Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2]([CH3:21])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([N:13]([CH3:20])[C:14]([CH:16]2[CH2:19][CH2:18][CH2:17]2)=[O:15])[CH:10]=[CH:11][CH:12]=1)=O.N[C:23]1[C:27]([C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=C[NH:25][N:24]=1>C(O)(=O)C>[C:28]([C:27]1[CH:23]=[N:24][N:25]2[C:5]([C:7]3[CH:8]=[C:9]([N:13]([CH3:20])[C:14]([CH:16]4[CH2:17][CH2:18][CH2:19]4)=[O:15])[CH:10]=[CH:11][CH:12]=3)=[CH:4][CH:3]=[N:2][C:21]=12)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CN(C)C=CC(=O)c1cccc(N(C)C(=O)C2CCC2)c1
Reactant: Nc1n[nH]cc1C(=O)c1ccccc1
Solvent: CC(=O)O
Product: CN(C(=O)C1CCC1)c1cccc(-c2ccnc3c(C(=O)c4ccccc4)cnn23)c1

Procedure:
A reaction mixture comprising 2.86 g of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-methylcyclobutanecarboxamide, 1.88 g of 3-amino-4-benzoylpyrazole and 100 ml of glacial acetic acid was refluxed for 8 hours and then the solvent was removed in vacuo. The residue was partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and then passed through a short pad of hydrous magnesium silicate. The addition of hexane to the refluxing eluate induced crystallization. After cooling, the desired product was collected, giving 3.05 g, mp 168°-170° C.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH2:6]([NH2:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.O>[Br:1][CH2:2][C:3]([NH:24][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:4]
Reactant: O=C(Br)CBr
Reactant: CCCCCCCCCCCCCCCCCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCCCCCCCCCCNC(=O)CBr
Yield: 70 %

Procedure:
A solution of bromoacetyl bromide (44.4 g; 0.22 mol) in CH2Cl2 (50 mL) was added dropwise in 2.5 h at 20° C. to a mixture of octadecylamine (59.3 g; 0.22 mol) and K2CO3 (30.4 g; 0.22 mol) in CH2Cl2 (600 mL) and H2O (600 mL). After 16 h at room temperature the organic layer was separated, washed with H2O, dried over Na2SO4 and evaporated. The crude product was purified by flash chromatography (CH2Cl2/MeOH=100/1 (v/v)) to give the desired product (60 g; 0.154 mol). Yield 70%. GC: 96% (area %), K. F.: <0.1%; 1H-NMR, 13C-NMR and MS spectra were consistent with the postulated structure.
Reaction SMILES: C(OCC1CSC2N(C(=O)C2NC(=O)CC2N=C(C3C=CC=CC=3O)SC=2)C=1C(O)=O)(=O)C.C1(C([O:47][C:48]([C:50]2[N:51]3[CH:54]([S:55][CH2:56][C:57]=2[Cl:58])[CH:53]([NH:59][C:60](=[O:74])[CH2:61][C:62]2[N:63]=[C:64]([C:67]4[C:72]([OH:73])=[CH:71][CH:70]=[CH:69][N:68]=4)[S:65][CH:66]=2)[C:52]3=[O:75])=[O:49])C2C=CC=CC=2)C=CC=CC=1.[SiH](CC)(CC)CC.FC(F)(F)C(O)=O>C(Cl)CCl>[Cl:58][C:57]1[CH2:56][S:55][CH:54]2[N:51]([C:52](=[O:75])[CH:53]2[NH:59][C:60](=[O:74])[CH2:61][C:62]2[N:63]=[C:64]([C:67]3[C:72]([OH:73])=[CH:71][CH:70]=[CH:69][N:68]=3)[S:65][CH:66]=2)[C:50]=1[C:48]([OH:49])=[O:47]
Reactant: O=C(Cc1csc(-c2ncccc2O)n1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(Cl)CSC12
Agent: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(-c4ccccc4O)n3)C2SC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: O=C(Cc1csc(-c2ncccc2O)n1)NC1C(=O)N2C(C(=O)O)=C(Cl)CSC12
Yield: 90.2 %

