Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.C[O:20][C:21](=[O:31])[C:22]([CH3:30])([CH3:29])[CH2:23][CH2:24][C:25](=O)[CH2:26][CH3:27]>C(O)(C)(C)C>[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C:10]3[C:15](=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[C:26]([CH3:27])=[C:25]2[CH2:24][CH2:23][C:22]([CH3:30])([CH3:29])[C:21]([OH:31])=[O:20])=[CH:5][CH:4]=1
Reactant: NN(Cc1ccc(Cl)cc1)c1ccc(F)cc1
Reactant: CCC(=O)CCC(C)(C)C(=O)OC
Agent: Cl
Solvent: CC(C)(C)O
Product: Cc1c(CCC(C)(C)C(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(F)cc12

Procedure:
Following the method of Example 2, but using 1-[4-chlorobenzyl]-1-[4-fluorophenyl]hydrazine hydrochloride and methyl-2,2-dimethyl-5-oxoheptanoate as starting materials, in t-butanol as solvent, the title compound was prepared.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][N:5]=[C:4]([Cl:10])[CH:3]=1.[Br:11][CH2:12][CH:13](OC)OC.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>CC#N.CCOC(C)=O>[Br:11][C:12]1[CH:13]=[N:1][C:2]2[C:7]([CH:8]=1)=[CH:6][N:5]=[C:4]([Cl:10])[CH:3]=2
Reactant: COC(CBr)OC
Reactant: Nc1cc(Cl)ncc1C=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Clc1cc2ncc(Br)cc2cn1
Temperature: 25 °C
Yield: 53.7 %

Procedure:
Heat a mixture of 4-amino-6-chloronicotinaldehyde (2.00 g, 12.77 mmol), 2-bromo-1,1-dimethoxyethane (6.48 g, 38.3 mmol) and ytterbium(III) trifluoromethanesulfonate (1.981 g, 3.19 mmol) in MeCN (25 mL) at 80° C. overnight. Cool to RT, dilute with EtOAc, collect the solids via filtration, rinse with EtOAc and dry. Wash the filtrate with H2O, then brine, dry over Na2SO4, concentrate to dryness and purify via silica gel chromatography (EtOAc/Hex). Combine the two solids to afford the title compound (1.67 g, 53%) as an off-white solid. MS(ESI) m/z: 244.9 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.C(NCBr)(O[C:18](C)([CH3:20])[CH3:19])=O>>[C:8]([C:6]1[CH:5]=[C:4]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=[C:2]([C:18]([CH3:20])=[CH2:19])[CH:7]=1)#[N:9]
Reactant: CS(=O)(=O)Nc1cc(Br)cc(C#N)c1
Reactant: CC(C)(C)OC(=O)NCBr
Product: C=C(C)c1cc(C#N)cc(NS(C)(=O)=O)c1

Procedure:
N-(3-cyano-5-(prop-1-en-2-yl)phenyl)methanesulfonamide was synthesized from N-(3-bromo-5-cyanophenyl)methanesulfonamide following the general procedure as described for the Cbz protected Boc aminomethyl bromide.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][OH:14].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[S:23]([O:14][CH2:13][CH2:12][CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)(=[O:25])(=[O:24])[CH3:22]
Reactant: OCCCc1ccc2ccccc2c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCc1ccc2ccccc2c1

