Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[N:7]1[CH2:12][CH2:11][CH2:10][C@H:9]([CH2:13][NH:14]C(=O)OC(C)(C)C)[CH2:8]1.C(OC([NH:30][C:31]1[S:35][C:34]([C:36]2[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=2[F:43])=[N:33][C:32]=1[C:44](O)=[O:45])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[NH2:30][C:31]1[S:35][C:34]([C:36]2[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=2[F:43])=[N:33][C:32]=1[C:44]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[N:7]1[CH2:12][CH2:11][CH2:10][C@@H:9]([CH2:13][NH2:14])[CH2:8]1)=[O:45]
Reactant: Cn1ncc(N)c1N1CCC[C@H](CNC(=O)OC(C)(C)C)C1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CCC[C@@H](CN)C1
Yield: 6.2 %

Procedure:
Following the procedures as described in Example 113, (R)-tert-butyl (1-(4-amino-1-methyl-1H-pyrazol-5-yl)piperidin-3-yl)methylcarbamate, 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid, and HATU were reacted to give 131 as a white solid (12 mg, 6.2%) over two steps. 1H NMR (400 MHz, DMSO) δ 8.74 (d, J=4.0, 1H), 7.60-7.42 (m, 4H), 7.28 (t, J=8.8, 2H), 3.63 (d, J=3.3, 3H), 3.24-2.81 (m, 4H), 2.77-2.61 (m, 2H), 1.84-1.42 (m, 4H), 1.03 (d, J=10.6, 1H). ESIMS m/z=448.1 (M+1)
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([O:11][C:12](=[O:33])[NH:13][C@@H:14]1[C:19](=[O:20])[C@H:18]([CH2:21][C:22]2[CH:27]=[C:26]([F:28])[C:25]([N+:29]([O-:31])=[O:30])=[C:24]([F:32])[CH:23]=2)[CH2:17][S:16][CH2:15]1)([CH3:10])([CH3:9])[CH3:8]>C1COCC1>[C:7]([O:11][C:12](=[O:33])[NH:13][C@@H:14]1[C@@H:19]([OH:20])[C@H:18]([CH2:21][C:22]2[CH:23]=[C:24]([F:32])[C:25]([N+:29]([O-:31])=[O:30])=[C:26]([F:28])[CH:27]=2)[CH2:17][S:16][CH2:15]1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N[C@H]1CSC[C@@H](Cc2cc(F)c([N+](=O)[O-])c(F)c2)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CSC[C@@H](Cc2cc(F)c([N+](=O)[O-])c(F)c2)[C@@H]1O
Temperature: -78 °C
Reaction time: 5 h

Procedure:
To a suspension of LiAlH4 (2.137 g, 53.5 mmol) in anhydrous THF (200 mL) was added under argon a solution of [(3R*,5S*)-5-(3,5-difluoro-4-nitro-benzyl)-4-oxo-tetrahydro-thiopyran-3-yl]-carbamic acid tert-butyl ester (19.56 g, 48.6 mmol) in anhydrous THF (300 mL) below −70° C. over a period of 2 h. After stirring for 5 h at −78° C. the reaction was quenched with 4.2 mL H2O at 0° C., 4.2 mL 4N aq. NaOH and after stirring for 30 min an additional 12.6 mL H2O were added. After addition of MgSO4, the reaction mixture was filtered over Celite, and the colorless filtrate was evaporated. The title compound was obtained after two crystallizations from EtOH as a single diastereoisomer. The racemate [(3R*,4S*,5S*)-5-(3,5-difluoro-4-nitro-benzyl)-4-hydroxy-tetrahydro-thiopyran-3-yl]-carbamic acid tert-butyl ester was separated by preparative HPLC on Chiralpak AD-I (5×20 cm) with hexane-AcOEt-iPrOH 80:15:5 to yield the (3R,4S,5S)-diastereoisomer with >99% ee (peak 1) and the (3S,4R,5R)-diastereoisomer with >98% ee as light yellow crystalline solid: TLC (hexane-EtOAc 1:1) Rf=0.38; HPLC RtA=2.05 min; ESIMS [M+H-isobutylene]+=349; 1H NMR (400 MHz, CDCl3): δ 6.92 (d, 2H), 5.55 (d, 1H), 4.34 (m, 1H), 3.54 (m, 1H), 3.22 (dd, 1H), 2.91 (m, 1H), 2.75 (m, 1H), 2.46 (dd, 1H), 2.36 (dd, 1H), 2.26 (m, 2H), 2.03 (m, 1H), 1.36 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[N:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[CH:25]=[C:24]2[C:20]([C:21]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][C:22]=3[N:23]2[CH3:26])=[CH:19][CH:18]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[N:13][N:12]([C:17]2[CH:25]=[C:24]3[C:20]([C:21]4[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][C:22]=4[N:23]3[CH3:26])=[CH:19][CH:18]=2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c2c(c3ccc(Br)cc31)CCN(C(=O)OC(C)(C)C)C2
Reactant: O=c1cc(OCc2ccccc2)cn[nH]1
Product: Cn1c2c(c3ccc(-n4ncc(OCc5ccccc5)cc4=O)cc31)CCN(C(=O)OC(C)(C)C)C2
Yield: 27.7 %