Procedure:
The procedure used for the preparation of 9a was repeated with 8j (186 mg, 0.301 mmol), Et3SiH (0.480 mL, 3.01 mmol), and trifluoroacetic acid (0.927 mL, 12.0 mmol) in dry ClCH2CH2Cl (6 mL) at 0° C. under nitrogen to give 9j (123 mg, 90%) a s a brownish solid after crystallization from THF/CH2Cl2 /hexane. mp 175° C. (dec); IR (KBr) 3600-2700 (br), 3277, 1780, 1730, 1663 cm-1 ; 1H NMR (DMSO-d6) δ3.63 (1H, d, J=18.0 Hz), 3.78 (2H, s, CH2), 3.98 (1H, d, J=18.0 Hz), 5.15 (1H, d, J=4.8 Hz), 5.69 (1H, dd, J=8.1 and 4.8 Hz), 7.37 (1H, dd, J=8.4 and 4.3 Hz), 7.44 (1H, dd, J=8.4 and 1.1 Hz), 7.58 (1H, s), 8.14 (1H, dd, J=4.3 and 1.1 Hz), 9.23 (1H, d, J=8.1 Hz, NH), 11.62 (1H, s, OH), 13.80 (1H, br s, CO2H); FDMS m/z 453 (M+ +1, 35Cl), 455 (M+ +1, 37Cl); HRMS m/z Calcd for C17H1435ClN4O5S2 (M+ +1): 453.0094, Found: 453.0090.
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][CH2:8][CH2:9][NH:10][C:11]([N:13]1[CH:18]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:17]([C:26]([O:28][CH3:29])=[O:27])=[C:16]([CH3:30])[N:15]=[C:14]1[O:31]C)=[O:12])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:25][C:22]1[CH:23]=[CH:24][C:19]([CH:18]2[N:13]([C:11]([NH:10][CH2:9][CH2:8][CH2:7][C:6]([OH:33])=[O:5])=[O:12])[C:14](=[O:31])[NH:15][C:16]([CH3:30])=[C:17]2[C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:21]=1
Reactant: COC(=O)C1=C(C)N=C(OC)N(C(=O)NCCCC(=O)OC(C)(C)C)C1c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1=C(C)NC(=O)N(C(=O)NCCCC(=O)O)C1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
Into a solution of methyl 1-{[(4-tert-butoxy-4-oxobutyl)amino]carbonyl}-6-(4-fluorophenyl)-2-methoxy-4-methyl-1,6-dihydro-5-pyrimidinecarboxylate (77.3 mg, 0.166 mmol) in dichloromethane (2.00 mL) at 0° C. was slowly added trifluoroacetic acid (189 mg, 1.66 mmol). The reaction mixture was stirred at room temperature for 10 min and concentrated in vacuo. The residue was dissolved in iso-PrOH/CHCl3 (1:3, 10 mL) and basified to pH 11 with 10% KOH solution, washed with H2O, followed by brine. The organic layer was dried over MgSO4 and concentrated in vacuo to afford the desired product (58.1 mg, 88.9%). ESMS m/e: 394.1 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(O[N:47]1N=[N:54][C:49]2C=[CH:51][CH:52]=[CH:53][C:48]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.NC1C=NC=CC=1>CN(C=O)C>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([NH:47][C:48]2[CH:49]=[N:54][CH:51]=[CH:52][CH:53]=2)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:38]
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1cccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)Nc3cccnc3)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.2 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (31.3 mg, 0.06 mmol) in DMF (0.5 mL) were added HBTU (27.3 mg, 0.072 mmol), triethylamine (16.9 uL, 0.12 mmol) and 3-aminopyridine (11.3 mg, 0.08 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (3.3 mg, 9%). LC-MS m/z 598 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=[C:4]([CH:11]=[O:12])[CH:3]=1.[CH:13]([Mg]Cl)([CH3:15])[CH3:14].[Cl-].[NH4+]>CCOCC>[Br:1][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=[C:4]([CH:11]([OH:12])[CH:13]([CH3:15])[CH3:14])[CH:3]=1
Reactant: O=Cc1cc(Br)c2c(c1)OCO2
Reactant: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)C(O)c1cc(Br)c2c(c1)OCO2
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
To a solution of 7-bromo-benzo[1,3]dioxole-5-carbaldehyde (437 mg, 1.91 mmol) in dry ether (6 mL) was added slowly under argon at −30° C. isopropylmagnesium chloride (1.15 mL, 2.0 M in ether, 2.29 mmol) and the solution stirred for 30 minute. A solution of aqueous ammonium chloride was added and the layers separated. The aqueous layer was extrated with ethyl acetate and the organic combined and washed with water, brine, dried (MgSO4), filtered and evaporated to give 503 mg of 1-(7-bromo-benzo[1,3]dioxol-5-yl)-2-methyl-propan-1-ol.
Reaction SMILES: [CH2:1]([C@:3]1([OH:28])[C:25]2[CH:24]=[C:23]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:22])[CH:18]=[CH:19][C:20]=3[CH:21]=4)[C:9](=[O:26])[C:8]=2[CH2:7][O:6][C:5](=[O:27])[CH2:4]1)[CH3:2].[CH:29](=O)[CH2:30][CH2:31]C>>[CH2:1]([C@:3]1([OH:28])[C:25]2[CH:24]=[C:23]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:22])[CH:18]=[CH:19][C:20]=3[C:21]=4[CH2:29][CH2:30][CH3:31])[C:9](=[O:26])[C:8]=2[CH2:7][O:6][C:5](=[O:27])[CH2:4]1)[CH3:2]
Reactant: CCCC=O
Reactant: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2cc3ccc(F)cc3nc2-1
Product: CCCc1c2c(nc3cc(F)ccc13)-c1cc3c(c(=O)n1C2)COC(=O)C[C@]3(O)CC

