Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]1([CH2:40][NH:41]C(=O)OC(C)(C)C)[CH2:16][CH2:15][N:14]([C:17]2[C:18]3[O:39][CH:38]=[CH:37][C:19]=3[N:20]=[C:21]([NH:23][C:24]3[CH:36]=[CH:35][C:27]4[O:28][C:29]([CH3:34])([CH3:33])[C:30](=[O:32])[NH:31][C:26]=4[CH:25]=3)[N:22]=2)[CH2:13][CH2:12]1)(C(C)(C)C)(C)C.ICCO.CC([Si](Cl)(C)C)(C)C.C(N1CCC(C#N)CC1)C1C=CC=CC=1.C([Si](OCCI)(C)C)(C)(C)C.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.ClC1N=C(Cl)C2OC=CC=2N=1.NC1C=CC2OC(C)(C)C(=O)NC=2C=1.Cl>O1CCOCC1>[NH2:41][CH2:40][C:11]1([CH2:10][CH2:9][OH:8])[CH2:16][CH2:15][N:14]([C:17]2[C:18]3[O:39][CH:38]=[CH:37][C:19]=3[N:20]=[C:21]([NH:23][C:24]3[CH:36]=[CH:35][C:27]4[O:28][C:29]([CH3:34])([CH3:33])[C:30](=[O:32])[NH:31][C:26]=4[CH:25]=3)[N:22]=2)[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)NCC1(CCO[Si](C)(C)C(C)(C)C)CCN(c2nc(Nc3ccc4c(c3)NC(=O)C(C)(C)O4)nc3ccoc23)CC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: CC(C)(C)[Si](C)(C)OCCI
Solvent: C1COCCO1
Product: CC1(C)Oc2ccc(Nc3nc(N4CCC(CN)(CCO)CC4)c4occc4n3)cc2NC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 43 %

Procedure:
tert-Butyl (4-(2-(tert-butyldimethylsilyloxy)ethyl)-1-(2-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-ylamino)furo[3,2-d]pyrimidin-4-yl)piperidin-4-yl)methylcarbamate (0.40 g, 0.587 mmol, prepared using AH from 2-iodoethanol with TBDMSCl, AF with 1-benzylpiperidine-4-carbonitrile [Ryan] with tert-butyl(2-iodoethoxy)dimethylsilane, AE, O with Boc2O, G, A with 2,4-dichlorofuro[3,2-d]pyrimidine [ArkPharm] and B with 6-amino-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one [Arkpharm]) and an aqueous solution of aqueous HCl (4 M, 7.34 mL, 29.4 mmol) were dissolved in 1,4-dioxane (15 mL) and stirred for about 4 h at rt. The mixture was concentrated under vacuum and the residue was purified by Prep-TLC (EtOAc/pet ether 1:2) to give 6-(4-(4-(aminomethyl)-4-(2-hydroxyethyl)piperidin-1-yl)furo[3,2-d]pyrimidin-2-ylamino)-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3 (4H)-one (0.121 g, 43%): LC/MS (Table 2, Method h) Rt=1.69 min.; MS m/z: 467 (M+H)+. Syk IC50=A
Reaction SMILES: C(O[AlH-](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].C(=O)=O.CC(C)=O.[F:25][C:26]1[CH:27]=[C:28]([C:36](=[O:50])[C@@H:37]([NH:39][C:40](=[O:49])OCC2C=CC=CC=2)[CH3:38])[CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1.[OH-].[K+].Cl>C(O)C.CO.C1COCC1>[F:25][C:26]1[CH:27]=[C:28]([C@H:36]2[O:50][C:40](=[O:49])[NH:39][C@H:37]2[CH3:38])[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)c1cc(F)cc(C(F)(F)F)c1
Agent: CC(C)(C)O[AlH-](OC(C)(C)C)OC(C)(C)C
Agent: Cl
Agent: O=C=O
Solvent: CCO
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H]1NC(=O)O[C@@H]1c1cc(F)cc(C(F)(F)F)c1
Reaction time: 0.17 h

