Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[CH2:10](Br)[CH:11]=[CH2:12].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.O.CCOC(C)=O>[CH2:10]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:11]=[CH2:12]
Reactant: C=CCBr
Reactant: CCNc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: C=CCN(CC)c1ccccc1
Temperature: 25 °C
Yield: 100 %

Procedure:
A mixture of ethyl-phenyl-amine (4.15 mL, 33 mmol), allyl bromide (4.3 mL, 1.5 eq.) and K2CO3 (9.1 g, 2.0 eq.) in acetone (50 mL) was heated at reflux for overnight. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and EtOAc (100 m). The separated organic phase was dried over Na2SO4, filtered and concentrated and the product was purified by chromatography (10% EtOAc/hexanes) to give allyl-ethyl-phenyl-amine (5.32 g, 100%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:17])[CH2:10][C:11]([CH3:16])([CH3:15])[O:12]2)=[C:7]([OH:18])[CH:6]=1)[CH:2]=[CH2:3].[C:19](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:17])[CH2:10][C:11]([CH3:15])([CH3:16])[O:12]2)=[C:7]([O:18][CH3:19])[CH:6]=1)[CH:2]=[CH2:3]
Reactant: O=C([O-])[O-]
Reactant: C=CCOc1cc(O)c2c(c1)OC(C)(C)CC2=O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: C=CCOc1cc(OC)c2c(c1)OC(C)(C)CC2=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 91.1 %

Procedure:
2.90 g of 7-allyloxy-5-hydroxy-2,2-dimethyl-4-oxochromane was dissolved in 50 ml of N,N-dimethylformamide. Thereafter, 2.42 g of potassium carbonate and 2.32 g of iodomethane were added to the reaction solution, and the obtained mixture was then stirred at room temperature for 3 days. Thereafter, the reaction solution was diluted with ethyl acetate. The resultant product was washed with a saturated sodium chloride aqueous solution. The organic layer was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), so as to obtain 2.79 g of the subject compound.
Reaction SMILES: [CH3:1][CH2:2][C:3](=[O:7])[CH:4]=[CH:5][CH3:6].[CH:8]1[CH2:12][CH:11]=[CH:10][CH:9]=1.Cl(O)(=O)(=O)=O.C([C@@H]1N[C@H](C2OC(C)=CC=2)N(C)C1=O)C1C=CC=CC=1>O>[CH3:6][C@H:5]1[C@@H:10]2[CH2:11][C@H:12]([CH:8]=[CH:9]2)[C@@H:4]1[C:3](=[O:7])[CH2:2][CH3:1]
Reactant: CC=CC(=O)CC
Reactant: C1=CCC=C1
Agent: Cc1ccc([C@H]2N[C@@H](Cc3ccccc3)C(=O)N2C)o1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Product: CCC(=O)[C@@H]1[C@@H](C)[C@H]2C=C[C@H]1C2
Yield: 89 %

Procedure:
Prepared according to general procedure A from 4-hexen-3-one (70 μL, 0.61 mmol), cyclopentadiene (75 μL, 0.91 mmol), 70% aqueous perchloric acid (10.5 μL, 0.12 mmol) and (2S, 5S)-5-Benzyl-3-methyl-2-(5-methyl-furan-2-yl)-imidazolidin-4-one (30.7 mg, 0.12 mmol) in water (203 μL) for 22 hours at 0° C. Purification by silica gel chromatography (9:1 pentane:ether) provided the title compound as a colorless oil in 89% yield (88.7 mg, 0.54 mmol); 25:1 endo:exo, endo 90% ee. Product ratios were determined by GLC analysis (150° C., 23 psi); (1R, 2R, 3S, 4R) endo isomer tr=3.7 min, and (1S, 2S, 3R, 4S) endo isomer tr=3.6 min, exo isomers tr=3.4, 3.5 min. H NMR, 13C NMR, and IR data 1 were consistent with previously reported values (Zhu et al. (1997) J. Am. Chem. Soc. 119:3507-3512; Ahrendt et al. (2000) J. Am. Chem. Soc. 122:4243-4244). [α]D=+101.7 (c=1.0, CHCl3).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=1)[C:20]([O:22][CH3:23])=[O:21].C([O-])(=O)C.[Na+].[Br:32]Br>C(O)(=O)C>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:32])[N:6]2[CH2:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=1)[C:20]([O:22][CH3:23])=[O:21]
Reactant: BrBr
Reactant: COCCOc1nc(N)c2ncn(Cc3cccc(C(=O)OC)c3)c2n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COCCOc1nc(N)c2nc(Br)n(Cc3cccc(C(=O)OC)c3)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.1 %

