Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(=O)(OC)[O:8][C:9]1[CH:14]=[C:13]([OH:15])[C:12]([F:16])=[CH:11][C:10]=1[CH3:17].Cl>CO>[F:16][C:12]1[CH:11]=[C:10]([CH3:17])[C:9]([OH:8])=[CH:14][C:13]=1[OH:15]
Reactant: COC(=O)Oc1cc(O)c(F)cc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1cc(F)c(O)cc1O
Temperature: 50 °C
Yield: 70.7 %

Procedure:
Potassium carbonate (870 mg, 6.3 mmol) was added to a solution of (4-fluoro-5-hydroxy-2-methylphenyl) methyl carbonate (1.2 g, 6 mmol) in methanol (20 ml) and the mixture was heated at 50° C. for 1 hour. The mixture was allowed to cool, adjusted to pH3 with hydrochloric acid and extracted with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4) and the volatiles removed by evaporation. The residue was purified by column chromatography eluting with petroleum ether/ethyl acetate (7/3) to give 2-fluoro-5-hydroxy-4-methylphenol (603 mg, 70%) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH:10]([NH:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([NH2:28])[CH:24]=3)[N:19]=2)[CH2:9]1>>[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH:10]([NH:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([NH:28][S:3]([N:2]([CH3:7])[CH3:1])(=[O:5])=[O:4])[CH:24]=3)[N:19]=2)[CH2:9]1
Reactant: Nc1ccc2nc(NC3COc4ccccc43)ccc2c1
Reactant: CN(C)S(=O)(=O)Cl
Product: CN(C)S(=O)(=O)Nc1ccc2nc(NC3COc4ccccc43)ccc2c1

Procedure:
The title compound was prepared in accordance with the general method described in example 66 from dimethylsulfamoylchloride and rac-N2-(2,3-dihydro-benzofuran-3-yl)-quinoline-2,6-diamine; MS: m/e=385.6 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:27])=[C:6]([C:8]2[C:23](=[O:24])[N:22]([O:25][CH3:26])[C:11]3[N:12]=[C:13]([NH:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[N:14]=[CH:15][C:10]=3[CH:9]=2)[CH:7]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:59][C:60]1[CH:68]=[CH:67][C:63]([C:64](O)=[O:65])=[CH:62][C:61]=1[C:69]([F:72])([F:71])[F:70]>CN(C=O)C>[Cl:59][C:60]1[CH:68]=[CH:67][C:63]([C:64]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([Cl:27])=[C:6]([C:8]3[C:23](=[O:24])[N:22]([O:25][CH3:26])[C:11]4[N:12]=[C:13]([NH:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[N:14]=[CH:15][C:10]=4[CH:9]=3)[CH:7]=2)=[O:65])=[CH:62][C:61]=1[C:69]([F:70])([F:71])[F:72]
Reactant: COn1c(=O)c(-c2cc(N)ccc2Cl)cc2cnc(NCCN(C)C)nc21
Reactant: O=C(O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COn1c(=O)c(-c2cc(NC(=O)c3ccc(Cl)c(C(F)(F)F)c3)ccc2Cl)cc2cnc(NCCN(C)C)nc21
Temperature: 25 °C
Yield: 70 %