Procedure:
Lithium tri-tert-butoxyaluminohydride (18.27 ml, 74.0 mmol) was added into a cold (dry ice/acetone bath) solution of benzyl {(2S)-1-[3-fluoro-5-(trifluoromethyl)phenyl]-1-oxopropan-2-yl}carbamate (5.4655 g, 14.80 mmol) in ethanol (100 ml). LCMS indicated the reaction was completed in 10 min. The reaction was quenched by HCl (1N). The crude mixture was diluted with ethyl acetate and filtered through a bed of Celite® 521 (slow filtration). Volatiles were removed from the filtrate under reduced pressure. The resulting pot residue was worked up with aqueous sodium hydrogen carbonate/brine, extracted with ethyl acetate, dried over Na2SO4, filtered and evaporated to afford a white solid. This solid was stirred with potassium hydroxide (10 ml, 75 mmol) in a THF (100 ml)/methanol (50 ml) mixture at room temp for 2 hrs. LCMS indicated completion of reaction. HCl (1N) was added to acidify the reaction mixture. Volatiles were removed under reduced pressure. The pot residue was worked up with brine, extracted with ethyl acetate, dried over Na2SO4, filtered and evaporated to afford a dark mixture. The resulting mixture was purified by flash chromatography (SiO2, Biotage 65i cartridge). The column was eluted by an ethyl acetate/hexanes mixture (0% to 100% ethyl acetate). Related fractions were pooled and evaporated under reduced pressure to afford a white solid of 2.6765 g as the titled compound. LCMS calc.=263.06. found=262.11 (M−1)−. 1H-NMR (CDCl3, 500 MHz) δ 7.36 (s, 1H), 7.34 (d, J=8.5 Hz, 1H), 7.27 (d, J=9 Hz, 1H), 5.8 (d, J=7.5 Hz, 2H), 4.3 (ps quintet, J=6.9 Hz, 1H), 0.85 (d, J=6.5 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[C:12]1[S:16][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][OH:25])[N:19]=2)=[C:14]([C:26]([NH2:28])=[O:27])[CH:13]=1>CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:11])([CH3:9])[CH3:10])[CH:5]=[CH:4][C:3]=1[C:12]1[S:16][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]=[O:25])[N:19]=2)=[C:14]([C:26]([NH2:28])=[O:27])[CH:13]=1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(CO)n3)s2)c(F)c1
Solvent: CS(C)=O
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(C=O)n3)s2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl)-2-((6-(hydroxymethyl)-2-pyridinyl)amino)-3-thiophenecarboxamide (Example 43) (513 mg, 1.28 mmol) in DMSO (83 ml) was added IBX polystyrene (2.9 g, 3.19 mmol). The reaction mixture was shaken at room temperature overnight. The reaction mixture was filtered and washed with DMSO (1 ml). Water was added to the eluent and a yellow precipitate was filtered, washed with water and dried in vacuo to afford the title compound.
Reaction SMILES: [C:1]([N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]1[C:19]#[N:20])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-:22].[Na+].OO>CC(C)=O>[C:1]([N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]1[C:19]([NH2:20])=[O:22])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: N#CC1C=Cc2ccccc2N1C(=O)c1ccccc1
Agent: OO
Agent: [Na+]
Solvent: CC(C)=O
Product: NC(=O)C1C=Cc2ccccc2N1C(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 55 %

Procedure:
1-(Benzoyl)-1,2-dihydro-quinoline-2-carbonitrile (26.0 g) was dissolved in acetone (500 mL). Solid sodium bicarbonate (15 g) was added. The mixture was stirred for 30 minutes. 30% Hydrogen peroxide solution (250 mL of a 30% solution) was added drop-wise. After stirring for 4 hours, the acetone was evaporated under vacuum. The residue was acidified with 1N HCl. The precipitate was collected, washed with water and air dried. The solid was slurried in ether then filtered. The title compound (15.3 g) was obtained as an off-white solid, m.p. 169-171° C.
Reaction SMILES: [F:1][C:2]1[C:3]([C:14]2([C:17]([OH:19])=[O:18])[CH2:16][O:15]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([O:12]C)=[N:5]2.[OH-].[Li+]>O1CCOCC1.O>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6](=[O:12])[N:5]3[CH2:16][C:14]([OH:15])([C:17]([OH:19])=[O:18])[C:3]=1[C:4]=23
Reactant: COc1cnc2ccc(F)c(C3(C(=O)O)CO3)c2n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)C1(O)Cn2c(=O)cnc3ccc(F)c1c32
Temperature: 80 °C

