Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([CH3:20])([CH3:19])[CH2:10][C:11]([OH:18])([C:14]([F:17])([F:16])[F:15])[CH:12]=O.[NH2:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[N:25][N:26]2[CH3:31]>[Ti](Cl)(Cl)(Cl)Cl>[CH3:31][N:26]1[C:27]2[C:23](=[C:22]([NH:21][CH:12]3[C:5]4[C:4](=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][CH:6]=4)[C:9]([CH3:20])([CH3:19])[CH2:10][C:11]3([C:14]([F:15])([F:17])[F:16])[OH:18])[CH:30]=[CH:29][CH:28]=2)[CH:24]=[N:25]1
Reactant: Cn1ncc2c(N)cccc21
Reactant: COc1ccccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Agent: Cl[Ti](Cl)(Cl)Cl
Product: COc1cccc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1cccc2c1cnn2C
Yield: 23.4 %

Procedure:
Analogously to Example 3, the corresponding imine is produced starting from 296 mg of 4-(2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 150 mg of 4-amino-1-methylindazole. By reaction of 100 mg of the imine with 0.5 ml of titanium tetrachloride, 100 mg of the title compound is obtained.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[NH:14]1[CH2:18][CH2:17][CH2:16][C@@H:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(N(CC)CC)C>ClCCl.C(#N)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([N:14]2[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:5][CH:4]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)[C@H]1CCCN1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 27.2 %

Procedure:
A suspension of 4-(trifluoromethyl)phenylboronic acid (190 mg), copper (II) acetate (27 mg) and 4 Å molecular sieves (188 mg) in dichloromethane (4 mL) was stirred at room temperature for 5 min, and (R)-tert-butyl pyrrolidine-2-carboxylate (86 mg) in acetonitrile (0.5 mL) was added followed by triethylamine (0.07 mL). The reaction vial was flushed with oxygen, sealed and stirred at 50° C. for 24 h. The reaction mixture was filtered through a pad of Celite, and the filtrate was evaporated in vacuo. The residue was purified by preparative TLC eluting with 10% ethyl acetate/90% hexanes to give the title compound as a colorless oil (43 mg). HPLC retention time: 1.99 min (method A). MS (ESI) (M+H)+ 316.14. 1H NMR (400 MHz, CDCl3) δ 7.41 (1H, d, J=8.4 Hz), 6.52 (1H, d, J=8.4 Hz), 4.15 (1H, m), 3.53 (1H, m), 3.40 (1H, m), 2.0-2.3 (3H, m), 1.41 (9H, s).
Reaction SMILES: [CH2:1]([N:3]([CH2:30][CH3:31])[C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[C:19]([CH3:21])[C:18]([O:22][CH2:23][C@@H:24]4[CH2:26][O:25]4)=[C:17]([CH2:27][CH3:28])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:29])[N:5]=1)[CH3:2].[CH3:32][O-:33].[Na+]>CO.CC(=O)OCC>[CH2:30]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[C:19]([CH3:21])[C:18]([O:22][CH2:23][C@@H:24]([OH:25])[CH2:26][O:33][CH3:32])=[C:17]([CH2:27][CH3:28])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:29])[N:5]=1)[CH3:31]
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1OC[C@@H]1CO1
Reactant: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1OC[C@@H](O)COC