Procedure:
A solution of Compound (4) (4.09 g, 11.45 mmol) and sodium acetate (14.26 g, 171.84 mmol) in acetic acid (50 mL) was cooled to 0° C. in an ice bath. Bromine (23.8 g, 148.93 mmol) was added dropwise by syringe. The reaction mixture was allowed to warm to room temperature and stirred overnight (16 hr), and subsequently quenched with saturated sodium sulfite solution. The quenched reaction mixture was extracted with dichloromethane (3×50 mL), dried over sodium sulfate and solvent evaporated to give Compound (5) as a yellow solid (3.35 g, 67% yield). 1H NMR (300 MHz, CDCl3) δ 3.44 (s, 3H), 3.77 (t, J=5.1, 9.9 Hz, 2H), 3.92 (s, 3H), 4.52 (t, J=4.8, 9.9 Hz, 2H), 5.35 (s, 2H), 7.41 (t, J=7.5, 13.5, Hz, 1H), 7.49 (d, J=7.8 Hz, 1H), 7.98 (d, J=7.8 Hz, 1H), 8.09 (s, 1H). LCMS: m/z for C17H18BrN5O4++H observed 437.0 and 438.0 at 3.62 minutes of a 6 minute run, gradient 5-95% CH3CN in H2O (C18 column).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].[CH3:12][NH:13][CH3:14]>>[OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([N:13]([CH3:14])[CH3:12])=[O:6]
Reactant: Cc1c(O)cccc1C(=O)O
Reactant: CNC
Product: Cc1c(O)cccc1C(=O)N(C)C
Yield: 42 %

Procedure:
The title compound was prepared from 3-hydroxy-2-methylbenzoic acid and dimethylamine, using the same method as that described for preparation 75, as a solid in 42% yield. 1H NMR (400 MHz, CDCl3) δ: 1.95 (s, 3H), 2.70 (s, 3H), 2.95 (s, 3H), 6.55 (d, 1H), 6.80 (d, 1H), 7.00 (m, 1H), 9.50 (s, 1H); LRMS APCI m/z 180 [M+H]+
Reaction SMILES: [C:1]12([SH:11])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[Na+].[Br:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:16]=1[C:17]#[N:18].C(OCC)C>CS(C)=O>[C:1]12([S:11][C:19]3[CH:20]=[CH:21][CH:22]=[C:15]([Br:14])[C:16]=3[C:17]#[N:18])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: N#Cc1c(F)cccc1Br
Reactant: SC12CC3CC(CC(C3)C1)C2
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: N#Cc1c(Br)cccc1SC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
1-Adamantanethiol (278 mg) was dissolved in dimethyl sulfoxide (10 mL). Sodium hydride (60% in mineral oil, 42 mg) was added, and the solution was stirred at room temperature for 20 minutes. 2-Bromo-6-fluorobenzonitrile (300 mg) was added and the solution was heated to 130° C. for 1 hour. The solution was cooled, added to diethyl ether, washed with 1 M aqueous HCl three times, washed with brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was removed under vacuum to yield the title compound.
Reaction SMILES: C[O:2][C:3](=[O:25])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[NH:5][C:6](=[O:16])[CH2:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].COC(=O)[C@H](CC1C=CC=CC=1)NC(=O)CNC(OC(C)(C)C)=O>>[C:12]([O:11][C:9]([NH:8][CH2:7][C:6]([NH:5][C@H:4]([C:3]([OH:25])=[O:2])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[O:16])=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)[C@H](Cc1ccc(F)cc1)NC(=O)CNC(=O)OC(C)(C)C
Agent: COC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)O

