Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[N:9]=[N:10][O:11][CH:12]=2)=[CH:5][CH:4]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C[N:28]1C(=O)CCC1>C(Cl)Cl>[NH2:28][CH2:1][C:3]1[S:7][C:6]([C:8]2[N:9]=[N:10][O:11][CH:12]=2)=[CH:5][CH:4]=1
Reactant: CN1CCCC1=O
Reactant: O=Cc1ccc(-c2conn2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: NCc1ccc(-c2conn2)s1
Reaction time: 2 h

Procedure:
To a solution of the 5-formyl-thiophen-2-yl-oxadiazol derivative (1 eq., usual scale 0.02-0.25 mmol) and the appropriate amine (2-40 eq.) in DCM (24 mL/mmol) and NMP (6 mL/mmol), sodium triacetoxy borohydride (NaBH(OAc)3) (3 eq.) is added. The mixture is stirred for 2 h before another portion of NaBH(OAc)3 (3 eq.) is added. Stirring of the suspension is continued for another 2 h and a third portion of NaBH(OAc)3 (3 eq.) is added. The mixture is stirred for 16 h before the DCM is evaporated. The remaining residue is diluted with water (4 mL/mmol) and formic acid (4 mL/mmol) and the resulting solution is separated by prep. HPLC (XBridge Prep C18, 19×50 mm, 5 μm, 10% to 95% acetonitrile in water containing 0.5% formic acid) to give the desired 5-aminomethyl-thiophen-2-yl-oxadiazol derivative as a colourless to pale yellow resin.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([NH2:16])=[CH:11][C:10]=1[F:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O.Cl>C1COCC1>[CH2:1]([O:8][C:9]1[C:10]([F:17])=[CH:11][C:12]([NH2:16])=[C:13]([Br:18])[C:14]=1[F:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(F)c(OCc2ccccc2)c(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: Cl
Solvent: C1CCOC1
Product: Nc1cc(F)c(OCc2ccccc2)c(F)c1Br
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
To a solution of 4-benzyloxy-3,5-difluorophenylamine (3.0 g) in THF (30 mL) was added N-bromosuccinimide (2.32 g) under ice-cooling, and the mixture was stirred for 30 minutes. Conc. Hydrochloric acid (2 mL) was added to the reaction mixture to precipitate a solid. The solid was collected by filtration and dried. The dried solid was dissolved in water, and the solution was added with saturated aqueous sodium bicarbonate, and then extracted with ethyl acetate. The extract was dried over sodium sulfate and concentrated to give 4-benzyloxy-2-bromo-3,5-difluorophenylamine (3.33 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:25])([CH2:19][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1)[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[OH:11].C(N(CC)CC)C.C(Cl)(=O)[C:34](Cl)=[O:35].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:19][N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)[CH:10]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[O:11][C:34](=[O:35])[O:25]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: OC(c1ccc(F)cc1)C(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C1OC(c2ccc(F)cc2)C(Cn2cncn2)(c2ccc(Cl)cc2Cl)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.3 %

Procedure:
To a solution of 400 mg of 2-(2,4-dichlorophenyl)-1-(4-fluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-1,2-propanediol and 430 mg of triethylamine in 20 ml of dry chloroform is added a solution of 532 mg of oxalyl chloride and 2 ml of dry chloroform in small portions with ice-cooling, and the mixture is stirred at room temperature for 1 hour. The reaction mixture is mixed with ice-water and aqueous sodium bicarbonate solution and extracted with methylene chloride. The organic layer is washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue is chromatographed on a column of silica-gel and eluted with benzene-ethyl acetate (1:1 v/v). The eluate is concentrated, and the resulting residue is crystallized from ethyl acetate-isopropyl ether to give 219 mg of 4-(2,4-dichlorophenyl)-5-(4-fluorophenyl)-2-oxo-4-(1H-1,2,4-triazol-1-yl)methyl-1,3-dioxolane as crystals. m.p. 190°-191° C. Yield: 51.3%
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]2[N:9]=[C:8]([CH3:10])[NH:7][C:6]=2[CH:11]=1.Br[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[Cl:24].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]2[N:9]=[C:8]([CH3:10])[N:7]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[Cl:24])[C:6]=2[CH:11]=1
Reactant: Clc1cccc(CBr)c1Cl
Reactant: Cc1nc2c([N+](=O)[O-])cc(Br)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc2c([N+](=O)[O-])cc(Br)cc2n1Cc1cccc(Cl)c1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 83.8 %