Procedure:
A solution of diethyl-{4-[3-((S)-3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-6-methyl-pyridin-2-yl}-amine (100 mg, 0.229 mmol) in 5.4 M NaOMe in methanol (5 mL) is stirred at 70° C. for 72 h. The mixture is diluted with EA and washed with water and brine. The org. extract is dried over Na2SO4, filtered and concentrated. The crude product is purified on prep. TLC plates with heptane:EA 1:1 to give the title compound (91 mg) as a yellow solid; LC-MS*: tR=1.21 min, [M+1]+=455.09; 1H NMR (CDCl3): δ 1.25 (t, J=7.0 Hz, 6H), 1.33 (t, J=7.5 Hz, 3H), 2.41 (s, 3H), 2.50 (s, 3H), 2.58 (d, J=5.0 Hz, 1H), 2.77 (q, J=7.8 Hz, 2H), 3.47 (s, 3H), 3.59-3.70 (m, 6H), 3.92 (d, J=5.3 Hz, 2H), 4.19-4.27 (m, 1H), 7.01 (s, 1H), 7.10 (s, 1H), 7.87 (s, 1H), 7.88 (s, 1H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][SH:12])=[CH:9][C:4]=2[O:3][CH2:2]1.Br[CH2:14][CH2:15][S:16]([O-:19])(=[O:18])=[O:17].[Na+:20].[OH-].[Na+]>C(O)C.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][S:12][CH2:14][CH2:15][S:16]([O-:19])(=[O:18])=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1.[Na+:20]
Reactant: SCCc1ccc2c(c1)OCO2
Reactant: O=S(=O)([O-])CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=S(=O)([O-])CCSCCc1ccc2c(c1)OCO2
Yield: 73.9 %

Procedure:
15 g of 2-(1,3-benzodioxol-5-yl)ethanethiol and 17.4 g of sodium 2-bromoethanesulfonate were dissolved in a mixture of 280 ml of ethanol and 120 ml of water. 3.3 g of sodium hydroxide was added to the solution and the mixture was heated under reflux for 1 h. The reaction mixture was concentrated and 500 ml of ethyl acetate and 500 ml of water were added thereto. After separation of the layers, the aqueous layer was acidified with hydrochloric acid. After extraction with n-butanol, the extract was washed with a saturated aqueous common salt solution. The solvent was distilled off to obtain 19 g of a faint yellow residue. This product was dissolved in a solution of 2.94 g of sodium hydroxide in dilute methanol and recrystallized therefrom to obtain 14.7 g of the intended compound in the form of colorless crystals.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=[N:2]1.NC1C=CC=CC=1>[Pd]>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: O=[N+]([O-])c1ccc(OCCn2ccnn2)cc1
Agent: [Pd]
Solvent: Nc1ccccc1
Product: Nc1ccc(OCCn2ccnn2)cc1

Procedure:
4-[2-(1,2,3-Triazol-1-yl)ethoxy]aniline was prepared from 4-[2-(1,2,3-triazol-1-yl)ethoxy]nitrobenzene (5.98 g, 25.5 mmol) and 10% palladium on charcoal (1.5 g) in a manner similar to the aniline intermediate of Example 12 to give the desired material (4.91 g) as a yellow solid m.p. 141°. δH (CDCl3) 7.69 (1H, d, J 0.5 Hz), 7.62 (1H, d J 0.5 Hz), 6.65 (2H, d, J 5.8 Hz), 6.58 (2H, d, J 5.8 Hz), 4.71 (2H, t, J 5.0 Hz), 4.24 (2H, t, J 5.0 Hz) and 3.43 (2H, s).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH2:12][CH3:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.C(B(CC)[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)C.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:12]([C:7]1[CH:8]=[N:9][C:10]2[C:5]([CH:6]=1)=[CH:4][CH:3]=[C:2]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[CH:11]=2)[CH3:13]
Reactant: CCc1cnc2cc(Br)ccc2c1
Reactant: CCB(CC)c1cccnc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1cnc2cc(-c3cccnc3)ccc2c1
Temperature: 90 °C
Reaction time: 5 h
Yield: 58 %

Procedure:
To a well-stirred mixture consisting of the title compound of Step 1, this Example (1.40 g, 5.93 mmol), diethyl(3-pyridyl)borane (0.96 g, 6.53 mmol) and bis(triphenylphosphine) palladium (II) chloride (458 mg, 0.65 mmol) in tetrahydrofuran (15 ml), a 7.5 ml aqueous solution of sodium carbonate (2.51 g, 23.7 mmol) was added. The reaction mixture was then stirred at 90° C. for 5 hours, and then at ambient temperature for 18 hours. The aqueous phase of the biphasic reaction mixture is separated and extracted with an equal volume of ethyl acetate. The solvent of the organic phase of the reaction mixture was removed in vacuo and the residue is extracted with ethyl acetate (25 ml). The combined organic extracts are dried (anhydrous sodium sulfate) and concentrated in vacuo, yielding a dark viscous oil. Flash chromatography of the entire sample (silica gel, 47-61 micron mesh; elution with ethyl acetate) afford the title compound (807 mg, 58% yield) as a viscous yellow syrup.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[C:11]([S:13](=[O:16])(=[O:15])[NH2:14])[S:10][C:9]=2[CH:17]=1)(=O)C.O.C([O-])(O)=O.[Na+]>Cl>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[C:11]([S:13](=[O:15])(=[O:16])[NH2:14])[S:10][C:9]=2[CH:17]=1
Reactant: CC(=O)Nc1ccc2cc(S(N)(=O)=O)sc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Nc1ccc2cc(S(N)(=O)=O)sc2c1
Yield: 213.2 %