Procedure:
When in the procedure of Example 7a, 6b is substituted for 6a, the title compound is produced.
Reaction SMILES: CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.[CH:19]([C@H:22]1[CH2:27][NH:26][CH2:25][CH2:24][N:23]1C(OC(C)(C)C)=O)([CH3:21])[CH3:20].[NH2:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](O)=[O:41])=[CH:38][C:37]=1[F:45].C(N(CC)CC)C.FC(F)(F)C(O)=O>ClCCl.C(OCC)(=O)C>[NH2:35][C:36]1[CH:44]=[CH:43][C:39]([C:40]([N:26]2[CH2:25][CH2:24][NH:23][C@@H:22]([CH:19]([CH3:20])[CH3:21])[CH2:27]2)=[O:41])=[CH:38][C:37]=1[F:45]
Reactant: CC(C)[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: Nc1ccc(C(=O)O)cc1F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)[C@H]1CN(C(=O)c2ccc(N)c(F)c2)CCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
1-Propanephosphonic acid cyclic anhydride (1.752 mmol. 1.043 ml, 1115 mg) was added to a solution of (S)-tert-butyl 2-isopropylpiperazine-1-carboxylate (0.876 mmol, 200 mg), 4-amino-3-fluorobenzoic acid (0.876 mmol, 136 mg) and triethylamine (1.752 mmol, 0.244 ml, 177 mg) in dichloromethane and stirred at room temperature for 2 hours. After this time, ethyl acetate (100 mL) was then added to the reaction. The organic mixture was washed with saturated sodium hydrogen carbonate, water, dried over sodium sulphate and concentrated under vacuum. The residue was then dissolved in dichloromethane (5 ml) and trifluoroacetic acid (17.52 mmol, 1997 mg) added. The resultant solution was allowed to stand at room temperature overnight. The reaction was concentrated under vacuum and purified by strong cation exchange chromatography to give the title compound (200 mg) as a clear oil. MS (ESI) m/z 266.3 [M+H]+
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[CH2:14][CH:15]([CH:24]([C:29]([O:31][CH3:32])=[O:30])[C:25]([O:27][CH3:28])=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)([O-:3])=[O:2].[H-].[Na+].[CH2:35](Br)[CH:36]=[CH2:37]>CN(C)C=O>[CH2:37]([C:24]([CH:15]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH2:14][C:5]1[CH:6]=[C:7]([C:10]([F:11])([F:12])[F:13])[CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])([C:29]([O:31][CH3:32])=[O:30])[C:25]([O:27][CH3:28])=[O:26])[CH:36]=[CH2:35]
Reactant: COC(=O)C(C(=O)OC)C(Cc1cc(C(F)(F)F)ccc1[N+](=O)[O-])c1ccc(OC)cc1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCC(C(=O)OC)(C(=O)OC)C(Cc1cc(C(F)(F)F)ccc1[N+](=O)[O-])c1ccc(OC)cc1
Reaction time: 6 h

Procedure:
[2-(2-Nitro-5-trifluoromethylphenyl)-1-(4-methoxyphenyl)ethyl]propanedioic acid, dimethyl ester (46.54 g; 0.102 mole; see Example 4A) was dissolved in dry dimethylformamide (290 ml) under argon. Fifty percent sodium hydride (5.89 g; 0.123 mole; prewashed-hexane) was added with stirring which was continued for 20 minutes before allyl bromide (44 ml; 61.7 g; 0.510 mmole; d=1.398; 5 eq.) was added dropwise. After six hours, 40 minutes, the reaction was quenched with 1N hydrochloric acid. The solution was extracted with ethyl acetate (two times) and the extract was washed with 1N hydrochloric acid (two times), saturated potassium carbonate (two times), saturated sodium chloride, and dried (magnesium sulfate). The concentrated solution (viscous oil) was flash chromatographed (silica gel/9:1-hexane: ethyl acetate, followed by 8:2-hexane:ethyl acetate) in two portions. After drying in vacuo overnight, the yellow viscous oil product weighed 54.77 g. The product was used "as is" in the next step.
Reaction SMILES: C1(=O)CCC([C:7]2[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)CC1.[C:27]([NH:29][C:30]([NH2:32])=[NH:31])#[N:28]>C(OCCOCCO)C>[NH2:31][C:30]1[N:29]=[C:27]([NH2:28])[C:8]2[CH2:9][CH:10]([CH:17]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[C:12]([C:13]([F:16])([F:15])[F:14])[CH:7]=3)[CH2:11][CH2:12][C:7]=2[N:32]=1
Reactant: N#CNC(=N)N
Reactant: O=C1CCC(c2c(COCc3ccccc3)cccc2C(F)(F)F)CC1
Solvent: CCOCCOCCO
Product: Nc1nc(N)c2c(n1)CCC(C(OCc1ccccc1)c1cccc(C(F)(F)F)c1)C2