Procedure:
The product of Example 84 is treated with butyraldehyde according to a procedure similar to Stage 95e in order to produce the expected solid.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[O:10][C:9](=[O:11])[CH:8]=[CH:7]1)(=[O:3])[CH3:2].C(C1C=CC=CC=1)(=O)C1C=CC=CC=1.[C:26]([O:29][CH2:30][CH3:31])(=[O:28])C.C(Cl)(Cl)Cl>O1CCOC1>[C:1]([O:4][CH2:5][C@H:6]1[O:10][C:9](=[O:11])[CH2:8][C@@H:7]1[CH:26]1[O:29][CH2:30][CH2:31][O:28]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@@H]1C=CC(=O)O1
Reactant: CCOC(C)=O
Agent: O=C(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: C1COCO1
Product: CC(=O)OC[C@H]1OC(=O)C[C@@H]1C1OCCO1
Yield: 92 %

Procedure:
A solution containing 1.20 g (7.69 mmol) of compound (2c) and 107 mg (0.587 mmol) benzophenone in 230 mL [1,3]-dioxolane was irradiated at 0° C. for 8.5 hours according to the general procedure. Column chromatography (silica gel 120 g, ethyl acetate in hexanes 50%) gave compound (3c) (1.63 mg. 92%) as a colorless solid, Rf=0.32, [α]25D 36.2°, c 1.3, CHCl3, IR (neat) 1780, 1745, 1216, 759 cm−1; 1H-NMR (500 MHz, CDCl3) δ: 2.08 (s, 3H), 2.52 (dd, 1H, J=10.4 Hz, J=21.7 Hz), 2.61-2.66 (m, 2H), 3.84-3.88 (m, 2H), 3.94-3.98 (m, 2H), 4.09 (dd, 1H, J=5.0 Hz, J=12.3 Hz), 4.32 (dd, 1H, J=2.9 Hz, J=12.3 Hz), 4.62 (mc, 1H), 4.87 (d, 1H, J=3.6 Hz). 13C-NMR (125.8 MHz, CDCl3, Dept) δ: 21.11 (+), 30.16 (−), 40.45 (+), 65.65 (−), 65.78 (−), 65.91 (−), 77.82 (+), 103.54 (+), 170.91 (quat), 175.88 (quat). C10H14O6; Exact Mass: 230.08; Mol. Wt.: 230.21; C, 52.17; H, 6.13; O, 41.70.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[C:11]([S-:13])#[N:12].[K+]>C(O)C.O>[S:13]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4])[C:11]#[N:12]
Reactant: O=C(CCl)c1ccccc1
Reactant: N#C[S-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CSCC(=O)c1ccccc1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
150 g of ω-chloroacetophenone are dissolved at 50° C. in 1000 ml of ethanol, followed by the addition of a solution of 102 g of KSCN in 40 ml of water. After stirring for 10 minutes at 50° C., the ω-thiocyano acetophenone formed is precipitated with water.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5](O)=[O:6].C(Cl)(=O)C([Cl:17])=O>CN(C)C=O.ClCCl>[Cl:1][C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5]([Cl:17])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(F)c(F)c(Cl)c1F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(F)c(F)c(Cl)c1F
Yield: 28.1 %