Procedure:
In a 3 ml vial equipped with a small triangular magnetic stirring bar was placed 6-(5-amino-2-chlorophenyl)-2-(2-(dimethylamino)ethylamino)-8-methoxypyrido[2,3-d]pyrimidin -7(8H)-one (348 μmol). Triethylamine (344 μmol) was added, followed by aliquots of DMF stock solutions of HATU (320 μmol) and 4-chloro-3-(trifluoromethyl)benzoic acid (129 μmol), and the mixture was stirred at room temperature over night. The solution was transferred to maximum recovery HPLC vials and purified by prep. HPLC-MS. The collected fractions were transferred to centrifuge vials and lyophilized, giving 4-chloro-N-(4-chloro-3-(2-(2-(dimethylamino)ethylamino)-8-methoxy-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl) -3-(trifluoromethyl)benzamide as a solid (70%).
Reaction SMILES: [CH2:1]([C@@H:3]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:13][C:5]=2[O:4]1)[CH3:2].[H-].[Na+].I[CH:21]([CH3:23])[CH3:22].O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C@@H:3]1[C:8](=[O:9])[N:7]([CH:21]([CH3:23])[CH3:22])[C:6]2[CH:10]=[CH:11][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:13][C:5]=2[O:4]1)[CH3:2]
Reactant: CC(C)I
Reactant: CC[C@H]1Oc2cc(C(=O)OC)ccc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC[C@H]1Oc2cc(C(=O)OC)ccc2N(C(C)C)C1=O
Temperature: 60 °C
Reaction time: 3 h
Yield: 37 %

Procedure:
To a solution of (R)-2-ethyl-7-methoxycarbonyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (3.90 g) in dimethylformamide (100 ml) were added 60% sodium hydride (in oil) (0.71 g) and 2-iodopropane (3.0 g) and the mixture was stirred at 60° C. for 3 hours. Water was added to the reaction solution and extraction with ethyl acetate was conducted. The solvent was distilled off under reduced pressure and the resulting residue was subjected to purification by column chromatography using ethyl acetate/hexane [1:4 (v/v)] to give (R)-2-ethyl-7-methoxycarbonyl-4-(2-propyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (1.70 g) as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[CH:10]=1.[CH3:11][S-:12].[Na+]>CN(C=O)C>[CH3:11][S:12][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[CH:10]=1
Reactant: Brc1ccc2ccsc2c1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc2ccsc2c1
Temperature: 90 °C
Reaction time: 6 h
Yield: 83.2 %

Procedure:
A mixture of 6-bromobenzo[b]thiophene (2.0 g, 9.4 mmol) and sodium thiomethoxide (1.30 g, 18.8 mmol) in DMF (15 mL) is stirred at 90° C. under nitrogen for 6 hours. The reaction is cooled to room temperature, extracted with ethyl acetate and saturated aqueous sodium chloride, washed with 2 N aqueous NaOH solution, saturated aqueous sodium chloride, dried over Na2SO4, filtered, and evaporated. The residue is purified by chromatography on silica gel, eluting with ethyl acetate:hexanes 3:7, to give the title product as a red liquid (1.41 g) which is used for next reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:18]([OH:20])=O)=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:7]=1.[NH:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH2:31][CH2:30][CH2:29][C@H:28]2[CH2:32][O:33][C:34](=[O:41])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:23][CH2:22]1>>[CH3:1][C:2]1[C:3]([C:18]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]3[CH2:31][CH2:30][CH2:29][C@H:28]3[CH2:32][O:33][C:34](=[O:41])[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:23][CH2:22]2)=[O:20])=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)[CH:7]=1
Reactant: O=C(OC[C@@H]1CCCN1C1CCNCC1)c1ccccc1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)cnc1C(=O)O
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)cnc1C(=O)N1CCC(N2CCC[C@H]2COC(=O)c2ccccc2)CC1

Procedure:
In analogy to the procedures described for example 1 and for intermediate 1B, 3-methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid (intermediate 1B) was reacted with benzoic acid (S)-1-piperidin-4-yl-pyrrolidin-2-ylmethyl ester (intermediate 6) to give benzoic acid (S)-1-{1-[3-methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-carbonyl]-piperidin-4-yl}-pyrrolidin-2-ylmethyl ester, which was subsequently saponified to give the title compound as light brown solid. MS: 448.1 (MH+).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13].[NH3:15]>CO>[CH3:13][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([CH3:12])[C:6]=1[NH:5][CH2:4][C:3]([NH2:15])=[O:2]
Reactant: N
Reactant: COC(=O)CNc1c(C)cccc1C
Solvent: CO
Product: Cc1cccc(C)c1NCC(N)=O
Reaction time: 8 h