Procedure:
Following the procedure described in example 1§B, but starting from 3-(2-naphtyl)propan-1-ol (11.7 mmol), triethylamine (2.5 mL), methanesulfonyl chloride (1.7 mL) and dichloromethane (50 mL), affords 1.7 g of 3-(2-naphtyl)propan-1-ol mesylate used without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:18]3[C:10](=[CH:11][C:12]4[CH2:13][CH2:14][NH:15][C:16]=4[CH:17]=3)[O:9][CH2:8]2)[CH2:4][CH2:3]1.[CH3:19][O:20][C:21]([C:23]1[CH:24]=[CH:25][C:26]([CH3:38])=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([C:35](O)=[O:36])=[CH:31][CH:30]=2)[CH:28]=1)=[O:22]>>[CH3:19][O:20][C:21]([C:23]1[CH:24]=[CH:25][C:26]([CH3:38])=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([N:15]3[C:16]4[CH:17]=[C:18]5[C:5]6([CH2:8][O:9][C:10]5=[CH:11][C:12]=4[CH2:13][CH2:14]3)[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]6)=[O:36])=[CH:31][CH:30]=2)[CH:28]=1)=[O:22]
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCC3
Reactant: COC(=O)c1ccc(C)c(-c2ccc(C(=O)O)cc2)c1
Product: COC(=O)c1ccc(C)c(-c2ccc(C(=O)N3CCc4cc5c(cc43)C3(CCN(C)CC3)CO5)cc2)c1

Procedure:
The title compound was prepared from 1'-methyl-2,3,6,7-tetrahydrospiro [furo[2,3-f]indole-3,4'-piperidine] (D8) and 5'-methoxycarbonyl-2'-methylbiphenyl-4-carboxylic acid (D42) using a similar procedure to Example 1 (51%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7](Br)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1Br
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1N1CCOCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83 %

Procedure:
1-Bromo-6-methoxy-3-phenyl-1H-indene-2-carboxylic acid ethyl ester (10 mg, 0.40 mmol) obtained in Example 18 was dissolved in THF (15 mL), and morpholine (175.01 mg, 0.18 mL, 2.01 mmol) was added dropwise thereto. The mixture was stirred for 12 hrs at RT, and the solvent was removed under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 126 mg of the titled compound (yield: 83%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[C:6]2[O:31][CH2:32][O:33][C:5]2=[CH:4][CH:3]=1.Cl[CH2:35][C:36]#[N:37].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:22][CH2:23][CH2:24][N:25]4[CH2:26][CH2:27][N:28]([CH2:35][C:36]#[N:37])[CH2:29][CH2:30]4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[C:6]2[O:31][CH2:32][O:33][C:5]2=[CH:4][CH:3]=1
Reactant: COc1cc2c(Nc3c(Cl)ccc4c3OCO4)ncnc2cc1OCCCN1CCNCC1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3c(Cl)ccc4c3OCO4)ncnc2cc1OCCCN1CCN(CC#N)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-(6-chloro-2,3-methylenedioxyanilino)-6-methoxy-7-(3-piperazin-1-ylpropoxy)quinazoline (0.19 g), 2-chloroacetonitrile (0.038 ml), potassium iodide (0.020 g), potassium carbonate (0.139 g) and DMF (2.5 ml) was stirred at ambient temperature for 16 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with water and with brine, dried over magnesium sulphate and evaporated. The crude product was purified by column chromatography on silica using a 93:7 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound (0.13 g) as a solid; NMR Spectrum: (DMSOd6 and CF3CO2D) 2.3 (m, 2H), 2.6 (m, 2H), 3.05 (m, 2H), 3.15 (m, 2H), 3.35 (m, 2H), 3.65 (m, 2H), 3.9 (s, 2H), 4.05 (s, 3H), 4.35 (m, 2H), 6.15 (s, 2H), 7.05 (d, 1H), 7.15 (d, 1H), 7.4 (s, 1H), 8.15 (s, 1H), 8.9 (s, 1H); Mass Spectrum: [M−H]− 509 and 511; Elemental Analysis: Found C, 58.41; H, 5.62; N, 15.93. C25H27ClN6O40.2H2O requires C, 58.35; H. 5.37; N, 16.33%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[CH:16][NH:15][N:14]=3)[N:3]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Reactant: OB(O)c1ccccc1
Product: c1ccc(-c2nc(Nc3cc[nH]n3)cc3ccccc23)cc1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and phenylboronic acid to give (1-phenyl-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine. LC-MS m/e 287(MH+).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[NH:25][C:24](=[O:26])[C:23]2[C:18](=[C:19]([CH:27]([CH:29]([OH:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH3:28])[CH:20]=[CH:21][CH:22]=2)[N:17]=1)[CH2:7][CH3:8].C(N(CC)CC)C>C(Cl)Cl>[CH2:6]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[NH:25][C:24](=[O:26])[C:23]2[C:18](=[C:19]([CH:27]([CH:29]([O:35][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH3:28])[CH:20]=[CH:21][CH:22]=2)[N:17]=1)[CH2:7][CH3:8]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCC(O)C(C)c1cccc2c(=O)[nH]c(-c3ccccc3OCCC)nc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCC(OS(C)(=O)=O)C(C)c1cccc2c(=O)[nH]c(-c3ccccc3OCCC)nc12
Reaction time: 0.5 h