Procedure:
A solution of 9.4g (45 mmol) of 3-chloro-2,4,5-trifluorobenzoic acid, oxalyl chloride (7.6 g, 60 mmol), 3 drops of dimethylformamide, and 100 ml of dichloro-methane was stirred at room temperature for three hours. The solvent and excess oxalyl chloride were evaporated on the steam bath, and the residue was distilled at 121°-123° C. at 30 mm Hg to give 2.9 g of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10]Cl)=[N:5][N:4]=[N:3]1.[OH:12][C:13]1[C:14]([SH:19])=[N:15][CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][S:19][C:14]2[C:13]([OH:12])=[CH:18][CH:17]=[CH:16][N:15]=2)=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1SCCCCl
Reactant: Oc1cccnc1S
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1nnnc1SCCCSc1ncccc1O
Yield: 42.9 %

Procedure:
1-Methyl-5-(3-chloropropyl)thio-1,2,3,4-tetrazole (1.9 g) and 3-hydroxy-2-mercaptopyridine (1.3 g) are dissolved in acetone (50 ml). To the mixture are added potassium carbonate (1.4 g) and potassium iodide (0.1 g), and the mixture is refluxed for 5 hours. After acetone is distilled off, water is added to the residue, and the mixture is extracted with chloroform. The chloroform solution is washed with saturated aqueous sodium chloride and dried over magnesium sulfate. After chloroform is distilled off, the residue is purified by column chromatography (Kieselgel 60), followed by eluting with chloroform-methanol and recrystallizing from ethyl acetate-n-hexane to give 1-methyl-5-[3-(3-hydroxy-2-pyridyl)thiopropyl]thio-1,2,3,4-tetrazole (1.2 g) as pale yellow granules, m.p. 87.5°-88.5° C.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:12]([O:16][C:17](=[O:21])[C@H:18]([CH3:20])[NH2:19])[CH:13]([CH3:15])[CH3:14]>>[CH2:12]([O:16][C:17](=[O:21])[C@H:18]([CH3:20])[NH:19][C:8](=[O:9])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)COC(=O)[C@H](C)N
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Product: CC(C)COC(=O)[C@H](C)NC(=O)Cc1ccccc1

Procedure:
Following General Procedure BB and using phenylacetyl chloride (Aldrich) and L-alanine iso-Butyl Ester hydrochloride (from Example BB above), the title compound was prepared as a solid having a melting point of 45°-47° C. The reaction was monitored by tlc on silica gel and purification was by extraction with Et2O followed by washes with aqueous K2CO3 and aqueous HCl.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[N:12]([CH3:14])[CH3:13].[CH2:22]([N:24]([CH2:38][CH3:39])[C:25](=[O:37])[NH:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1)[CH3:23]>CCCCCC.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:33]([C:30]1[CH:29]=[CH:28][C:27]([NH:26][C:25]([N:24]([CH2:38][CH3:39])[CH2:22][CH3:23])=[O:37])=[CH:32][CH:31]=1)(=[O:35])=[O:34])[C:6](=[O:11])[C:5]2([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[N:12]([CH3:14])[CH3:13]
Reactant: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN(C)C1(c2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)N2C(=O)C(c3ccccc3Cl)(N(C)C)c3cc(Cl)ccc32)cc1