Procedure:
22.3 g of 2,6-dimethylanilinoacetic acid methyl ester are dissolved in 150 ml of absolute methanol and dry ammonia is passed in with stirring until the solution is saturated. In the course thereof the temperature rises to 37° C. The reaction mixture is left to stand overnight. It is then concentrated in vacuo to leave as residue a yellow oil which crystallises on scratching. Recrystallisation from toluene yields 15.3 g of 2,6-dimethylanilino acetic acid amide which melts at 89°-92° C.
Reaction SMILES: C(O)=[O:2].[CH:4](=[N:11][N:12]([C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:30][CH:29]=1)[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])=[CH:18][CH:17]=1)=[O:14])C1C=CC=CC=1>O1CCCC1.C(O)C.[OH-].[Pd+2].[OH-]>[CH:4]([NH:11][N:12]([C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:30][CH:29]=1)[C:13]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])=[CH:20][CH:21]=1)=[O:14])=[O:2]
Reactant: O=CO
Reactant: CN(C)CCOc1ccc(NC(=O)N(N=Cc2ccccc2)c2ccc(Oc3ccccc3)cc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc(NC(=O)N(NC=O)c2ccc(Oc3ccccc3)cc2)cc1

Procedure:
Palladium(II) hydroxide (60 mg) and formic acid (4.6 g) were added to a solution of 1-benzylidene-2-(4-phenoxyphenyl)-4-[4-(2-dimethylamino-ethoxy)phenyl]semicarbazide (600 mg) in tetrahydrofuran/ethanol (1:1, 30 mL). The mixture was heated under reflux for five hours and then filtered. The filtrate was concentrated and the residue was purified by HPLC. The product with the molecular weight of 434.50 (C24H26N4O4); MS (ESI): 435 ([M+H]+), was obtained in this way.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1.[CH3:28][CH:29]([CH3:32])[CH:30]=O.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>CN(C=O)C>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:28][CH:29]([CH3:32])[CH3:30])[CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: O=C(c1cccnc1Oc1cc(Cl)ccc1Cl)N1CCNc2ccccc21
Reactant: CC(C)C=O
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: CN(C)C=O
Product: CC(C)CN1CCN(C(=O)c2cccnc2Oc2cc(Cl)ccc2Cl)c2ccccc21
Temperature: 150 °C
Yield: 37.6 %

Procedure:
To a solution of [2-(2,5-dichloro-phenoxy)-pyridin-3-yl]-(3,4-dihydro-2H-quinoxalin-1-yl)-methanone (24 mg, 0.06 mmol, 1.0 equiv; Example 122) in anhydrous DMF (1 mL) was added 2-methyl-propionaldehyde (17.3 mg, 22 μL, 0.24 mmol, 4.0 equiv; [CAS RN 78-84-2]), dibutyltin dichloride (1.8 mg, 0.006 mmol, 0.1 equiv; [CAS RN 683-18-1]) and phenylsilane (13.0 mg, 15 μL, 0.12 mmol, 2.0 equiv; [CAS RN 694-53-1]). The reaction mixture was heated by microwave irradiation to 150° C. for 15 min. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 10.3 mg (38%) of the title compound as a light yellow powder. MS (ISP): 456.4 [M+H]+.
Reaction SMILES: [N:1]([CH:4]1[CH2:7][C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)([C:8]#[N:9])[CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O.Cl.CCOC(C)=O>[NH2:1][CH:4]1[CH2:7][C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)([C:8]#[N:9])[CH2:5]1
Reactant: N#CC1(c2ccccn2)CC(N=[N+]=[N-])C1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: N#CC1(c2ccccn2)CC(N)C1