Procedure:
0.17 ml (2.17 mmoles) of methanesulfonyl chloride is added at 0° C. to 740 mg (1.81 mmoles) of the compound from Example 17 and 0.3 ml (2.17 mmoles) of triethylamine in 18 ml of absolute CH2Cl2. The mixture is allowed to come to room temperature and is stirred 30 minutes longer. The mixture is first extracted twice with 30 ml portions of 1 N NaOH and twice with 30-ml portions of 1 N HCl, the organic phase is dried over MgSO4, and the solvent is evaporated under vacuum in a rotary evaporator. The solid residue is stirred with a mixture of 30 ml ethyl acetate and 30 ml petroleum ether, and the product is filtered off. Yield: 650 mg (73.8%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].N1C=CC=CC=1.[CH3:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Nc1ccccc1Br
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2ccccc2Br)cc1
Temperature: 40 °C

Procedure:
To a suspension of 2-bromoaniline (7.3 mL) and pyridine (13.5 mL) in toluene (110 mL) was added 4-methoxybenzoyl chloride (11 mL) and the mixture was heated at 40° C. for 2.5 hours. The solid was filtered, washed with diethyl ether and water and dried to afford the title compound.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[CH2:5][C:6]1[C:7]([NH:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[N:8][C:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][CH:11]=1.S(=O)(=O)(O)O>C(O)(=O)C.C(OCC)(=O)C>[CH2:20]([N:19]1[C:7]2[N:8]=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[CH:11][C:6]=2[CH2:5][CH:4]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[C:3]1=[O:2])[CH:21]([CH3:22])[CH3:23]
Reactant: COC(=O)C(Cc1cnc(Nc2ccccc2)nc1NCC(C)C)c1ccc(OC)cc1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(C2Cc3cnc(Nc4ccccc4)nc3N(CC(C)C)C2=O)cc1
Temperature: 85 °C

Procedure:
To the solution of 3-(2-phenylamino-4-isobutylamino-pyrimidin-5-yl)-2-(4-methoxy-phenyl)-propionic acid methyl ester (17.1 mg, 0.04 mmol) in glacial acetic acid (1 mL) was added concentrated sulfuric acid (0.1 mL) in one portion. The reaction mixture was heated at 85° C. overnight. After cooling, the reaction mixture was diluted with ethyl acetate (50 mL) and quenched with 2 N aqueous sodium hydroxide solution. The organic layer was separated and successively washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 8-isobutyl-6-(4-methoxy-phenyl)-2-phenylamino-5,8-dihydro-6H-pyrido[2,3-d]pyrimidine-7-one as a brown solid. (14.3 mg, 90.5%). HRMS m/z Calcd for C24H26N4O2 [(M+H)+]: 403.2129. Found: 403.2131.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH3:13])[CH:5]=O.[CH3:14][C:15]([C:17]1[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=1)=[O:16].[OH-].[Na+]>CO>[OH:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:14]/[C:15]([C:17]2[CH:18]=[C:19]([O:27][CH3:28])[C:20]([O:25][CH3:26])=[C:21]([O:23][CH3:24])[CH:22]=2)=[O:16])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH3:13]
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Reactant: CCCOc1ccc(C=O)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCOc1ccc(/C=C/C(=O)c2cc(OC)c(OC)c(OC)c2)cc1O
Yield: 60.7 %