Procedure:
This compound is prepared in a manner analogous to that of Example 1, using 4.7 grams (0.013 mole) of phenylmethyl [(cyclohexanon-4-yl)(3-trifluoromethylphenyl)]methyl ether and 1.2 grams (0.01 4 mole) of cyanoguanidine in 2-(2-ethoxyethoxy)ethanol, yielding 2,4-diamino-6-[(phenylmethoxy)(3-trifluoromethylphenyl)methyl]-5,6,7,8-tetrahydroquinazoline.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[CH3:5][O:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][O:12][CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH3:5][O:6][CH2:7][CH2:8][N:9]([CH2:10][CH2:11][O:12][CH3:13])[CH2:1][C:2]#[CH:3]
Reactant: COCCNCCOC
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: C#CCN(CCOC)CCOC
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
Propargyl bromide (17.8 g, 150 mmol) was added dropwise to a mixture of bis(2-methoxy-ethyl)amine (20 g, 150 mmol) and cesium carbonate (49 g, 150 mmol) in 350 mL of acetone. The mixture was stirred overnight under nitrogen at room temperature. The inorganic salts were then filtered off, and the solvent was removed. The residue was dissolved in saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic extracts were then evaporated to give 20 g of bis-(2-methoxy-ethyl)-prop-2-ynyl-amine: mass spectrum (m/e): M+H 172.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]([CH3:33])[CH3:32])[C:26]=1[N:34]=[C:35]=[O:36])([CH3:24])[CH3:23]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[C:35]([NH:34][C:26]2[C:25]([CH:22]([CH3:23])[CH3:24])=[CH:30][CH:29]=[CH:28][C:27]=2[CH:31]([CH3:33])[CH3:32])=[O:36])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1ccc(CNc2ccc(C(C)(C)C)cc2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)N(Cc1ccc(N(C)C)cc1)c1ccc(C(C)(C)C)cc1

Procedure:
By the reaction and treatment in the same manner as in Example 1 using (4-tert-butylphenyl)[(4-dimethylaminophenyl)methyl]amine (0.7 g) and 2,6-diisopropylphenyl isocyanate (0.59 mL) as starting materials, N-(4-tert-butylphenyl)-N′-(2,6-diisopropylphenyl)-N-[(4-dimethylaminophenyl)methyl]urea (0.29 g) was obtained. melting point: 154–155° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[O:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1>>[NH2:1][C:2]1[CH:9]=[C:8]([O:17][CH:14]2[CH2:15][CH2:16][O:11][CH2:12][CH2:13]2)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: OC1CCOCC1
Reactant: N#Cc1cnc(N)cc1F
Product: N#Cc1cnc(N)cc1OC1CCOCC1

Procedure:
From intermediate 21 and tetrahydro-2H-pyran-4-ol, reacted in an analogous manner to the preparation of intermediate 45. (UPLC-MS 3) tR 0.53 min; ESI-MS 220.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([CH3:8])=[CH:4][N:3]=1.[C:9]([O:13][C:14]([N:16]1[CH:20]=[CH:19][CH:18]=[C:17]1B(O)O)=[O:15])([CH3:12])([CH3:11])[CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O>[CH3:8][C:5]1[N:6]=[CH:7][C:2]([C:17]2[N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[CH:20]=[CH:19][CH:18]=2)=[N:3][CH:4]=1
Reactant: Cc1cnc(Br)cn1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: Cc1cnc(-c2cccn2C(=O)OC(C)(C)C)cn1
Temperature: 100 °C
Reaction time: 19 h
Yield: 95.9 %