Procedure:
To a solution of 3-azido-1-(pyridin-2-yl)cyclobutanecarbonitrile (3.375 g, 16.94 mmol) in THF (30 mL) and water (8 mL) was added triphenylphosphine (5.33 g, 20.33 mmol) with cooling and stirring in an ice-water bath. The mixture was stirred at RT overnight. The reaction was diluted with 1N aqueous HCl and EtOAc. The acidic aqueous layer was separated and retained. The organic layer was washed with water, and then the combined aqueous layers were washed with EtOAc and basified by addition of 6 N aq NaOH. The product amine was extracted with EtOAc. The organic phase was concentrated to afford the title compound as a colorless oil and a 3:1 mixture of geometrical isomers, which was dried under vacuum and used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N+:12]([O-])=O)=[CH:4][N:3]=1.[Cl-].[Ca+2].[Cl-]>C(O)C.O.[Fe]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([NH2:12])=[CH:6][C:7]=1[C:8]([F:11])([F:9])[F:10]
Reactant: O=[N+]([O-])c1cnc(Cl)c(C(F)(F)F)c1
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: Nc1cnc(Cl)c(C(F)(F)F)c1

Procedure:
Heat a mixture of 2-chloro-5-nitro-3-trifluoromethyl-pyridine (2.27 g, 10 mmol), calcium chloride (1.1 g, 10 mmol) and iron powder (4.5 g) in ethanol (30 mL) and water (5 mL) at reflux for 1 hour. Cool the mixture and filter through Celite. Evaporate the filtrate, dissolve the residue in EtOAc (200 mL) and wash with saturated NaHCO3(aq) (100 mL) and brine (100 mL). Dry the organic extract over MgSO4 and remove the solvent under reduced pressure to yield the title compound.
Reaction SMILES: [C:1]([C:6]1[C:15](=O)[C:14]2[C:9](=[C:10]([O:17][CH3:18])[CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].C(=O)(O)[O-].[Na+].P(Cl)(Cl)([Cl:26])=O>>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:26])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCC(=O)c1c[nH]c2c(OC)cccc2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCC(=O)c1cnc2c(OC)cccc2c1Cl
Yield: 58.5 %

Procedure:
3-Butyryl-8-methoxy-4(1H)-quinolone (9.0 g, 0.037 mol) and phosphorus oxychloride (100 ml) were heated under reflux for 30 minutes. When cool, the mixture was poured onto ice, adjusted to pH 4 with sodium bicarbonate and extracted with dichloromethane. Evaporation and crystallisation from ethyl acetate-petroleum ether gave 3-butyryl-4-chloro-8-methoxyquinoline (5.5 g. 58.5%), m.p. 114°-116°.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[CH2:10][N:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:6]=2[N:7]=1.Cl.Cl[C:23]1N=C(N2CCOC[C@@H]2C)C2CNCC=2N=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][C@@H:20]2[CH3:23])[C:5]2[CH2:10][N:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:6]=2[N:7]=1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CNC2
Reactant: COC(=O)N1Cc2nc(Cl)nc(N3CCOCC3)c2C1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N1Cc2nc(Cl)nc(N3CCOC[C@@H]3C)c2C1

Procedure:
Method as described for methyl 2-chloro-4-morpholino-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 25) using (S)-4-(2-chloro-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)-3-methylmorpholine (intermediate 6) as a TFA salt to yield a dark brown oil, which was used without further purification.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[C:8]3[C:13]([N:14]=[CH:15][C:6]2=[N:5][CH:4]=[C:3]1[C:16]([OH:18])=O)=[CH:12][CH:11]=[CH:10][CH:9]=3.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:31][C:32]1[NH:36][N:35]=[N:34][N:33]=1.O>CN(C)C=O>[NH:33]1[C:32]([NH:31][C:16]([C:3]2[C:2](=[O:1])[N:7]3[C:8]4[C:13]([N:14]=[CH:15][C:6]3=[N:5][CH:4]=2)=[CH:12][CH:11]=[CH:10][CH:9]=4)=[O:18])=[N:36][N:35]=[N:34]1
Reactant: O=C(O)c1cnc2cnc3ccccc3n2c1=O
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1nnn[nH]1)c1cnc2cnc3ccccc3n2c1=O
Reaction time: 1 h
Yield: 75.1 %