Procedure:
5-(Benzyloxy)pyridazin-3(2H)-one (197 mg, 0.974 mmol) and tert-butyl 7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (353 mg, 0.966 mmol) were coupled following the procedure of Example 30 (step g) to provide the title compound (130 mg, 28%) as a yellow/green solid: 1H NMR (300 MHz, CDCl3) δ 7.77 (d, J=2.7 Hz, 1H), 7.52 (d, J=8.2 Hz, 1H), 7.45-7.40 (m, 7H), 7.21 (dd, J=8.4, 1.5 Hz, 1H), 5.08 (s, 2H), 4.64 (br m, 2H), 3.75 (br m, 2H), 3.63 (s, 3H), 2.80 (br m, 2H), 1.52 (s, 9H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].[C:20](Cl)(=[O:32])[O:21][CH2:22][C:23]1[CH:28]=[C:27]([C:29]#[N:30])[CH:26]=[C:25]([Cl:31])[CH:24]=1>C(Cl)Cl>[C:10]([O:9][C:8]([NH:7][CH:4]1[CH2:3][CH2:2][N:1]([C:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]#[N:30])[CH:26]=[C:25]([Cl:31])[CH:24]=2)=[O:32])[CH2:6][CH2:5]1)=[O:14])([CH3:11])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: N#Cc1cc(Cl)cc(COC(=O)Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)OCc2cc(Cl)cc(C#N)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl piperidin-4-ylcarbamate (1.045 g, 5.22 mmol) in DCM (25 mL) at RT was added a saturated solution of sodium bicarbonate (5.6 ml). 3-Chloro-5-cyanobenzyl carbonochloridate (Example 36, step 4) (1.2 g, 5.22 mmol) was then added in DCM (2 ml) and the reaction mixture stirred at RT for 2 hours. The layers were separated and the organic portion was washed with a saturated solution of brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford the title product;
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:15][CH2:16][C:17]2[CH:18]=[N:19][C:20](Cl)=[CH:21][CH:22]=2)=[O:14])[CH:3]=1.[CH3:24][O:25][C:26]([CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)=[O:27]>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N:31]3[CH2:32][CH2:33][CH:28]([C:26]([O:25][CH3:24])=[O:27])[CH2:29][CH2:30]3)=[N:19][CH:18]=2)=[O:14])[CH:3]=1
Reactant: COC(=O)C1CCNCC1
Reactant: CCOc1nc(C(=O)NCc2ccc(Cl)nc2)cc(N)c1C#N
Product: CCOc1nc(C(=O)NCc2ccc(N3CCC(C(=O)OC)CC3)nc2)cc(N)c1C#N

Procedure:
A mixture of Example 185 (50 mg, 0.15 mmol) and piperidine-4-carboxylic acid methyl ester (0.75 mL) were heated to 140° C. for 20 min. in a microwave reactor. The reaction mixture was extracted with ethyl acetate (5 mL) and washed with 1M HCl (2×10 mL). The organic layer was concentrated in vacuo and purified by silica gel chromatography (50-100% ethyl acetate in hexanes) providing the title compound as an off white solid (34 mg, 52%). 1H NMR (300 MHz, DMSO-d6) δ 8.92 (t, J=6.44 Hz, 1H), 8.05 (d, J=2.03 Hz, 1H), 7.47 (dd, J=8.82, 2.37 Hz, 1H), 7.30 (s, 2H), 7.06 (s, 1H), 6.80 (d, J=8.48 Hz, 1H), 4.48 (q, J=7.12 Hz, 2H), 4.31 (d, J=6.10 Hz, 2H), 4.14 (d, J=13.22 Hz, 2H), 3.60 (s, 3H), 2.82-2.98 (m, 2H), 2.56-2.67 (m, 1H), 1.85 (dd, J=13.56, 3.39 Hz, 2H), 1.43-1.62 (m, 2H), and 1.30 (t, J=7.12 Hz, 3H); MS (ESI) m/e positive ion 461 [M+Na]+, 439 [M+H]+; negative ion 437 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=2[S:5][C:6]=1[CH2:7][OH:8].C[N+]1([O-])CCOCC1>C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[Cl:1][C:2]1[C:3]2[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=2[S:5][C:6]=1[CH:7]=[O:8]
Reactant: OCc1sc2ccccc2c1Cl
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: O=Cc1sc2ccccc2c1Cl
Reaction time: 0.17 h
Yield: 84.7 %