Procedure:
Commercially available 2-bromo-5-methylpyrazine (260 mg, 1.50 mmol) and commercially available 1-(t-butoxycarbonyl)pyrrole-2-boronic acid (380 mg, 1.80 mmol) were dissolved in 1,2-dimethoxyethane (20 mL), and palladium (II) acetate (17.0 mg, 0.076 mmol), triphenylphosphine (79.0 mg, 0.301 mmol) and an aqueous potassium carbonate solution (1.5M, 2.0 mL, 3.00 mmol) were added, followed by stirring at 100° C. for 19 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (20 mL) and ethyl acetate (20 mL) were added, and the solution was separated. The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=5%-30%) to afford the desired compound (373 mg, yield 96%) as a yellow oil.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Cl)=[CH:35][CH:34]=1>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:37][C:36]3[CH:39]=[CH:40][C:33]([O:32][CH3:31])=[CH:34][CH:35]=3)[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Reactant: COc1ccc(CCl)cc1
Product: COc1ccc(Cn2ccc3c(-c4ccc5c(c4)CCCO5)c(C(OC(C)(C)C)C(=O)O)c(C)nc32)cc1

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 4-methoxybenzyl chloride. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.50-7.42 (m, 1 H), 7.27-7.16 (m, 3 H), 7.03 (t, J=3.2 Hz, 1 H), 6.93 (dd, J=6.1, 8.3 Hz, 1 H), 6.88 (d, J=8.6 Hz, 2 H), 6.25 (dd, J=3.5, 11.3 Hz, 1 H), 5.60-5.49 (m, 2 H), 5.47-5.38 (m, 1 H), 4.28 (t, J=4.9 Hz, 2 H), 3.80 (s, 3 H), 2.95-2.79 (m, 2 H), 2.78 (s, 3 H), 2.10-2.04 (m, 2 H), 1.01-0.91 (s, 9 H); LC/MS (m/z) ES+=515.38 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][CH2:5][O:6][C:7]([N:9]1[C:15]2[CH:16]=[CH:17][C:18]([NH2:20])=[CH:19][C:14]=2[O:13][CH2:12][CH2:11][CH2:10]1)=[O:8].Cl[C:23]1[N:28]=[C:27]([NH:29][C:30]2[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:31]=2[C:32]([NH:34][CH2:35][C:36]#[CH:37])=[O:33])[C:26]([Cl:43])=[CH:25][N:24]=1>>[CH3:21][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]([N:9]1[C:15]2[CH:16]=[CH:17][C:18]([NH:20][C:23]3[N:28]=[C:27]([NH:29][C:30]4[C:31]([C:32](=[O:33])[NH:34][CH2:35][C:36]#[CH:37])=[CH:38][CH:39]=[CH:40][C:41]=4[F:42])[C:26]([Cl:43])=[CH:25][N:24]=3)=[CH:19][C:14]=2[O:13][CH2:12][CH2:11][CH2:10]1)=[O:8]
Reactant: C#CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CN(C)CCCOC(=O)N1CCCOc2cc(N)ccc21
Product: C#CCNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)OCCCN3C(=O)OCCCN(C)C)ncc1Cl

Procedure:
3-[5-Chloro-4-(2-fluoro-6-prop-2-ynylcarbamoyl-phenylamino)-pyrimidin-2-ylamino]-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid 3-dimethylamino-propyl ester was prepared from 3-amino-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid 3-dimethylamino-propyl ester and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-prop-2-ynyl-benzamide in an analogous manner to Example 1410. Product isolated as an orange foam (85 mg, 49%). LCMS (m/e) 596 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 9.47-9.36 (m, 1H), 9.25-9.14 (m, 1H), 9.05-8.94 (m, 1H), 8.19 (s, 1H), 7.58-7.40 (m, 3H), 7.33-7.22 (m, 1H), 7.15-7.04 (m, 1H), 6.97-6.89 (m, 1H), 4.14-3.80 (m, 6H), 3.65-3.39 (m, 2H), 3.13-3.08 (m, 1H), 2.21-1.99 (m, 8H), 1.97-1.82 (m, 2H), 1.62-1.48 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-])=O)(=[O:7])=[O:6]>CO.[Pd]>[NH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[S:5]([NH:4][CH2:3][CH2:2][OH:1])(=[O:7])=[O:6]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCO
Agent: [Pd]
Solvent: CO
Product: Nc1ccccc1S(=O)(=O)NCCO
Reaction time: 8 h
Yield: 80.1 %