Procedure:
A mixture of Example 1 (1.17 g) (prepared as described previously described), 1-(bromomethyl)-2,3-dichlorobenzene (1.19 g) and K2CO3 (1.27 g) in DMF (80 mL) was stirred at 80° C. for 3 h. When TLC showed no starting material, the mixture was cooled to room temperature and filtered. The filtrate was then poured into water. It was then filtered to afford a solid and the solid was washed with water and then dried in-vacuo to afford the desired product (1.59 g, 83%)1H NMR (300 MHz, CDCl3) δ ppm 2.67 (s, 3H), 5.45 (m, 2H), 6.24 (t, 1H, J=7.8 Hz), 7.10 (t, 1H, J=7.8 Hz), 7.47 (t, 1H, J=7.8 Hz), 7.59 (d, 1H, J=1.8 Hz), 8.24 (d, 1H, J=1.8 Hz); LC-MS: m/e=416 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][N:4]=1.[Li]CCCC.CN([CH:19]=[O:20])C.[Cl-].[NH4+]>C1COCC1>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([CH:19]=[O:20])[CH:6]=[CH:5][N:4]=1
Reactant: COc1cccnc1OC
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1nccc(C=O)c1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
To a solution of 2,3-dimethoxypyridine (1.0 g, 7.19 mmol) in dry THF (30 mL), cooled to −78° C., was added 2.5 M nBuLi in hexanes (6.33 mL, 15.8 mmol). The mixture was allowed to warm to 0° C. and stirred for 1 hour, before cooling to −78° C. A solution of DMF (2.4 mL, 31.5 mmol) in THF (5 mL) was added. The reaction mixture was allowed to warm to 0° C. and saturated aqueous ammonium chloride solution was added. The resultant biphasic mixture separated and extracted twice with diethyl ether. The combined organic phase was washed with water, and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 15 to 20% ethyl acetate in cyclohexane) to afford the title compound (0.79 g, 65%) as a white solid. LCMS (Method B): RT-=2.71 min, [M+H]+=168.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]([NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])([CH2:35][O:36][Si](C(C)(C)C)(C)C)[CH:27]=[CH:28][P:29](=[O:34])([O:32][CH3:33])[O:30][CH3:31])=[C:18]([Cl:52])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O1CCCC1.O>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]([NH:44][C:45]([O:47][C:48]([CH3:50])([CH3:49])[CH3:51])=[O:46])([CH2:35][OH:36])[CH2:27][CH2:28][P:29](=[O:34])([O:32][CH3:33])[O:30][CH3:31])=[C:18]([Cl:52])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COP(=O)(C=CC(CCCCc1ccc(Sc2cccc(OCc3ccccc3)c2)cc1Cl)(CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COP(=O)(CCC(CO)(CCCCc1ccc(Sc2cccc(OCc3ccccc3)c2)cc1Cl)NC(=O)OC(C)(C)C)OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The compound of Example 287 was reduced in the same manner as in Reference Example 123 and the resulting compound (107 mg) was dissolved in tetrahydrofuran (5.0 mL). A 1 mol/L TBAF-tetrahydrofuran solution (160 μL) was added dropwise and the mixture was stirred for 3 hours at room temperature. Subsequently, water was added and the reaction mixture was extracted with ethyl acetate. The extract was washed sequentially with water and a saturated aqueous solution of sodium chloride and the organic phase was dried over anhydrous sodium sulfate. The solvent was removed by distillation and the residue was purified on a silica gel column chromatography (ethyl acetate only) to obtain the desired product as a colorless oil (47 mg).
Reaction SMILES: [CH3:1][C:2]1([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][NH:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.[CH3:21][N:22]=[C:23]=[O:24]>C1CCCCC1>[CH3:1][C:2]1([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][N:3]1[C:23]([NH:22][CH3:21])=[O:24])=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: CN=C=O
Reactant: CCOC(=O)CC1(C)NCCc2c1[nH]c1ccccc21
Solvent: C1CCCCC1
Product: CCOC(=O)CC1(C)c2[nH]c3ccccc3c2CCN1C(=O)NC