Procedure:
6-Acetamido-2-sulfamoylbenzo[b]thiophene (0.8 g, 3 mmole) was suspended in 1N HCl (24 ml). The stirred mixture was heated to refluxing for 1 hour when a clear solution was obtained. After dilution with water (25 ml), the cooled solution was neutralized with saturated NaHCO3 solution. The product precipitated and was collected to obtain 0.57 g (83%), m.p. 240-241° C. dec. This material was combined with 1.3 g of comparable crude product from two other runs and recrystallized from CH3CN, decolorizing with charcoal, to yield 1.46 g of 6-amino-2-sulfamoylbenzo[b]thiophene, m.p. 239-240° C (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](=S)[NH:7][C:6]=2[CH:17]=1.[NH2:18][CH2:19][CH2:20][N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1>C(OCCO)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([NH:18][CH2:19][CH2:20][N:21]3[CH:25]=[CH:24][N:23]=[CH:22]3)=[N:7][C:6]=2[CH:17]=1
Reactant: S=C1Nc2cc(Cl)ccc2Nc2ccccc21
Reactant: NCCn1ccnc1
Solvent: CCOCCO
Product: Clc1ccc2c(c1)N=C(NCCn1ccnc1)c1ccccc1N2
Yield: 56.6 %

Procedure:
A solution of 0.6 g (2.3 mmol) of 8-chloro-5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-thione in 15 mL of 2-ethoxyethanol was treated with 0.6 mL (4.6 mmol) of 1-(2-aminoethyl)imidazole and heated at reflux for 2 days. The solvent was removed under reduced pressure and the residue taken up in EtOAc and washed three times with H2O, then saturated NaHCO3 solution, and saturated NaCl solution. Drying over MgSO4 and removal of the solvent under reduced pressure left the crude product. This was recrystallized from EtOAc/hexane using charcoal to give 0.44 g (57.1% yield) of the product as pale yellow crystals, mp 168-170° C. The structure was confirmed by NMR and mass spectroscopy. (m+H)+ =338.
Reaction SMILES: [CH2:1](Cl)/[CH:2]=[CH:3]/[CH2:4]Cl.[C:7]([O:14][CH3:15])(=[O:13])[CH2:8][C:9]([O:11][CH3:12])=[O:10]>>[CH:2]([CH:3]1[CH2:4][C:8]1([C:7]([O:14][CH3:15])=[O:13])[C:9]([O:11][CH3:12])=[O:10])=[CH2:1]
Reactant: ClC/C=C/CCl
Reactant: COC(=O)CC(=O)OC
Product: C=CC1CC1(C(=O)OC)C(=O)OC

Procedure:
The procedure of Example 2 was followed except that trans-1,4-dichlorobutene-2 as obtained by the procedure of Example 4 was condensed with dimethyl malonate. High yields of dimethyl 2-vinylcyclopropane-1,1-dicarboxylate of high purity were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[NH:11][C:10](=O)[CH:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:13]=[C:12]([CH3:14])[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(-c2ccc(Cl)cc2)cc(=O)[nH]1
Product: Cc1cc(-c2ccc(Cl)cc2)cc(Cl)n1