Procedure:
N-(2-Hydroxyethyl)-2-nitrobenzene sulfonamide (1.25 g, 5.08 mmol) was dissolved in methanol (50 ml) and placed under an atmosphere of nitrogen prior to the addition of 10% Pd/C (10 Wt %, 125 mg) in one portion. The reaction was evacuated, placed under an atmosphere of hydrogen (1 bar) and stirred vigorously overnight. The reaction was filtered through celite and the filtrate was concentrated in vacuo to afford the named product (0.88 g, 80%); LCMS Rt=2.05 min, m/z (ES+) 217 (M+H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][N:6]=1)=O.[Cl-].[Ca+2].[Cl-].[BH4-].[Na+].C=O>C1COCC1.CO.C(Cl)Cl>[CH3:14][O:13][C:11](=[O:12])[C:8]1[CH:9]=[CH:10][C:5]([CH2:3][OH:2])=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(C(=O)OC)nc1
Agent: C=O
Agent: [BH4-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CO)nc1
Temperature: 0 °C
Yield: 95.9 %

Procedure:
Dimethylpyridine-2,5-dicarboxylate (II, 3.6 g, 18.4 mmol) was dissolved in THF/MeOH/CH2Cl2 (1:2:1 v/v, 120 ml). Calcium chloride (7.0 g, 63.1 mmol, 3.4 eq) was added in one portion. The resulting clear light yellow solution was cooled to 0° C. NaBH4 (0.85 g, 22.5 mmol, 1.2 eq) was added portion wise. The mixture was stirred at 0° C. for 1.5 hours, at the end of which TLC (ethyl acetate/hexanes 1:1) indicated completion of reaction. Aqueous formaldehyde (37 wt %, 4.5 g, 55.5 mmol, 3 eq) in 50 ml ice-water was added dropwise. The mixture was extracted with CHCl3 (3×150 ml). The combined organic layers were dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and then passed through a silica gel pad (eluent 5% MeOH in CH2Cl2) to afford the desired product (2.95 g, 96%) as a light yellow waxy solid. MS-ESI m/z 168.12 (M+H)+; 1H NMR (CDCl3) δ 9.17 (d, J=1 Hz, 1H), 8.30 (dd, J=2 and 8.5 Hz, 1H), 7.37 (d, J=8.5 Hz, 1H), 4.84 (d, J=5 Hz, 2H), 3.96 (s, 3H), 3.63 (t, J=5 Hz, 1H) ppm.
Reaction SMILES: [CH:1]([O:14][N:15]1[CH:20]=[C:19]([O:21][CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:18](=[O:35])[CH:17]=[C:16]1[CH2:36][OH:37])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:39]1[C:43](=[O:44])[C:42]2=[CH:45][CH:46]=[CH:47][CH:48]=[C:41]2[C:40]1=[O:49].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+](C(OCC)=O)(C(OCC)=O)=[N-]>CN(C)C=O.O.C(OCC)(=O)C.O1CCCC1>[C:43]1(=[O:44])[N:39]([O:37][CH2:36][C:16]2[N:15]([O:14][CH:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:20]=[C:19]([O:21][CH:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:18](=[O:35])[CH:17]=2)[C:40](=[O:49])[C:41]2=[CH:48][CH:47]=[CH:46][CH:45]=[C:42]12
Reactant: O=c1cc(CO)n(OC(c2ccccc2)c2ccccc2)cc1OC(c1ccccc1)c1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)[N+](=[N-])C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1OCc1cc(=O)c(OC(c2ccccc2)c2ccccc2)cn1OC(c1ccccc1)c1ccccc1
Reaction time: 0.17 h
Yield: 50.2 %

Procedure:
12.3 g (0.0251 mol) of the product of Step (3) was added and dissolved in dimethylformamide (125 ml). Then, dried tetrahydrofuran (250 ml), 4.1 g (0.0251 mol) of N-hydroxyphthalimide and 9.9 g (0.0376 mol) of triphenylphosphine were added thereto. Further, 5.8 ml (0.0377 mol) of diethyl diazodicarboxylate was dropwise added under cooling with ice. The mixture was stirred at the same temperature for 10 minutes, and then ethyl acetate (500 ml) and water (1,500 ml) were added thereto. The ethyl acetate layer was washed with water and a saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate, and then concentrated to dryness. The residue was subjected to silica gel column chromatography and eluted by benzene/ethyl acetate (4/1) to obtain 8.0 g of the above identified compound (yield: 50.2%)