Procedure:
10.9 g (0.04 mol) of ethyl 1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-acetate are suspended in 200 ml of cyclohexane. 3 ml (0.04 mol) of methyl isocyanate are added. The mixture is heated under reflux for 1 hour. It is allowed to cool overnight in a refrigerator. The precipitate is filtered off. The product is recrystallised from ethanol.
Reaction SMILES: C([O:5][NH:6][C:7](=[O:32])[CH2:8][N:9]([S:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)(=[O:23])=[O:22])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)(C)(C)C.C(O)C>C(Cl)Cl>[OH:5][NH:6][C:7](=[O:32])[CH2:8][N:9]([S:21]([C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)(=[O:23])=[O:22])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1
Reactant: COc1ccc(S(=O)(=O)N(CC(=O)NOC(C)(C)C)Cc2ccc3ccccc3n2)cc1
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(S(=O)(=O)N(CC(=O)NO)Cc2ccc3ccccc3n2)cc1
Reaction time: 8 h

Procedure:
(a) N-(t-Butyloxy)-2-[[4-methoxybenzenesulfonyl](2-quinolinylmethyl)amino]acetamide (1.15 g, 2.42 mmol) is dissolved in methylene chloride (30.0 mL) and ethanol (0.20 mL) in a glass sealed tube. Hydrochloric acid gas (from a lecture bottle) is bubbled through the solution for 20 minutes, and then the tube is sealed and stands at room temperature overnight. The next day, additional hydrochloric acid gas is bubbled through the solution for 20 minutes, more ethanol (0.20 mL) is added, and then the tube is sealed and stands at room temperature for two days. After that time, the solvent is removed. The product is purified by silca gel chromatography (5% to 15% methanol/methylene chloride with ~1% ammonium hydroxide) to give N-hydroxy-2-[[4-methoxybenzenesulfonyl](2-quinolinylmethyl)amino]acetamide, m.p. 177°-178° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:21]=1[NH2:22]>>[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:21]=1[NH:22][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)[N:3]=1
Reactant: COCc1cc(Cl)nc(-c2cccc(C)c2)n1
Reactant: COc1ccc(OC)c(N)c1
Product: COCc1cc(Nc2cc(OC)ccc2OC)nc(-c2cccc(C)c2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-6-(methoxymethyl)-2-(3-methylphenyl)pyrimidine (100 mg, 0.402 mmol) and 2,5-dimethoxyaniline (62 mg, 0.402 mmol) similar to Example 13 and isolated as a pale white solid (65 mg, 45%). 1H NMR (CDCl3): 8.30 (d, J=3.0 Hz, 1H), 8.26–8.23 (m, 2H), 7.37–7.25 (m, 3H), 6.81 (d, J=9.0 Hz, 1H), 6.73 (s, 1H), 6.55 (dd, J=3.0, 8.7 Hz, 1H), 4.52 (d, J=0.9 Hz, 2H), 3.87 (s, 3H), 3.83 (s, 3H), 3.51 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: O1[C:11]2([CH3:12])[CH:2]1[C:3](=[O:14])[C:4]1[C:9]([C:10]2=[O:13])=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:15]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>C(O)C>[CH3:12][C:11]1[C:10](=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:14])[C:2]=1[N:18]1[CH2:17][CH2:16][N:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19]1
Reactant: CC12OC1C(=O)c1ccccc1C2=O
Reactant: CCOC(=O)N1CCNCC1
Solvent: CCO
Product: CCOC(=O)N1CCN(C2=C(C)C(=O)c3ccccc3C2=O)CC1
Temperature: 50 °C
Reaction time: 12 h
Yield: 30.5 %

