C:17](=O)OC(C)(C)C)[CH3:15])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][N:7]2[S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:26])=[O:25])=O.C(O)(C(F)(F)F)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:15][C@H:14]1[NH:16][CH2:17][C:3]2=[C:4]3[C:8](=[CH:9][CH:10]=[C:11]2[O:12][CH2:13]1)[N:7]([S:24]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)(=[O:25])=[O:26])[CH:6]=[CH:5]3
Reactant: C[C@H](COc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1C=O)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1COc2ccc3c(ccn3S(=O)(=O)c3ccccc3)c2CN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
tert-Butyl ((1R)-2-{[4-formyl-1-(phenylsulfonyl)-1H-indol-5-yl]oxy}-1-methylethyl)carbamate (Intermediate 19, 0.040 g, 0.087 mmol) was dissolved in DCM (2 mL) and TFA (0.5 mL) was added. The mixture was stirred for 1 hour at room temperature and evaporated. The residue was dissolved in THF (2 mL) and sodium triacetoxyborohydride (37.0 mg, 0.176 mmol) was added. The mixture was stirred for 1 hour, evaporated and purified by flash chromatography using 2.5%-5% MeOH in DCM as the eluent to give the title compound (25 mg) as a white solid. MS m/z 343 [M+H]+.