Procedure:
A solution of 2-[6-fluoro-3-(methyloxy)-5-quinoxalinyl]-2-oxiranecarboxylic acid (3.22 g, 0.012 mol) in 1,4-dioxane (210 mL) and water (90 mL) was treated with lithium hydroxide (584 mg, 0.024 mol) dropwise at RT. The reaction mixture was heated at 80° C. for 35 hours then cooled, quenched to pH 7 with a 2M solution of hydrochloric acid and then the solvent was evaporated. The residue was placed directly onto a 100 g silica gel column and chromatographed, eluting with a 0-50% methanol in dichloromethane gradient to afford the product as a yellow solid (7.07 g of a 3:1 mixture of product/starting material).
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH:12]=O)=[CH:10][C:5]=2[CH2:4][O:3]1.[N:14]1(C(OC(C)(C)C)=O)[CH2:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[ClH:28].N1(CCC2C=CC3C(=O)OCC=3C=2)CCNCC1>>[ClH:28].[N:14]1([CH2:12][CH2:11][C:9]2[CH:8]=[CH:7][C:6]3[C:2](=[O:1])[O:3][CH2:4][C:5]=3[CH:10]=2)[CH2:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: O=CCc1ccc2c(c1)COC2=O
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: Cl
Agent: O=C1OCc2cc(CCN3CCNCC3)ccc21
Product: O=C1OCc2cc(CCN3CCCNCC3)ccc21

Procedure:
5-[2-(1,4-Diazepan-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride was prepared from (1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde and tert-butyl 1,4-diazepane-1-carboxylate in an analogous fashion to that described above for the synthesis of 5-(2-piperazin-1-ylethyl)-2-benzofuran-1(3H)-one hydrochloride (Method 1, steps C and D). MS: m/z 261 (M+1)+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc2c(ccn2Cc2ccccc2)c1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: c1ccc(Cn2ccc3cc(-c4ccccc4)ccc32)cc1
Yield: 34.5 %

Procedure:
1-Benzyl-5-phenyl-1H-indole was prepared by coupling 1-benzyl-5-bromo-1H-indole (2.72 g, 9.50 mmol), and phenylboronic acid (1.39 g, 11.4 mmol), using [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (0.266 g, 0.326 mmol), and potassium carbonate (2.06 g, 14.9 mmol) in dioxane (72 mL) and water (7.2 mL), following the procedure described in Step 1 of Example 11. Purification by flash chromatography (Biotage apparatus) using hexane as an eluant yielded the title compound as a light yellow solid (0.928 g, 35%), mp: 105-106° C. Mass spectrum (+ES, [M+H]+) m/z 284; 1HNMR (500 MHz, DMSO-d6): δ 7.8 (d, 1H, J=0.92 Hz), 7.65 (dd, 2H, J=8.2 Hz and 0.84 Hz), 7.5-7.55 (m, 2H), 7.35-7.45 (m, 3H), 7.2-7.3 (m, 6H), 6.55 (dd, 1H, J=3.1 Hz and 0.61 Hz), and 5.45 ppm (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:15]=[C:14]([Cl:16])[C:11]([C:12]#[N:13])=[C:10]([Cl:17])[CH:9]=2)[N:3]=1.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1.C(O)(=O)C.Cl>CO>[Cl:17][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[N:3]=[C:2]([NH:1][CH2:24][C:23]3[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:28])[F:29])=[CH:27][CH:26]=3)[NH:6][N:5]=2)[CH:15]=[C:14]([Cl:16])[C:11]=1[C:12]#[N:13]
Reactant: N#Cc1c(Cl)cc(Nc2n[nH]c(N)n2)cc1Cl
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: N#Cc1c(Cl)cc(Nc2n[nH]c(NCc3ccc(C(F)(F)F)cc3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.7 %