Procedure:
A mixture of 1.88 g of 2,3-epoxy-3-methyl-1,4-naphthoquinone, 3.16 g of piperazinecarboxylic acid, ethyl ester and 100 ml of absolute ethanol was stirred for 12 hours at 50°C. The solvent was then removed and the remainder filtered through a one inch plug of silica gel and eluted with chloroform. The eluate was evpaorated, giving 1 g of the desired product as a viscous red oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2.[CH2:22]([NH2:25])[CH2:23][CH3:24].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH:25][CH2:22][CH2:23][CH3:24])[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2
Reactant: CCCN
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCNc1cc2c(cc1Cl)C=C(C(=O)OCC)C(C(F)(F)F)O2
Temperature: 90 °C
Yield: 78.5 %

Procedure:
A mixture of ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-chromene-3-carboxylate (Example 7a, Step 2) (0.5 g, 1.54 mmole) and propylamine (0.13 mL, 1.54 mmole) was dissolved in anhydrous DMF (5 mL), which was warmed to 90° C. and treated with K2CO3 (0.25 g, 1.84 mmole). The mixture was maintained at 90° C. for 24 hrs, cooled to room temperature, filtered through celite and condensed to a viscous oil. The oil was purified by flash chromatography (silica gel) with 40% methylene chloride in hexane to give a light yellow oil (0.44 g, 79%): GCMS m/z 363.00 (M+). 1H NMR (CDCl3/400 MHz) 7.57 (s, 1H), 7.08 (s, 1H), 6.23 (s, 1H), 5.63 (q, 1H, J=7.0 Hz), 4.73 (brs, 1H), 4.26 (m, 2H), 3.14 (m, 2H), 1.66 (m, 2H), 1.31 (m, 3H), 1.01 (m, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[O:9][C:4]=2[CH:3]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1F)[CH:19]=[O:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:11][C:8]1([CH3:10])[O:7][C:6](=[O:12])[C:5]2[CH:13]=[CH:14][C:2]([O:1][C:23]3[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][C:16]=3[F:15])=[CH:3][C:4]=2[O:9]1
Reactant: CC1(C)OC(=O)c2ccc(O)cc2O1
Reactant: O=Cc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)c2ccc(Oc3ccc(C=O)cc3F)cc2O1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
7-Hydroxy-2,2-dimethyl-benzo[1,3]dioxin-4-one (I-1a: 12.9 g), 3,4-difluorobenzaldehyde (9.45 g) and potassium carbonate (27.6 g) were combined in dimethylformamide (100 mL) and stirred as the reaction mixture was heated to 80° C. After 24 hours, the reaction mixture was cooled to ambient temperature, combined with water, and extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered, and evaporated. The residue was purified by column chromatography on silica gel eluting with 10-15% ethyl acetate in heptane to give the title compound (I-1b-1).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH2:6][CH2:7][N:8]1[C:13]2[CH:14]=[C:15]([C:19]([OH:21])=O)[C:16]([CH3:18])=[CH:17][C:12]=2[S:11][CH:10]([CH3:22])[C:9]1=[O:23])=[O:4].C(N(C(C)C)C(C)C)C.[CH:33]([NH:36][C@@H:37]1[CH2:42][CH2:41][CH2:40][N:39]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:38]1)([CH3:35])[CH3:34].[Cl-].[Na+]>CN(C)C=O>[CH:33]([N:36]([C:19]([C:15]1[C:16]([CH3:18])=[CH:17][C:12]2[S:11][CH:10]([CH3:22])[C:9](=[O:23])[N:8]([CH2:7][CH2:6][NH:5][C:3]([O:2][CH3:1])=[O:4])[C:13]=2[CH:14]=1)=[O:21])[C@@H:37]1[CH2:42][CH2:41][CH2:40][N:39]([C:43]([O:45][C:46]([CH3:48])([CH3:47])[CH3:49])=[O:44])[CH2:38]1)([CH3:35])[CH3:34]
Reactant: COC(=O)NCCN1C(=O)C(C)Sc2cc(C)c(C(=O)O)cc21
Reactant: CC(C)N[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NCCN1C(=O)C(C)Sc2cc(C)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21
Reaction time: 8 h