Procedure:
A mixture of 3-hydroxy-4-propoxybenzaldehyde (0.8 g, 4.4 mmol), 3,4,5-trimethoxyacetophenone (0.934 mg, 4.4 mmol) and 50% w/v of aqueous sodium hydroxide (7.0 ml, 0.089 mol) in methanol (10 ml) at room temperature for 18 h. The orange solid isolated by filtration was washed sequentially with cold methanol and ether and finally dried in a vacuum dessicator. Purification was achieved using column chromatography (SiO2, petroleum:ether (40:60 v/v) with an increasing gradient of ethyl acetate) which gave 0.995 g (60%) of a yellow solid. 1H-NMR (CDCl3) δ 7.7 (d, 1H), 7.2 (m, 4H), 7.1 (dd, 3H), 6.9 (d, 1H), 5.7 (s, 1H), 4.1 (t, 2H), 3.9 (s×2, 9H), 1.9 (m, 2H), 1.1 (t, 3H). 13C-NMR (CDCl3) δ 189.1, 153.1, 148.3, 146.0, 144.7, 142.4, 133.7, 128.4, 122.9, 119.8, 112.7, 111.4, 106.1, 70.6, 60.9, 56.4, 22.4, 10.4. Mass Spectrum m/e (M+1) 373. Anal. Calcd. for C21H24O6: C, 67.73; H, 6.5. Found C, 68.01; H, 6.72.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:13])=[CH:4][C:3]=2[O:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:26][CH2:27][CH:28]([OH:30])[CH3:29]>C(Cl)Cl>[OH:13][C:5]1[CH:4]=[C:3]2[O:2][CH2:1][O:12][C:11]2=[CH:10][C:6]=1[C:7]([NH:26][CH2:27][CH:28]([OH:30])[CH3:29])=[O:9]
Reactant: CC(O)CN
Reactant: O=C(O)c1cc2c(cc1O)OCO2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC(O)CNC(=O)c1cc2c(cc1O)OCO2
Yield: 67 %

Procedure:
4,5-Methylenedioxysalicylic acid was activated by carbonyldiimidazole in methylene chloride and combined with 1-amino-2-propanol in essentially an identical manner as for Example 1 above. An acidic quench and subsequent purification by flash chromatography (SiO2) using (1:1) hexane-ethyl acetate gave 1-(2-hydroxy-4,5-methylenedioxybenzamido)-2-propanol as a waxy white solid in 67% yield.
Reaction SMILES: [NH2:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[Cl:38][CH2:39][C:40](Cl)=[O:41]>ClCCl>[Cl:38][CH2:39][C:40]([NH:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1)=[O:41]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N)c3ccccc32)cc1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(NC(=O)CCl)c3ccccc32)cc1
Reaction time: 0.08 h