Procedure:
To a solution of 4-(5-Amino-1H-[1,2,4]triazol-3-ylamino)-2,6-dichloro-benzonitrile (60 mg, 223 μmol) in MeOH (3.5 ml) was added 4-(trifluoromethyl)benzaldehyde (46.6 mg, 268 μmol, Aldrich) followed by acetic acid (36.7 mg, 35 μl, 611 μmol). The reaction was stirred at room temperature for 15 minutes, 2-picoline borane complex (32.2 mg, 349 μmol) was added and the stirring was continued for 4 days. The reaction mixture was poured into 0.1N HCl solution (20 ml) and extracted with EtOAc (3×20 ml). The combined organic solution was washed with brine, dried and concentrated in vacuo. Crystallization from DCM afforded a white solid as desired product (55 mg, 57% yield). MS +m/z: 427 (M+H)+
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([N:10]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:8][S:7][CH:6]=1)=[O:4]>CCOCC>[CH2:22]([N:10]([S:11]([C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)(=[O:13])=[O:12])[C:9]1[C:5]([C:3]([OH:4])=[O:2])=[CH:6][S:7][CH:8]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1cscc1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Solvent: CCOCC
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)c2cscc2C(=O)O)cc1
Yield: 84 %

Procedure:
In the same manner as described in Example 9, 1.157 g (2.775 mmol) of the product of Example 6 provided 0.94 g (84%) of the desired carboxylic acid as a tan solid after trituration with ether. Electrospray Mass Spec: 404 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[C:17]([C:19]1[CH:20]=[C:21]([N:25]=[C:26]=[O:27])[CH:22]=[CH:23][CH:24]=1)#[N:18]>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:26]([NH:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([C:17]#[N:18])[CH:20]=2)=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: N#Cc1cccc(N=C=O)c1
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2cccc(C#N)c2)cc1-c1c(Br)cnn1C
Yield: 61.5 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.037 g, 0.13 mmol) was treated with 3-cyanophenyl isocyanate (0.020 g, 0.14 mol, 1.05 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.10 to afford Compound 21 (0.032 g, 0.08 mmol, 58%) as a white powder. LCMS m/z (%)=426 (M+H79Br, 99), 428 (M+H81Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.45 (s, 1H), 8.26 (d, J=9.6 Hz, 1H), 8.05 (t, J=1.7 Hz, 1H), 7.74 (dd, J=1.5, 8.2 Hz, 1H), 7.70 (dd, J=2.7, 9.0 Hz, 1H), 7.50 (s, 1H), 7.48 (t, J=8.1 Hz, 1H), 7.43 (d, J=2.7 Hz, 1H), 7.36 (d, J=7.6 Hz, 1H), 7.15 (d, J=9.0 Hz, 1H), 3.83 (s, 3H), 3.69 (s, 3H).
Reaction SMILES: C([O:5][C:6](=[O:54])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:53])[C@H:13]([CH2:41][CH2:42][CH2:43][CH2:44][NH:45]C(OC(C)(C)C)=O)[NH:14][CH:15]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]1[CH2:25][CH2:24][N:23](C(OCC2C=CC=CC=2)=O)[CH2:22][CH2:21]1)(C)(C)C.Br.C(O)(=O)C.C(OCC)C>C(O)(=O)C>[CH2:39]([O:38][C:36]([CH:15]([NH:14][C@H:13]([C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([OH:54])=[O:5])=[O:53])[CH2:41][CH2:42][CH2:43][CH2:44][NH2:45])[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:37])[CH3:40]
Reactant: CCOC(=O)C(CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)C(CCCCC1CCNCC1)N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 1 h
Yield: 113 %