Procedure:
A solution of alcohol 12 (4.32 g, 21.6 mmol) in 40 mL of CH2Cl2 was treated with 4A molecular sieves, NMO (3.81 g, 32.5 mmol), and TPAP (381 mg, 1.08 mmol). The reaction was stirred for 10 min. and then was evaporated to dryness. Purification by flash chromatography on silica gel (2% ethyl acetate/hexane) gave 3.52 g (18.3 mmol, 84%) of the aldehyde (13).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([NH2:35])=[N:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])=[CH:23][CH:22]=3)[N:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:36]([O:43][C:44]1[CH:49]=[CH:48][C:47]([CH2:50][C:51](Cl)=[O:52])=[CH:46][CH:45]=1)([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:16]([NH:35][C:51](=[O:52])[CH2:50][C:47]3[CH:46]=[CH:45][C:44]([O:43][Si:36]([C:39]([CH3:41])([CH3:40])[CH3:42])([CH3:37])[CH3:38])=[CH:49][CH:48]=3)=[N:17][CH:18]=[C:19]([C:21]3[CH:22]=[CH:23][C:24]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:29])[CH3:30])=[CH:25][CH:26]=3)[N:20]=2)=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)n2)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Nc2ncc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)nc2-c2ccc(O[Si](C)(C)C(C)(C)C)cc2)cc1
Temperature: 50 °C
Reaction time: 15 h
Yield: 81.1 %

Procedure:
Under an argon atmosphere, to a mixture of 3,5-bis[4-(tert-butyldimethylsilyloxy)phenyl]pyrazin-2-amine (7j) (591 mg, 1.16 mmol) and 4-(dimethylamino)pyridine (15.7 mg, 129 μmol) dissolved in anhydrous pyridine (20 mL) was added 2-[4-(tert-butyldimethylsilyloxy)phenyl]acetyl chloride (10) prepared above at 0° C. and the mixture was heated with stirring at 50° C. for 15 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (200 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=4/1) to give Compound 11j (714 mg, 945 μmol, 81.1%) as a yellow foamy solid. Rf=0.37 (n-hexane/diethyl ether=2/3); 1H NMR (400 MHz, DMSO-d6) δ 0.14 (s, 6H), 0.19 (s, 6H), 0.20 (s, 6H), 0.92 (s, 9H), 0.95 (s, 18H), 3.47 (s, 2H), 6.71-6.78 (2AA′BB′, 4H), 6.94-7.02 (AA′BB′, 2H), 7.03-7.13 (AA′BB′, 2H), 7.57-7.63 (AA′BB′, 2H), 8.03-8.10 (AA′BB′, 2H), 8.91 (s, 1H), 10.49 (s, 1H); 13C NMR (75.5 MHz, DMSO-d6) δ −4.5 (6C), 17.9 (3C), 25.5 (9C), 41.7, 119.3 (2C), 119.5 (2C), 120.3 (2C), 127.9, 128.1 (2C), 128.9, 129.3 (2C), 130.4 (2C), 130.7, 136.9, 142.4, 147.2, 147.8, 153.8, 155.7, 156.7, 169.3; IR (KBr, cm−1) 523, 637, 677, 710, 781, 804, 839, 914, 1009, 1078, 1105, 1169, 1258, 1362, 1402, 1416, 1441, 1472, 1510, 1605, 1667, 2857, 2886, 2928, 2955, 3036, 3221; HRMS (ESP) m/z 778.3853 ([M+Na]+, C42H61N3NaO4Si3+ requires 778.3862).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=[O:13])[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.[CH2:15](OS([O-])(=O)=O)[CH3:16]>O>[CH2:15]([S:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=[O:13])[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1)[CH3:16]
Reactant: CCOS(=O)(=O)[O-]
Reactant: O=C(O)c1cc(S)cc2c1OCCO2
Solvent: O
Product: CCSc1cc2c(c(C(=O)O)c1)OCCO2
Yield: 80.9 %