Procedure:
The title compound was prepared from 4-(4-chloro-phenyl)-6-methyl-1H-pyridin-2-one (15 g, 68 mmol) and phosphoryl chloride (31.1 mL, 341 mmol) according to the general procedure Ia to d preparation of chlorides. Obtained as a brown solid (12.3 g, 75%). MS (ISP) 238.1 [(M+H)+], 240 [(M+2+H)+] and 242 [(M+4+H)+].
Reaction SMILES: [I:1]N1C(=O)CCC1=O.CN(C)C=O.[NH2:14][C:15]1[C:23]([O:24][CH3:25])=[C:22]([Br:26])[CH:21]=[C:20]([CH3:27])[C:16]=1[C:17]([OH:19])=[O:18].[OH-].[Na+]>[Cl-].[Na+].O.O>[NH2:14][C:15]1[C:23]([O:24][CH3:25])=[C:22]([Br:26])[C:21]([I:1])=[C:20]([CH3:27])[C:16]=1[C:17]([OH:19])=[O:18]
Reactant: COc1c(Br)cc(C)c(C(=O)O)c1N
Reactant: O=C1CCC(=O)N1I
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(N)c(C(=O)O)c(C)c(I)c1Br
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 57.3 %

Procedure:
N-Iodosuccinimide (104 mg, 461 μmol) was put into an N,N-dimethylformamide (2.0 ml) solution of 2-amino-4-bromo-3-methoxy-6-methylbenzoic acid (I-3) (100 mg, 384 μmol), followed by stirring at room temperature for 40 minutes. The reaction liquid was put into water (30 ml), followed by controlling at pH of 4 with aqueous 2 N sodium hydroxide solution, then saturated brine (30 ml) was added, the product was extracted with ethyl acetate (50 ml×2). The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, the residue was purified by silica gel column chromatography (chloroform:methanol=1:0→100:3) to obtain the entitled compound (84.9 mg, 57%) as a yellow white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)=[CH:16][C:15]([C:24]([NH2:26])=O)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].N1C(Cl)=NC(Cl)=NC=1Cl.CN(C)C=O>O>[C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:30])[CH3:31])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)=[CH:16][C:15]([C:24]#[N:26])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2cccs2)c2cc(C(N)=O)ccc2c1=O
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2cccs2)c2cc(C#N)ccc2c1=O
Yield: 91.4 %

Procedure:
A solution of tert-butyl[6-(aminocarbonyl)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.23 g, 0.5 mmol) and cyanuric chloride (0.28 g, 1.5 mmol) in N,N-dimethylformamide (10 mmol) was stirred at 0° C. for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl[6-cyano-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.20 g, 95.2%) as crystals.
Reaction SMILES: [ClH:1].Cl.Cl.[C:4]([C:7]1[CH:8]=[C:9](/[CH:13]=[CH:14]/[CH2:15][N:16]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[CH:19][CH:18]=2)[CH:10]=[CH:11][CH:12]=1)(=[NH:6])[NH2:5].Cl.[C:37](=[NH:42])(OCC)[CH3:38].C(N(CC)CC)C.Cl>CO.O1CCOCC1>[ClH:1].[ClH:1].[ClH:1].[C:37]([N:27]1[CH2:28][CH2:29][CH:24]([O:23][C:20]2[CH:21]=[CH:22][C:17]([N:16]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:15]/[CH:14]=[CH:13]/[C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([C:4](=[NH:5])[NH2:6])[CH:8]=3)=[CH:18][CH:19]=2)[CH2:25][CH2:26]1)(=[NH:42])[CH3:38]
Reactant: CCOC(=O)CN(C/C=C/c1cccc(C(=N)N)c1)c1ccc(OC2CCNCC2)cc1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(C/C=C/c1cccc(C(=N)N)c1)c1ccc(OC2CCN(C(C)=N)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 244.1 %