Procedure:
A mixture of 250 mg of 1-oxo-1H-pyrimido[1,2-a]quinoxaline-2-carboxylic acid and 200 mg of carbonyldiimidazole in 5 ml of dry dimethylformamide was heated over a steam bath for 15 minutes and then 100 mg of 5-aminotetrazole were added thereto. The mixture obtained was heated over a steam bath for another 30 minutes and was then poured into water and left at room temperature for 1 hour. The solid obtained was filtered off, was washed with water and ether and dried to obtain 240 mg (61% yield) of N-(5-tetrazolyl)-1-oxo-1H-pyrimido[1,2-a]quinoxaline-2-carboxamide melting above 300°.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.B([O-])([O-])O[C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.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>[F:29][C:28]([F:30])([F:31])[O:27][C:24]1[CH:25]=[CH:26][C:21]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:22][CH:23]=1
Reactant: [O-]B([O-])Oc1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2S(=O)(=O)CC1
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: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: COC(=O)C1=Cc2cc(-c3ccc(OC(F)(F)F)cc3)ccc2S(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.1 %

Procedure:
Under argon atmosphere, A mixture of methyl 7-bromo-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.80 g), 4-trifluoromethoxyphenyl borate (0.55 g) and potassium carbonate (0.67 g) in toluene/ethanol/water (30/3/3 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (0.14 g), and the mixture was refluxed for 20 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (ethyl acetate/hexane=1:2) to give pale yellow crystals of methyl 7-(4-trifluoromethoxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (638.5 mg).
Reaction SMILES: [CH3:1][C@:2]([N+:8]([O-])=O)([C@@H:5]([OH:7])[CH3:6])[CH2:3][OH:4].[C:11]([OH:14])(=[O:13])[CH3:12]>CCO.[Pd]>[C:11]([OH:14])(=[O:13])[CH3:12].[NH2:8][C@@:2]([CH3:1])([C@H:5]([OH:7])[CH3:6])[CH2:3][OH:4]
Reactant: C[C@H](O)[C@@](C)(CO)[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: C[C@@H](O)[C@](C)(N)CO
Reaction time: 48 h