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 1 from 0.500 g of 5-chloro-3-(2-chlorophenyl)-1,3-dihydro-3-(dimethylamino)indol-2-one and 0.453 g of 4-(N',N'-diethylureido)benzenesulfonyl chloride. Chromatography on silica using a gradient of a hexane/AcOEt mixture (80/20; v/v to 60/40; v/v) as the eluent gives the expected product after crystallization from a DCM/iso ether mixture. m=0.520 g. M.p.=146°-150° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]([CH2:11][C:12]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)(O)[CH3:13])[C:8]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>O=S(Cl)Cl.O>[Cl:1][C:2]1[C:10]2[N:9](/[CH:11]=[C:12](/[C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)\[CH3:13])[C:8]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCc2c(c3cccc(Cl)c3n2CC(C)(O)c2ccncc2)C1
Agent: [K+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: O
Product: C/C(=C\n1c2c(c3cccc(Cl)c31)CN(C)CC2)c1ccncc1
Temperature: 100 °C

Procedure:
1-(6-Chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-4-yl)propan-2-ol (650 mg, 1.8 mmol) in SOCl2 (6.5 mL) was stirred at RT for 2 h. The progress of reaction was monitored by TLC and 1H NMR. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in N-methyl-2-pyrrolidone (3 mL), KOH (737 mg, 13.1 mmol) was added and the reaction mixture was heated at 100° C. for 2 h. After it was cooled to RT, the reaction mixture was diluted with water and extracted with EtOAc. Organic was separated, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent 5% MeOH-DCM). 1H NMR (CD3OD, HCl salt) δ (ppm): 8.70 (d, 2H), 7.80 (d, 2H), 7.56 (s, 1H), 7.45 (d, 1H), 7.25 (d, 1H), 7.10 (t, 1H), 4.80 (m, 2H), 3.90 (m, 1H), 3.20 (m, 1H), 3.15 (s, 3H), 1.95 (s, 3H).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:24]=[CH:25][CH:26]=2)[O:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][NH:16][C:17](=[O:23])[CH2:18][S:19][CH2:20][CH2:21][NH2:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:27]([O:29][C:30](Cl)=[O:31])[CH3:28].[Cl-].[Na+]>N1C=CC=CC=1>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:24]=[CH:25][CH:26]=2)[O:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][NH:16][C:17](=[O:23])[CH2:18][S:19][CH2:20][CH2:21][NH:22][C:30]([O:29][CH2:27][CH3:28])=[O:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)Cl
Reactant: NCCSCC(=O)NC/C=C\COc1cccc(CN2CCCCC2)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CCOC(=O)NCCSCC(=O)NC/C=C\COc1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.7 %

Procedure:
There was dissolved 2.7 g (0.0072 mol) of N-[4-[3-(piperidinomethyl) phenoxy]-cis-2-butenyl]-2-(2-aminoethylthio)acetamide in 20 ml of pyridine and added dropwise 0.78 g (0.0072 mol) of ethylchlorocarbonate under cooling with ice, and the mixture was stirred for 18 hours at room temperature. The obtained reaction mixture was poured into ice water and saturated with sodium chloride. The deposited oily matter was extracted with chloroform and washed with saturated aqueous solution of sodium chloride, and then dried over Glauber's salt. Then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to give 0.8 g of the titled compound as oily matter.
Reaction SMILES: [CH3:1][Si:2]([CH2:5][Mg]Cl)([CH3:4])[CH3:3].[CH:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl-].[NH4+]>C(OCC)C>[CH3:1][Si:2]([CH3:3])([CH3:4])[CH2:5][CH:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C[Si](C)(C)C[Mg]Cl
Reactant: O=Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: C[Si](C)(C)CC(O)c1ccccc1