Procedure:
To a solution of ethyl 2-[N-[3-(3-amidinophenyl)-2-(E)-propenyl]-N-[4-(piperidin-4-yloxy)phenyl]amino]acetate trihydrochloride (400 mg) in methanol (20 ml) were added ethyl acetimidate hydrochloride (270 mg) and triethylamine (0.61 ml) at room temperature. The resulting mixture was stirred at room temperature for 12 hours. To the reaction mixture was added a 4M solution of hydrogen chloride in dioxane (1 ml) and the solution was concentrated in vacuo. The residue was purified by preparative HPLC (YMC-Pack ODS YMC) using 24% aqueous acetonitrile as an eluant to afford an amorphous solid. To a solution of the solid in methanol (10 ml) was added a 4M solution of hydrogen chloride in dioxane (0.5 ml) and the mixture was concentrated to dryness in vacuo. A solution of the residual solid in water (about 10 ml) was lyophilized to give the title compound (350 mg, yield 81%) as a pale yellow amorphous solid.
Reaction SMILES: [B:1]([O:10][CH:11]([CH3:13])[CH3:12])([O:6][CH:7]([CH3:9])[CH3:8])OC(C)C.[Br:14][CH2:15]Br.C([Li])CCC.CS(O)(=O)=O.OC(C(O)(C)C)(C)C>CCCCCC.O1CCCC1>[Br:14][CH2:15][B:1]1[O:6][C:7]([CH3:8])([CH3:9])[C:11]([CH3:12])([CH3:13])[O:10]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: BrCBr
Agent: CC(C)(O)C(C)(C)O
Agent: CS(=O)(=O)O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1(C)OB(CBr)OC1(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 65.5 %

Procedure:
To the mixture of triisopropyl borate (20 g, 110 mmol), dibromomethane (8.6 ml, 120 mmol), and tetrahydrofuran (150 ml), n-butyllithium (a 2.6 M n-hexane solution, 39 ml, 100 mmol) was added dropwise at −78° C. (an outer temperature) over 1.5 hours, and then the reaction mixture was stirred at the same temperature for 1.5 hours. Subsequently, the obtained mixture was stirred at room temperature for 2 hours, and then was cooled to 0° C. (an outer temperature). To the reaction mixture, methanesulfonic acid (6.5 ml, 100 mmol) was added, and then the reaction mixture was stirred at room temperature for 1 hour. The obtained mixture was cooled to 0° C. (an outer temperature), pinacol (12 g, 100 mmol) was added to the reaction mixture, and then the reaction mixture was stirred at room temperature for 1 hour. The solvents were evaporated under reduced pressure from the reaction mixture, and then the obtained residue was distilled under reduced pressure (74-76° C., 8 mmHg), thereby obtaining the entitled compound (16 g, 72 mmol, 68%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][OH:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][O:22][S:31]([CH3:30])(=[O:33])=[O:32])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](CO)N(C(=O)OCc2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of (2S,4R)-1-benzyloxycarbonyl-2-hydroxymethyl-4-methanesulfonyloxypyrrolidine (48.0 g) in dichloromethane (250 ml) was added triethylamine (26.4 ml) and methanesulfonyl chloride (14.3 ml) under ice-cooling and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was washed in turn with water (100 ml) and saturated aqueous sodium chloride (100 ml), dried over anhydrous magnesium sulfate and evaporated in vacuo to give (2S,4R)-1-benzyloxycarbonyl-4-methanesulfonyloxy-2-methanesulfonyloxymethylpyrrolidine (48.1 g).
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:21])[C:14]=2[N+:18]([O-])=O)[C:9]1=[O:22])[CH3:7])(=[O:3])[CH3:2].C(O)C.[Cl-].[NH4+].O>[Fe].C(Cl)Cl>[C:1]([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:21])[C:14]=2[NH2:18])[C:9]1=[O:22])[CH3:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@@H](C)n1ccc2c([N+](=O)[O-])c(C)ccc2c1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: CC(=O)OC[C@@H](C)n1ccc2c(N)c(C)ccc2c1=O
Temperature: 85 °C