Procedure:
To a solution of 4-{2-[(methoxycarbonyl)amino]ethyl}-2,7-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylic acid (460 mg) in N,N-dimethylformamide (4 ml) were added CIP reagent, N-ethyldiisopropylamine, tert-butyl (3R)-3-(isopropylamino)piperidine-1-carboxylate, and the mixture was stirred overnight. After the reaction was complete, to the mixture was added a saturated aqueous sodium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (284 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH:23]2[C:28](=[O:37])[NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[CH:31]=2)[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].[Cl:44][C:45]1[CH:46]=[C:47]([CH:49]=[CH:50][C:51]=1[F:52])[NH2:48]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1.CC(O)(C)C>[Cl:44][C:45]1[CH:46]=[C:47]([CH:49]=[CH:50][C:51]=1[F:52])[NH:48][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH:23]2[C:28](=[O:37])[NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[CH:31]=2)[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: COc1ccc(-c2ccc3nc(Cl)nc(N4CCNCC4C(=O)Nc4cccc(C)c4)c3n2)cc1OC
Reactant: Nc1ccc(F)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CC(C)(C)O
Product: COc1ccc(-c2ccc3nc(Nc4ccc(F)c(Cl)c4)nc(N4CCNCC4C(=O)Nc4cccc(C)c4)c3n2)cc1OC
Yield: 47.8 %

Procedure:
A suspension of 2-chloro-4-[(N-3-methyl-phenylcarbamoyl)-piperazin-1-yl]-6-(3,4-dimethoxyphenyl)-pyrido[3,2-d]pyrimidine (106 mg, 0.20 mmole), K2CO3 (62 mg, 0.45 mmole) and 3-chloro-4-fluoroaniline (60 mg 0.40 mmole) in a 1,4-dioxane/t-BuOH 5:1 mixture (2 ml) was purged with nitrogen for 15 minutes. Thereafter, tetrakis(triphenylphosphine)palladium(0) (28 mg, 24 μmol) was added and the reaction mixture was heated at reflux under a N2 atmosphere for 20 hours. Upon cooling, the mixture was partitioned between ethyl acetate and brine. The organic phase was evaporated under reduced pressure and the crude residue was purified by flash chromatography on silica, using an ethyl acetate/n-hexane mixture as the mobile phase (in a ratio gradually ranging from 1:1 to 4:1), thus affording the pure title compound (60 mg, yield 47%) which was characterized by its mass spectrum as follows: MS (m/z): 628 ([M+H]+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:18])[C:5]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[CH2:17])=[CH:12][CH:11]=2)=[C:6]([F:8])[CH:7]=1.B1C2CCCC1CCC2.[OH-:28].[Na+].OO>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([F:18])[C:5]([O:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][OH:28])=[CH:14][CH:15]=2)=[C:6]([F:8])[CH:7]=1
Reactant: [OH-]
Reactant: C=Cc1ccc(Oc2c(F)cc(Cl)cc2F)cc1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCc1ccc(Oc2c(F)cc(Cl)cc2F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
To the solution of 5-chloro-1,3-difluoro-2-(4-vinylphenoxy)benzene (2.6 g, 9.75 mmol) in dry THF (10 mL), was added 9-BBN (39.0 mL, 19.50 mmol) at 0° C. The mixture was stirred at room temperature overnight. aq. NaOH (7.0 mL, 21.00 mmol), and 30% H2O2 (2.0 mL, 19.58 mmol) were added then. The reaction mixture was heated at 50° C. for 4 h. Then THF was removed under reduced pressure, and the residue was diluted with EA. The organic layer was washed with water and brine, dried over anhydrous Na2SO4 and concentrated and purified by flash chromatography to afford the title compound (1.6 g, 5.62 mmol, 57.6% yield) as a white oil.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Cl:13])=[N:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.[CH3:15][C:16]1[CH:17]=[C:18]([CH:30]([NH2:32])[CH3:31])[CH:19]=[N:20][C:21]=1[O:22][CH2:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26]>>[Cl:13][C:12]1[C:3]2[CH2:2][N:32]([CH:30]([C:18]3[CH:19]=[N:20][C:21]([O:22][CH2:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])=[C:16]([CH3:15])[CH:17]=3)[CH3:31])[C:5](=[O:7])[C:4]=2[CH:9]=[CH:10][N:11]=1
Reactant: COC(=O)c1ccnc(Cl)c1CBr
Reactant: Cc1cc(C(C)N)cnc1OCC(F)(F)C(F)F
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1OCC(F)(F)C(F)F
Yield: 64 %