Procedure:
To a solution of (+-)(2R*,3R*)-2-methyl-2-nitro-1,3-butanediol (2B, 22.1 g, 0.148 mol) in 95% EtOH (150 mL) was added glacial acetic acid (25 mL) and 10% Pd/C (MCB, 2.0 g). The reduction was carried out in a Parr apparatus at 50 psi of H2 during a 48 h period at RT. The catalyst was removed by filtration through a Millipore® filter, and the solvent removed under vacuum (2 days). The viscous, colorless syrup was dissolved in abs. EtOH (30 mL). Dilution with abs. Et2O (300 mL) gave a cloudy liquid which was placed in a refrigerator for two days. During this time, colorless crystals formed. They were washed with Et2O and dried in a vacuum oven at RT for two days. The yield of (+-)(2R*,3R*)-2-amino-2-methyl-1,3-butanediol acetate was 25.6 g (97%) mp 117°-121°, (C,H,N).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=[O:7].OS([O-])=O.[Na+].[C-:18]#[N:19].[K+]>C(OCC)(=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]([OH:7])[C:18]#[N:19])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1ccc(C=O)cc1OC
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(C(O)C#N)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
To 3,4-dimethoxybenzaldehyde (1.66 g, 10 mmol) in ethyl acetate (20 mL) was added NaHSO3 (5.2 g, 50 mmol) in water (20 mL), followed by potassium cyanide (3.26 g, 50 mmol) in water (20 mL). The mixture was stirred overnight at rt, then warmed to 50° C. for 6 h. The reaction was cooled to rt, diluted with ethyl acetate, and the layers were separated. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The resulting residue was purified via silica gel chromatography (0-50% ethyl acetate/hexanes) to provide 137A (1.25 g, 65%) and starting material (0.52 mg). LC-MS: 176.22 (M−H2O)+.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:14]2[C:9](=[C:10]([NH2:15])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][N:6]=1)([CH3:3])[CH3:2].[Cl:16][C:17]1[C:22]([C:23](O)=[O:24])=[C:21]([F:26])[C:20]([CH2:27][NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])=[CH:19][CH:18]=1.S(Cl)(Cl)=O.CCN(C(C)C)C(C)C>C1COCC1>[Cl:16][C:17]1[C:22]([C:23]([NH:15][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:9]=2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][CH:1]([CH3:3])[CH3:2])=[O:24])=[C:21]([F:26])[C:20]([CH2:27][NH:28][C:29](=[O:33])[CH:30]([CH3:31])[CH3:32])=[CH:19][CH:18]=1
Reactant: CC(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Reactant: CC(C)Nc1ncnc2c(N)cccc12
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Nc1ncnc2c(NC(=O)c3c(Cl)ccc(CNC(=O)C(C)C)c3F)cccc12
Yield: 17.5 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-isopropylquinazoline-4,8-diamine (Intermediate-57, 50 mg, 0.25 mmol), 6-chloro-2-fluoro-3-(isobutyramidomethyl)benzoic acid (Intermediate-60, 100 mg, 0.37 mmol), thionyl chloride (1 mL), and DIPEA (127 mg, 0.99 mmol) in THF (2 mL) to afford 20 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.42 (s, 1H), 8.70-8.67 (d, J=7.2 Hz, 1H), 8.48 (s, 1H), 8.37 (t, 1H), 8.11-8.08 (d, J=7.8 Hz, 2H), 7.53 (t, 1H), 7.41 (m, 2H), 4.55 (m, 1H), 4.31 (d, 2H), 2.50 (m, 1H), 1.27 (d, J=6.6 Hz, 6H), 1.05-1.03 (d, J=6.9 Hz, 6H); MS [M+H]+: 458.47.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](=[O:12])[NH:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:7][CH2:8][C:9](=[O:11])[NH:29][CH:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[F:15])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:12])=[CH:13][CH:14]=1
Reactant: NC(c1ccccc1)c1ccccc1F
Reactant: O=C(O)CNC(=O)c1ccc(F)cc1
Product: O=C(CNC(=O)c1ccc(F)cc1)NC(c1ccccc1)c1ccccc1F

Procedure:
Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-(2-fluoro-phenyl)-C-phenyl-methylamine (CA [55095-24-4]).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)(=[O:9])=[O:8])[CH3:6])[CH3:2].[N:19]1([CH2:25][CH2:26][O:27][C:28]2[CH:35]=[CH:34][C:31]([CH2:32]Cl)=[CH:30][CH:29]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O>[CH2:1]([O:3][C:4](=[O:18])[C:5]([S:7]([C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=1)(=[O:8])=[O:9])([CH3:6])[CH2:32][C:31]1[CH:34]=[CH:35][C:28]([O:27][CH2:26][CH2:25][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:29][CH:30]=1)[CH3:2]
Reactant: CCOC(=O)C(C)S(=O)(=O)c1ccc(OC)cc1
Reactant: ClCc1ccc(OCCN2CCCCC2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)(Cc1ccc(OCCN2CCCCC2)cc1)S(=O)(=O)c1ccc(OC)cc1
Yield: 98 %

Procedure:
To a stirred mixture of 2.7 g (10 mmol) of 2-(4-methoxy-benzenesulfonyl)propionic acid ethyl ester, 3.03 gm (10 mmol) 4-(2-piperidin-1-yl-ethoxy)benzyl chloride, 10 gm of K2CO3 and 500 mg of 18-crown-6 in 250 ml of acetone was refluxed for 16 hours. At the end, the reaction mixture was filtered and the acetone layer was concentrated to a residue. The residue was extracted with chloroform, washed well with water, dried over anhydrous MgSO4, filtered and concentrated to a residue. The residue obtained was purified by silica-gel column chromatography by eluting with 50% ethyl acetate-hexanes to afford 4.8 gm (92%) of the desired product as an oil. MS: 490(M+H)+.