Procedure:
A round bottom flask was charged with (R)-2-(6-methyl-5-nitro-1-oxoisoquinolin-2(1H)-yl)propyl acetate (110.0 mg, 0.0003615 mol), ethanol (10 mL, 0.2 mol) and the reaction heated at 85° C. and ammonium chloride (193.4 mg, 0.003615 mol) in water (2 mL, 0.1 mol) was added followed by iron (80.7 mg, 0.00144 mol) in two portions and continued to heat for 30 minutes. The reaction went to completion and was poured into DCM (50 mL) and extracted. The removal of the solvent under reduced pressure gave the pure product as an oil. MS m/z=275.4 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19](=[O:31])[C:20]2[CH:25]=[CH:24][C:23](F)=[CH:22][C:21]=2[O:27][CH2:28][CH2:29][OH:30])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].[CH3:32][N:33]1[CH2:39][CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19](=[O:31])[C:20]2[CH:25]=[CH:24][C:23]([N:36]3[CH2:37][CH2:38][CH2:39][N:33]([CH3:32])[CH2:34][CH2:35]3)=[CH:22][C:21]=2[O:27][CH2:28][CH2:29][OH:30])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(Cl)cn1)c1cc(F)ccc1NC(=O)c1ccc(F)cc1OCCO
Reactant: CN1CCCNCC1
Product: CN1CCCN(c2ccc(C(=O)Nc3ccc(F)cc3C(=O)Nc3ccc(Cl)cn3)c(OCCO)c2)CC1

Procedure:
Prepared from 5-fluoro-2-[4-fluoro-2-(2-hydroxyethoxy)-benzoylamino]-N-(5-chloropyridin-2-yl)-benzamide and 1-methyl-hexahydro-1,4-diazepine to afford 25 mg (24%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>CN(C=O)C>[CH3:18][N:19]([CH3:21])/[CH:20]=[CH:1]/[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1
Reactant: CCOC(=O)c1cc(C)c([N+](=O)[O-])cn1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(/C=C/N(C)C)c([N+](=O)[O-])cn1
Temperature: 90 °C

Procedure:
A mixture of ethyl 4-methyl-5-nitropyridine-2-carboxylate (39.5 g, 0.19 mol), dimethylformamide-dimethylacetal (DMF-DMA) (30.6 g, 0.26 mol, 1.35 eq) in DMF (470 mL) was heated to 90° C. for 30 min. The solvent was removed in vacuo. The residue (78 g) was used without further purification in the next step.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([F:22])([F:21])[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=2)[N:3]=1.C(OC([N:30]1[C:34]([CH3:35])=[CH:33][C:32]([NH2:36])=[N:31]1)=O)(C)(C)C.C(O)(=O)C>CC(N(C)C)=O>[F:21][C:13]([F:22])([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1)[C:4]1[N:3]=[C:2]([NH:36][C:32]2[CH:33]=[C:34]([CH3:35])[NH:30][N:31]=2)[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1cc(N)nn1C(=O)OC(C)(C)C
Reactant: Cc1cccc2c(Cl)nc(C(F)(F)c3ccc(F)cn3)nc12
Solvent: CC(=O)O
Solvent: CC(=O)N(C)C
Product: Cc1cc(Nc2nc(C(F)(F)c3ccc(F)cn3)nc3c(C)cccc23)n[nH]1
Temperature: 100 °C
Yield: 13 %

Procedure:
To 4-chloro-2-[difluoro-(5-fluoro-pyridin-2-yl)-methyl]-8-methylquinazoline (0.255 g, 0.79 mmol) in DMA (2 mL) were added 3-amino-5-methyl-pyrazole-1-carboxylic acid tert-butyl ester prepared according to US2007/219195 (0.31 g, 1.58 mmol) and acetic acid (0.15 mL) and the mixture was heated at 100° C. for 6.5 h. The mixture was allowed to cool to rt and then was purified by reverse phase HPLC using an ammonium acetate modifier. Fraction 1 containing pure product were combined, treated with saturated aq NaHCO3 and concentrated under reduced pressure. The aqueous residue was extracted with DCM and the combined extracts were washed with saturated aq NaHCO3 and brine, dried over MgSO4, filtered, and concentrated under reduced pressure to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-methyl-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (28 mg, 13%). 1H NMR (300 MHz, DMSO-d6) δ 12.15 (br s, 1H), 10.57 (s, 1H), 8.67 (s, 1H), 8.50 (d, J=8.3 Hz, 1H), 7.92-8.11 (m, 2H), 7.75 (d, J=7.0 Hz, 1H), 7.52 (t, J=7.6 Hz, 1H), 5.96 (s, 1H), 2.59 (s, 3H), 2.17 (s, 3H); LC-MS (ESI) m/z 385 (M+H)+.