Procedure:
The title compound is prepared in 64% yield (152 mg, yellow oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)ethanamine hydrochloride (172 mg, 0.57 mmol, Amine-17, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [C:1]([NH:9][NH:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1.C(OCC)C>[C:11]([N:10]([S:21]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:23])=[O:22])[NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)NNC(=O)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)(C)N(NC(=O)c1ccccc1)S(=O)(=O)c1ccccc1
Reaction time: 1 h

Procedure:
N-benzoyl-N'-t-butyl hydrazine (0.8 g) was stirred in pyridine (2 ml) at room temperature. Benzenesulfonyl chloride (0.8 g) was added slowly dropwise, stirred about 1 hour, diluted with diethyl ether (10 ml) and washed several times with a 10% HCl solution and then water. The organic layer was dried over magnesium sulfate. The mixture was filtered and the solvent rotavapped off to afford a white solid in good yield.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[C:5]([Cl:18])=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:21]=[C:22]([CH2:26][CH2:27][CH2:28][OH:29])[CH:23]=[CH:24][CH:25]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[Cl:18][C:5]1[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[N:7][C:2]([NH:19][C:20]2[CH:21]=[C:22]([CH2:26][CH2:27][CH2:28][OH:29])[CH:23]=[CH:24][CH:25]=2)=[N:3][CH:4]=1
Reactant: Nc1cccc(CCCO)c1
Reactant: COc1cccc(CNc2nc(Cl)ncc2Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(CNc2nc(Nc3cccc(CCCO)c3)ncc2Cl)c1
Temperature: 105 °C
Yield: 64.5 %

Procedure:
Into a reaction flask were added 2,5-dichloro-N-(3-methoxybenzyl)pyrimidin-4-amine (0.20 g, 0.70 mmol, prepared according to Example 1, step A), 1,4-dioxane (20 mL), 3-(3-aminophenyl)propan-1-ol (0.16 g, 1.0 mmol, prepared according to Example 12, step A & B), and p-toluenesulfonic acid monohydrate (0.049 g, 0.26 mmol). The mixture was heated at 105° C. for 2 days and NaHCO3 (saturated aqueous solution) was added. The organic solvent was removed under vacuum followed by an addition of water and EtOAc. The aqueous layer was extracted with EtOAc twice. The organic layers were combined, dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography to give the desired product (0.18 g, 64%) as a white solid. LCMS for C21H24lN4O2 (M+H)+: m/z=399.1.