Procedure:
In 1 ml of acetic acid is dissovled 0.43 g of N-[Nα -[5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]-Nε -tert-butoxycarbonyl-L-lysyl]-L-proline tert-butyl ester, and 2 ml of 30% hydrogen bromide-acetic acid solution is added to the solution, followed by standing at room temperature for 1 hour. 50 ml of ethyl ether is added to the reaction solution, followed by shaking, and the supernatant layer is removed by decantation. The precipitate is collected and dried under reduced pressure to give 0.3 g of N-[Nα -[1-ethoxycarbonyl-5-(4-piperidyl)pentyl]-L-lysyl]-L-proline.trihydrobromide as a colorless powder.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH2:28]([N:30]([CH2:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1)[CH3:31])[CH3:29]>>[CH2:28]([N:30]([CH2:32][C:33]1[CH:34]=[CH:35][C:36]([NH:37]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:38][CH:39]=1)[CH3:31])[CH3:29]
Reactant: CCN(C)Cc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: CCN(C)Cc1ccc(N/C(=C2\C(=O)Nc3cc(C(=O)OC)ccc32)c2ccccc2)cc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(N-ethyl-N-methyl-aminomethyl)-aniline Rf value: 0.3 (silica gel, methylene chloride/methanol=10:1) C27H27N3O3
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:9][CH3:10])=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:9][CH2:10][Br:17])=[CH:4][CH:3]=1
Reactant: CC=C(c1ccc(Br)cc1)c1cccnc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: BrCC=C(c1ccc(Br)cc1)c1cccnc1
Temperature: 80 °C

Procedure:
A mixture of 7.0 g (0.024 mol) of 1-(4-bromophenyl)-1-(3-pyridyl)-propene and 4.6 g (0.024 mol) of N-bromosuccinimide in 600 ml of carbontetrachloride was heated with stirring to 80° C. Then 0.5 g. of α,α-azabisbutyronitrile was added as radical initiator and the mixture was refluxed for 2 hours. After cooling to ambient temperature, the reaction mixture was filtered and the filtrate was evaporated in vacuo to 100 ml. NMR on the residual solution indicated a 1:1-mixture of the E- and Z-3-(4-bromophenyl)-3-(3-pyridyl)allylbromides. This solution was used directly in the preparation of the end product without further purification.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:32][C:33]1([CH3:40])[O:37][C@@H:36]([CH2:38]O)[CH2:35][O:34]1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:32][C:33]1([CH3:40])[O:37][C@@H:36]([CH2:38][O:1][N:2]2[C:3](=[O:12])[C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:7])[CH2:35][O:34]1
Reactant: CC1(C)OC[C@H](CO)O1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)OC[C@H](CON2C(=O)c3ccccc3C2=O)O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.5 %

Procedure:
A 3-L round-bottomed flask equipped with mechanical stirrer and additional funnel was charged with N-hydroxyphthalimide (68.0 g, 0.416 mol) and tetrahydrofuran (1.2 L) under nitrogen atmosphere. To this solution was added triphenylphosphine (109.2 g, 0.416 mol) and the product of Example 31, Step B, (S)-(2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (55.0 g, 0.416 mol). The mixture was cooled to 3° C. to 5° C. and diethyl azodicarboxylate (85.2 mL, 0.541 mol) was added dropwise, while keeping the inner temperature below 15° C. The reaction mixture was warmed to ambient temperature, and stirred for 18 hours. The tetrahydrofuran was evaporated under reduced pressure. To the remaining orange solid was added dichloromethane (0.5 L) and the mixture was stirred for 1 hour. The white solid (Ph3PO) was filtered and washed with dichloromethane (0.1 L). The solvent was removed and ethanol (0.5 L) was added to the resulting solid. The mixture was stirred for 2 hours at 3° C. to 5° C. The white solid was filtered, washed with a small amount of cold EtOH, and dried in vacuum oven at 40° C. to give (R)-2-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-isoindole-1,3-dione (112.5 g, 97%) as a white solid: 1H NMR (CDCl3): δ 1.33 (s, 3 H), 1.99 (s, 3 H), 3.96 (m, 1 H), 4.15 (m, 2 H), 4.30 (m, 1 H), 4.48 (m, 1 H), 7.59 (m, 2 H), 7.84 (m, 2 H); MS (APCI+)=278 (M++1). Step D: Preparation of (R)-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6](I)[CH:5]=[CH:4][N:3]=1.Cl.[NH:11]1[CH2:16][CH2:15][C:14]2([C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][O:17]2)[CH2:13][CH2:12]1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CC#N>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([N:11]2[CH2:16][CH2:15][C:14]3([C:24]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[CH2:18][O:17]3)[CH2:13][CH2:12]2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc(I)c1Cl
Reactant: c1ccc2c(c1)COC21CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Clc1nccc(N2CCC3(CC2)OCc2ccccc23)c1Cl
Temperature: 110 °C