Procedure:
A 1.0M solution (75 ml) of trimethylsilylmethyl magnesium chloride in diethyl ether was diluted with dry diethyl ether (50 ml). After the interior of an reaction vessel was replaced by nitrogen, a solution (50 ml) of benzaldehyde (5.3 g) in dry diethyl ether was slowly added dropwise to the solution in the reaction vessel while stirring. The reaction mixture was stirred at 40° C. for 2 hours under nitrogen atmosphere and cooled in an ice bath. A 25% aqueous solution (100 ml) of ammonium chloride was added dropwise thereto, the mixture was extracted with diethyl ether, washed with water and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 1-trimethylsilyl-2-hydroxy-2-phenylethane (13.1 g) as pale yellow oily material.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[OH:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([CH:24]=1)[C:20]([O:22][CH3:23])=[O:21].C(N(C(C)C)CC)(C)C>ClCCl>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2]([O:14][C:15]2[CH:16]=[N:17][CH:18]=[C:19]([CH:24]=2)[C:20]([O:22][CH3:23])=[O:21])=[O:3])=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: COC(=O)c1cncc(O)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cncc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
4-Nitrophenyl chloroformate (7.0 g) was added to a dichloromethane (100 ml) solution of methyl 5-hydroxynicotinate (5.3 g) and diisopropylethylamine (6.1 ml), followed by stirring at room temperature for 1 hour. The reaction liquid was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting solid was washed with EtOAc/hexane and dried under reduced pressure to obtain methyl 5-{[(4-nitrophenoxy)carbonyl]oxy}nicotinate (8.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:31][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1>CN(C=O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: ClCc1ccncc1
Reactant: COc1cc2c(Oc3ccc(Cl)cc3F)ncnc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(Cl)cc3F)ncnc2cc1OCc1ccncc1
Temperature: 80 °C
Yield: 79.8 %

Procedure:
A mixture of 4-(4-chloro-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline (112 mg, 0.35 mmol), potassium carbonate (138 mg, 1 mmol) and 4-(chloromethyl)pyridine hydrochloride (59 mg, 0.36 mmol) in DMF (2 ml) was heated at 80° C. for 1 hour. The mixture was allowed to cool and partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (95/5) to give 4-(4-chloro-2-fluorophenoxy)-6-methoxy-7-((4-pyridyl)methoxy)quinazoline (115 mg, 80%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[O:14][C:13]([C:15]3[CH:16]=[C:17]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[C:18]([NH2:21])=[CH:19][CH:20]=3)=[N:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.[C:31](=O)([O-])O.[Na+]>C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]4[N:21]=[CH:31][N:22]([C:23]5[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=5)[C:17]=4[CH:16]=3)=[N:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: COc1ccc(Nc2cc(-c3nnc(CCc4cccc(F)c4)o3)ccc2N)cc1
Agent: [Na+]
Solvent: O=CO
Product: COc1ccc(-n2cnc3ccc(-c4nnc(CCc5cccc(F)c5)o4)cc32)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
A mixture of 4-[5-[2-(3-fluorophenyl)ethyl]-1,3,4-oxadiazol-2-yl]-N2-(4-methoxyphenyl)benzene-1,2-diamine (0.20 g, 0.49 mmol) and formic acid (1.4 mL) was stirred at 100° C. overnight. After cooling, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=1/1) to give the title compound (0.10 g, yield 49%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.[NH:19]1[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:19]3[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20]3)[S:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Reactant: OC1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: OC1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36.1 %

Procedure:
To a solution of 2-chloro-4-morpholinothieno[2,3-d]pyrimidine-6-carbaldehyde (1.1 g, 3.9 mmol) in 1,2-dichloroethane (20 mL) was added pyrrolidin-3-ol (5.4 mmol), and AcOH (3.9 mmol). After the reaction mixture stirred 10 min at room temperature, Na(OAc)3BH (4.6 mmol) was added then the mixture stirred 72 h at room temperature. The reaction was quenched by the addition of saturated aqueous NaHCO3. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organics were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by silica gel chromatography (0-20% MeOH in CH2Cl2) to afford 1-((2-chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)pyrrolidin-3-ol (0.5 g). MS (Q1) 355 (M)+