Procedure:
To a solution of 5-amino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (2.5 g) in dichloromethane (30 ml) is added triethylamine (0.96 ml) and further thereto is added dropwise chloroacetyl chloride (0.55 ml) under ice-cooling. The mixture is stirred for 5 minutes. The reaction solution is concentrated and to the resulting residue is added water. The precipitated crystal is collected by filtration, washed with water, and dried to give 5-(2-chloroacetylamino)-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.4 g) as white powder.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[CH2:12]=[C:13]1[O:17][C:15](=[O:16])[CH2:14]1>O1CCCC1>[O:17]=[C:13]([CH3:12])[CH2:14][C:15]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1)=[O:16]
Reactant: CCOC(=O)C1CCNCC1
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(C(=O)CC(C)=O)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 18.70 g (0.12 mol) ethyl 4-piperidinecarboxylate in 50 ml tetrahydrofuran was added dropwise to a solution of 10.00 g of diketene (0.12 mol) in 200 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue purified by column chromatography.
Reaction SMILES: CO[C:3]1[C:30]([O:31][CH3:32])=[CH:29][C:6]2[C:7]([OH:28])=[CH:8][C:9]3[C:10]([CH3:27])([CH3:26])[C:11]4[CH:12]=[C:13]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=5[O:24][CH3:25])[CH:14]=[CH:15][C:16]=4[C:17]=3[C:5]=2[CH:4]=1.[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C([Li])CCC.Cl>CCCCCC.O1CCCC1>[N:33]1([C:3]2[C:30]([O:31][CH3:32])=[CH:29][C:6]3[C:7]([OH:28])=[CH:8][C:9]4[C:10]([CH3:27])([CH3:26])[C:11]5[CH:12]=[C:13]([C:18]6[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=6[O:24][CH3:25])[CH:14]=[CH:15][C:16]=5[C:17]=4[C:5]=3[CH:4]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: COc1cc2c(O)cc3c(c2cc1OC)-c1ccc(-c2ccccc2OC)cc1C3(C)C
Reactant: C1CCNCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccccc1-c1ccc2c(c1)C(C)(C)c1cc(O)c3cc(OC)c(N4CCCCC4)cc3c1-2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 500 mL one-neck flask was added the product from Step 1(10 g), piperidine (5.2 mL and anhydrous tetrahydrofuran (150 mL). n-Butyl lithium in hexane solution (2.5M, 35 mL) was dropped to the mixture through addition funnel slowly. The reaction mixture was stirred at room temperature for 3 hours. The mixture was poured into cold aqueous hydrochloric acid (10%, 60 mL). The resulting mixture was extracted with ethyl acetate (200 mL) and the recovered top layer was filtered through a silica gel plug using ethyl acetate and hexane mixture as eluent. All silica gel plug and chromatography mentioned herein was carried out using ethyl acetate and hexanesmixture as eluent if not specified. Solid 2-(piperidin-1-yl)-3-methoxy-7,7-dimethyl-9-(2-methoxyphenyl)-7H-benzo[C]fluoren-5-ol (10 g) was obtained by re-crystallization from solution in ethyl acetate/hexanes.
Reaction SMILES: [O:1]=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.CO.[CH3:15][C:16]1([CH3:23])[CH:21]([OH:22])[C:19](=[O:20])[O:18][CH2:17]1>>[C:19]([OH:1])(=[O:20])[C@@H:21]([C:16]([CH2:17][OH:18])([CH3:23])[CH3:15])[OH:22]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CC1(C)COC(=O)C1O
Solvent: CO
Product: CC(C)(CO)[C@@H](O)C(=O)O
Temperature: 28 °C
Reaction time: 0.33 h

Procedure:
A liquid medium (pH 6.5) consisting of 1% glucose, 0.5% peptone, 0.5% yeast extract and 0.5% corn steep liquor was dispensed in 5 ml portions into test tubes, and then heat-sterilized by autoclaving at 121° C. for 20 minutes. The various strains mentioned in Table 1 were each inoculated from slants into the medium in the test tubes, and subjected to aerobic shake culture at 28° C. for 5 days. After the cultivation, cells were collected by filtration. Into containers each containing different collected cells was dispensed a 2% D,L-pantolactone solution in Tris-HCl buffer (pH 7.5) in 2 ml portions, and the containers were shaken overnight at 28° C. After the reaction, cells were removed by filtration, and each reaction liquid was subjected to HPLC (Nucleosil 5C18 φ 4.6×l 150 mm; eluent 10% methanol; rate of flow 1 ml/min; wavelength for detection 230 nm) to determine the decrease in pantolactone and the amount of pantoic acid formed. Unreacted pantolactone in the reaction liquid is separated by extraction with ethyl acetate, and pantoic acid remaining in the reaction liquid is then heated under acidification with hydrochloric acid for lactonization. The resultant D-pantolactone was extracted with ethyl acetate. The optical purity of the D-pantolactone thus obtained from the pantoic acid was measured by GLC (Analytical Biochemistry 112, 9-19 (1981)). The results are as shown in Table 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[C:10]([CH3:21])=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][N:15]=[C:14]([NH:19][CH3:20])[CH:13]=3)=[CH:4][C:3]=1[NH:22][C:23](=[O:28])OC(C)=C.[CH3:29][C:30]([CH3:35])([CH3:34])[CH2:31][CH2:32][NH2:33].CN1CCCC1>O1CCOCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[C:10]([CH3:21])=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][N:15]=[C:14]([NH:19][CH3:20])[CH:13]=3)=[CH:4][C:3]=1[NH:22][C:23]([NH:33][CH2:32][CH2:31][C:30]([CH3:35])([CH3:34])[CH3:29])=[O:28]
Reactant: C=C(C)OC(=O)Nc1cc(-c2cc3cnc(NC)cc3nc2C)c(F)cc1F
Reactant: CC(C)(C)CCN
Agent: CN1CCCC1
Solvent: C1COCCO1
Product: CNc1cc2nc(C)c(-c3cc(NC(=O)NCCC(C)(C)C)c(F)cc3F)cc2cn1
Temperature: 25 °C
Yield: 88.7 %