Procedure:
166 g of 7-mercapto-1,4-benzodioxane-5-carboxylic acid, 242 cm3 of water, 216 cm3 of soda lye and 181 g of ethylsulfate were introduced into a balloon flask provided with a condenser. The mixture was heated under reflux and then cooled. The solution was poured into 1.3 l of water, filtered and treated with 110 cm3 of hydrochloric acid. The precipitate was dried off, washed with water and dried. 152 g of 7-ethylthio-1,4-benzodioxane-5-carboxylic acid were obtained (M.P: 153°-154° C.; yield: 81%).
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19](=[O:27])(=[O:26])[NH:18]2)=[C:9]1[CH3:28])(C)(C)C.I[CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34]>>[CH3:28][C:9]1[N:8]([CH2:7][C:6]([OH:5])=[O:29])[C:16]2[C:11]([C:10]=1[CH:17]1[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19](=[O:26])(=[O:27])[N:18]1[CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])=[CH:12][CH:13]=[CH:14][CH:15]=2
Reactant: Cc1c(C2NS(=O)(=O)c3ccccc32)c2ccccc2n1CC(=O)OC(C)(C)C
Reactant: CC(C)CCI
Product: Cc1c(C2c3ccccc3S(=O)(=O)N2CCC(C)C)c2ccccc2n1CC(=O)O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 3, step c) and 1-iodo-3-methyl-butane. MS: ESI (negative): 425 (M−H).
Reaction SMILES: CC(N=NC(C#N)(C)C)(C#N)C.[Br:13]N1C(=O)CCC1=O.[Br:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]=[C:27]([CH3:32])[CH:26]=[CH:25]2>C(Cl)(Cl)(Cl)Cl>[Br:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]=[C:27]([CH2:32][Br:13])[CH:26]=[CH:25]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2cc(Br)ccc2n1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2cc(Br)ccc2n1

Procedure:
148 mg (1.00 mmol) α,α-azoisobutyronitrile and 8.01 g (45.0 mmol) N-bromosuccinimide are added successively to a solution of 10.0 g (45.0 mmol) 6-bromo-2-methyl-quinoline in 60 mL carbon tetrachloride. The reaction mixture is refluxed for 8 h. It is filtered and the filtrate is washed twice with water. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac. The purification is carried out by column chromatography on silica gel (PE/EtOAc 4:1).
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([C:17]([OH:19])=O)=[N:12][C:11]([NH:20][C:21]1[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=1)=[CH:10]2>>[CH3:2][N:3]([CH3:4])[C:17]([C:13]1[C:14]2[C:9](=[CH:8][C:7]([O:6][CH3:5])=[CH:16][CH:15]=2)[CH:10]=[C:11]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)[N:12]=1)=[O:19]
Reactant: CNC
Reactant: COc1ccc2c(C(=O)O)nc(Nc3cc(C)[nH]n3)cc2c1
Agent: Cl
Product: COc1ccc2c(C(=O)N(C)C)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 317 was used, starting from dimethyl-amine hydrochloride and 6-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-1-carboxylic acid to give 6-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-1-carboxylic acid dimethylamide. LC-MS: m/e 326 (MH+).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7]([O:12][CH3:13])=[C:8]([CH:11]=1)[CH:9]=O.[CH3:14][C:15]([CH3:17])=[O:16]>O>[F:3][C:4]1[CH:5]=[CH:6][C:7]([O:12][CH3:13])=[C:8]([CH:9]=[CH:14][C:15](=[O:16])[CH3:17])[CH:11]=1
Reactant: CC(C)=O
Reactant: COc1ccc(F)cc1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(F)cc1C=CC(C)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In water (200 ml) was dissolved sodium hydroxide (3 g), and to the solution was added acetone (80 ml) and then was added dropwise a solution of 5-fluoro-2-methoxybenzaldehyde (10 g) in acetone (25 ml). The reaction solution was stirred at room temperature for 4 hours, and acetone was evaporated under reduced pressure. The residue was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine and concentrated under reduced pressure to give 4-(5-fluoro-2-methoxyphenyl)-3-buten-2-one (13 g).
Reaction SMILES: [Na].[C:2]([NH:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3].Br[CH:18]([CH2:23][C:24]([NH2:26])=[O:25])[C:19](OC)=[O:20]>C(O)C>[C:2]([NH:5][C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:23]1[CH2:18][C:19](=[O:20])[NH:26][C:24]1=[O:25])(=[O:4])[CH3:3]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: COC(=O)C(Br)CC(N)=O
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(NC(C)=O)(C(=O)OCC)C1CC(=O)NC1=O
Reaction time: 2 h