Procedure:
A mixture of D10 (1 g, 3.655 mmol), spiro[isobenzofuran-1(3H),4′-piperidine], hydrochloride [CAS 37663-44-8] (0.83 g, 4.386 mmol) and DIPEA (1.273 ml, 7.309 mmol) in CH3CN (9 ml) was heated in a sealed tube at 110° C. for 16 h. The mixture was then treated with NaHCO3 (aqueous sat. solution) and extracted with EtOAc. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; DCM/EtOAc up to 2% as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D21 (0.199 g, 16%) as a white solid. M.P. 160.8° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:21][NH:22][CH2:23][CH:24]1[CH:28]([CH3:29])[CH2:27][NH:26][CH2:25]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:26]4[CH2:27][CH:28]([CH3:29])[CH:24]([CH2:23][NH:22][CH3:21])[CH2:25]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CNCC1CNCC1C
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CNCC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC1C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
A mixture of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.5 g), anhydrous acetonitrile (5 ml), 3-methylaminomethyl-4-methylpyrrolidine (0.34 g) and DBU (0.27 g) was refluxed for an hour and allowed to stand overnight at room temperature. The resulting precipitate was collected by filtration, washed with acetonitrile and ether successively and recrystallized from chloroform-methanol-concentrated aqueous ammonia to give the title compound (0.41 g) as white powder, mp 252°-254° C.
Reaction SMILES: N#N.C(OC(=O)[N:9]([C:26]1[N:27]=[C:28]([CH2:31][N:32]2[CH:36]=[CH:35][C:34]([C:37](=[O:39])[CH3:38])=[N:33]2)[O:29][CH:30]=1)[C:10]([C:12]1[N:13]=[C:14]([CH:23]2[CH2:25][CH2:24]2)[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:37]([C:34]1[CH:35]=[CH:36][N:32]([CH2:31][C:28]2[O:29][CH:30]=[C:26]([NH:9][C:10]([C:12]3[N:13]=[C:14]([CH:23]4[CH2:24][CH2:25]4)[S:15][C:16]=3[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:11])[N:27]=2)[N:33]=1)(=[O:39])[CH3:38]
Reactant: CC(=O)c1ccn(Cc2nc(N(C(=O)OC(C)(C)C)C(=O)c3nc(C4CC4)sc3-c3ccccc3)co2)n1
Agent: N#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)c1ccn(Cc2nc(NC(=O)c3nc(C4CC4)sc3-c3ccccc3)co2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [2-(3-acetyl-pyrazol-1-ylmethyl)-oxazol-4-yl]-(2-cyclopropyl-5-phenyl-thiazole-4-carbonyl)-carbamic acid tert-butyl ester (13 mg, 0.02 mmol) in dry CH2Cl2 (1.0 mL) was treated at 0° C. with trifluoroacetic acid (0.08 mL, 1.00 mmol). After stirring at rt for 16 h, the reaction mixture was quenched with sat. aq. NaHCO3, extracted with CH2Cl2 (3×10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (5:1→3:1 hept:EA) gave the title compound as a white solid. TLC: rf (1:1 hept-EA)=0.34. LC-MS-conditions 02: tR=1.08 min, [M+H]+=433.89.