Procedure:
Heat a solution of prop-1-en-2-yl 2,4-difluoro-5-(2-methyl-7-(methylamino)-1,6-naphthyridin-3-yl)phenylcarbamate (1.449 g, 3.77 mmol), 3,3-dimethylbutylamine (0.572 g, 5.65 mmol), and 1-methylpyrrolidine (0.080 g, 0.942 mmol) in dioxane (30 mL) at 80° C. overnight. Cool to RT, collect the precipitate via filtration and dry. Concentrate the filtrate, treat with DCM, sonicate for 0.5 h, collect the solid via filtration and combine with the solid above to afford the title compound (1.43 g, 89%). 1H NMR (400 MHz, DMSO-d6): δ 8.86 (s, 1H), 8.35 (s, 1H), 8.13 (t, 1H), 8.00 (s, 1H), 7.40 (t, 1H), 8.85-8.82 (m, 1H), 6.52-6.49 (m, 2H), 3.07-3.04 (m, 2H), 2.82 (d, 3H), 2.38 (s, 3H), 1.34-1.30 (m, 2H), 0.87 (s, 9H); MS (ESI) m/z: 428.2 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[C:9]1(B(O)O)[C:22]2[C:23]3=[C:24]4[C:19](=[CH:20][CH:21]=2)[CH:18]=[CH:17][CH:16]=[C:15]4[CH:14]=[CH:13][C:12]3=[CH:11][CH:10]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>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.C1(C)C=CC=CC=1>[Br:8][C:4]1[CH:3]=[C:2]([C:16]2[C:15]3[C:24]4=[C:23]5[C:12](=[CH:13][CH:14]=3)[CH:11]=[CH:10][CH:9]=[C:22]5[CH:21]=[CH:20][C:19]4=[CH:18][CH:17]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)c1
Reactant: OB(O)c1ccc2ccc3cccc4ccc1c2c34
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Brc1cccc(-c2ccc3ccc4cccc5ccc2c3c45)c1
Temperature: 90 °C
Yield: 48.9 %

Procedure:
A mixture of 10 g (42.4 mmol) of 1,3-dibromobenzene, 10.43 g (42.4 mmol) of Pyren-1-ylboronic acid, 0.5 g (0.424 mmol) of Tetrakis(triphenylphosphine)palladium, 32 ml of 2M Na2CO3, 80 ml of EtOH and 160 ml toluene was degassed and placed under nitrogen, and then heated at 90° C. for 24 h. After the reaction finish, the mixture was allowed to cool to room temperature. The organic layer was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was removed and the residue was purified by column chromatography on silica (hexane-dichloromethane) to give product 7.4 g (49%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=S)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][NH2:30])=O)=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]2[NH:18][C:16]([NH:15][C:5]3[CH:6]=[CH:7][C:8]([N:9]4[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]4)=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:30][N:29]=2)=[CH:22][CH:21]=1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Reactant: NNC(=O)Cc1ccc(F)cc1
Product: COc1cc(Nc2nnc(Cc3ccc(F)cc3)[nH]2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogy to example 71c) starting with [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (200 mg, 0.76 mmol) and (4-fluoro-phenyl)-acetic acid hydrazide (141 mg, 0.76 mmol). Obtained as a greyish solid (21 mg, 7%).