Procedure:
In 1 l of ethanol was dissolved 31.6 g of sodium, and following addition of 300 g of diethyl acetylaminomalonate at room temperature, the mixture was stirred for 2 hours. To the reaction mixture, a solution of 144.5 g of methyl 2-bromosuccinamate in ethanol (350 ml) was added dropwise under ice-cooling and the mixture was stirred under ice-cooling for one hour and then at room temperature for an additional one hour. This reaction mixture was concentrated under reduced pressure, followed by addition of 1 l portions of water and ethyl acetate, and stirred. The aqueous layer was separated and the ethyl acetate layer was further extracted with 500 ml of water. These aqueous layers were combined, washed with 1 l of ethyl acetate, adjusted to pH 1.5 with conc. hydrochloric acid and allowed to stand in a refrigerator. The resultant crystals were collected by filtration, washed with water and dried under reduced pressure. Yield 140 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]([CH2:20][C:21](O)=[O:22])[S:10]([C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.[CH2:24]([NH:31][CH2:32][CH3:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([N:31]([CH2:32][CH3:33])[C:21](=[O:22])[CH2:20][N:9]([C:6]1[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[S:10]([C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=1)(=[O:11])=[O:12])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COc1ccc(N(CC(=O)O)S(=O)(=O)c2ncccc2C)cn1
Reactant: CCNCc1ccccc1
Product: CCN(Cc1ccccc1)C(=O)CN(c1ccc(OC)nc1)S(=O)(=O)c1ncccc1C

Procedure:
prepared by reaction of [(6-methoxy-pyridin-3-yl)-(3-methyl-pyridine-2-sulfonyl)-amino]-acetic acid with benzyl-ethyl-amine
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:12]([N:14]1[CH2:19][CH2:18][N:17]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH2:16][CH2:15]1)[CH3:13])[N:6]([CH3:31])[C:5]2=[O:32].[C:33](Cl)(=[O:35])[CH3:34]>CN(C=O)C>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([S:20]([N:17]2[CH2:16][CH2:15][N:14]([CH:12]([C:7]3[N:6]([CH3:31])[C:5](=[O:32])[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:33](=[O:35])[CH3:34])[CH:3]=4)[N:8]=3)[CH3:13])[CH2:19][CH2:18]2)(=[O:22])=[O:21])=[CH:24][CH:25]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(S(=O)(=O)N2CCN(C(C)c3nc4ccc(N)cc4c(=O)n3C)CC2)cc1
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N2CCN(C(C)c3nc4ccc(NC(C)=O)cc4c(=O)n3C)CC2)cc1
Reaction time: 2 h
Yield: 15.1 %

Procedure:
To the 1 ml DMF solution of 6-Amino-2-{1-[4-(4-methoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl}-3-methyl-3H-quinazolin-4-one (50.0 mg, 0.11 mmol) was added acetyl chloride (9.44 mg, 0.12 mmol). The reaction was stirred for 2 hours. The solvent was removed by reduce pressure and extracted with Na2CO3 aqueous and ethyl acetate, dried over anhydrous MgSO4, and concentrated by rotary evaporation. Purification was accomplished by HPLC (Gilson-215, 0.035% TFA in acetonitrile and 0.05% water as mobile phase). The product was collected and dried under reduced pressure to give the N-(2-{1-[4-(4-Methoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl}-3-methyl-4-oxo-3,4-dihydro-quinazolin-6-yl)-acetamide (Yield 8.29 mg, 14.9%). 1H NMR (400 MHz, MeOD-d4): δ 1.70 (d, 3H, J=6.57 Hz), 2.18 (s, 3H), 3.57-3.43 (m, 8H), 3.64 (s, 3H), 3.93 (s, 3H), 4.84 (q, 1H, J=6.57, 6.06 Hz), 7.19 (d, 2H, J=9.09 Hz), 7.64 (d, 1H, J=8.34 Hz), 7.79 (d, 2H, J=9.09 Hz), 7.98 (dd, 1H, J=8.59, 2.78 Hz), 8.46 (d, J=2.27 Hz). MS m/z calc. 499.2 found (ESI); 500.2 (M+1)+. Retention time 2.42 minutes.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:19][CH2:18]1.CC1(C)C(C)(C)OB([C:37]2[CH:42]=[CH:41][C:40]([OH:43])=[C:39]([O:44][C:45]([F:48])([F:47])[F:46])[CH:38]=2)O1>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[N:17]2[CH2:18][CH2:19][CH:20]([CH2:23][N:24]4[CH2:25][CH2:26][CH2:27][CH2:28]4)[CH2:21][CH2:22]2)=[CH:3][C:2]([C:37]2[CH:42]=[CH:41][C:40]([OH:43])=[C:39]([O:44][C:45]([F:46])([F:48])[F:47])[CH:38]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: O=C(c1cnc2ccc(Br)cc2c1N1CCC(CN2CCCC2)CC1)C1CC1
Reactant: CC1(C)OB(c2ccc(O)c(OC(F)(F)F)c2)OC1(C)C
Product: O=C(c1cnc2ccc(-c3ccc(O)c(OC(F)(F)F)c3)cc2c1N1CCC(CN2CCCC2)CC1)C1CC1

Procedure:
Following general procedure D, {6-bromo-4-[4-(pyrrolidin-1-ylmethyl)piperidin-1-yl]quinolin-3-yl}(cyclopropyl)methanone (30 mg, 0.068 mmol) was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethoxy)phenol (36 mg, 0.140 mmol) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 8.80 (s, 1H), 8.28 (d, J=1.6 Hz, 1H), 8.08-7.98 (m, 2H), 7.64-7.57 (m, 2H), 7.12 (d, J=9.0 Hz, 1H), 3.54 (d, J=12.8 Hz, 2H), 3.22 (t, J=11.5 Hz, 2H), 3.13 (s, 4H), 2.99 (s, 2H), 2.64-2.50 (m, 1H), 2.10-1.92 (m, 7H), 1.74-1.59 (m, 2H), 1.36-1.28 (m, 2H), 1.28-1.19 (m, 2H); ESI MS m/z 540 [C30H32F3N3O3+H]+; HPLC>99% (AUC), tR=11.16 min.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])[CH:6]=[CH:7][CH:8]=1>C(Cl)Cl.O=[Mn]=O>[CH:2]([C:3]1[CH:4]=[C:5]([CH:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])[CH:6]=[CH:7][CH:8]=1)=[O:1]
Reactant: CC(NC(=O)OC(C)(C)C)c1cccc(CO)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(NC(=O)OC(C)(C)C)c1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.1 %

Procedure:
To a solution of tert-butyl N-[1-[3-(hydroxymethyl)phenyl]ethyl]carbamate (4.91 g, 19.54 mmol) in DCM (40 mL) was added MnO2 (13.59 g, 156.3 mmol) and the reaction mixture was stirred at ambient temperature for 48 hours. An additional portion of MnO2 (3 g 34.5 mmol) was added and the reaction mixture was stirred at ambient temperature for an additional 12 hours. The reaction mixture was filtered through a pad of Celite and the filtrate concentrated in vacuo to give the sub-title compound as a colourless oil (4.0 g, 82% Yield). 1H NMR (400 MHz, DMSO) δ 1.30-1.41 (m, 12H) 4.64-4.75 (m, 1H), 7.55 (dd, 2H), 7.64 (d, 1H), 7.78 (d, 1H), 7.83 (s, 1H) and 10.00 (s, 1H) ppm; MS (ES+) 250.5.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[N:10][NH:11][CH:12]=1)=[O:7])[CH3:4].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O>[CH2:13]([N:10]1[CH:9]=[C:8]([C:6]([O:5][CH2:3][CH3:4])=[O:7])[CH:12]=[N:11]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (containing 63%, 652 mg) in dimethylformamide (abbreviated as DMF hereinafter) was added a solution of 4-ethoxycarbonylpyrazole (2.00 g) in DMF (15 ml) at room temperature. After stirred for 30 min at room temperature, to the mixture was added benzylbromide (2.04 ml). After stirred for 30 min, the mixture was quenched by addition of water. The mixture was extracted with ethyl acetate--n-hexane. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to give the title compound (2.98 g) having the following physical data.