Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[C:13]3[CH2:24][CH2:23][NH:22][CH2:21][C:14]3=[N:15][C:16]=2[NH:17][CH:18]([CH3:20])[CH3:19])[CH2:7][CH2:6]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:37][CH2:38][F:39]>CC(C)=O>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][CH:5]1[CH2:6][CH2:7][N:8]([C:11]2[N:12]=[C:13]3[CH2:24][CH2:23][N:22]([CH2:37][CH2:38][F:39])[CH2:21][C:14]3=[N:15][C:16]=2[NH:17][CH:18]([CH3:20])[CH3:19])[CH2:9][CH2:10]1
Reactant: FCCBr
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCN(CCF)C2
Temperature: 50 °C
Reaction time: 1 h
Yield: 38.3 %

Procedure:
To a suspension of 2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine (98.4 mg, 0.244 mmol) and K2CO3 (135 mg, 0.976 mmol) in acetone (4.0 mL) was added 1-bromo-2-fluoroethane (0.020 mL, 0.268 mmol) at 23° C. The reaction mixture was stirred at 50° C. for 1 hr. The reaction mixture was cooled to 23° C., an additional portion of 1-bromo-2-fluoroethane (8.2 μL, 0.110 mmol) was added, and the reaction mixture was heated for an additional 1.5 hr at 50° C., cooled to 23° C., and concentrated via rotary evaporation. The resulting crude material was reconstituted in DMSO, filtered, rinsed with DMSO, and purified by HPLC Method B using a 30% to 70% ACN gradient to give the title compound (42 mg, 38.3%) as a light yellow oil. 1H NMR (500 MHz, DMSO-d6, mixture of rotamers) δ ppm 1.17 (d, J=6.8 Hz, 6H), 1.82-1.93 (m, 2H), 2.02-2.11 (m, 2H), 2.62-2.69 (m, 2H), 2.73-2.80 (m, 3H), 2.81-2.91 (m, 3H), 3.20-3.29 (m, 2H), 3.48 (s, 2H), 4.04-4.12 (m, 1H), 4.47-4.54 (m, 1H), 4.56 (t, J=4.9 Hz, 1H), 4.66 (t, J=4.9 Hz, 1H), 5.38 (d, J=7.8 Hz, 1H), 6.98-7.05 (m, 1H), 7.26-7.34 (m, 2H); ESI-MS m/z [M+H]+ 450.0.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].CCN(C(C)C)C(C)C.Cl[C:17]1[C:26]2[C:21](=[C:22]([NH:27][S:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)(=[O:30])=[O:29])[CH:23]=[CH:24][CH:25]=2)[N:20]=[CH:19][CH:18]=1>C(O)CCC>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:17]1[C:26]2[C:21](=[C:22]([NH:27][S:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)(=[O:29])=[O:30])[CH:23]=[CH:24][CH:25]=2)[N:20]=[CH:19][CH:18]=1
Reactant: O=S(=O)(Nc1cccc2c(Cl)ccnc12)c1ccccc1
Reactant: CN(C)CCN
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCNc1ccnc2c(NS(=O)(=O)c3ccccc3)cccc12
Temperature: 100 °C
Yield: 33.7 %

Procedure:
N,N-dimethylethylenediamine (0.10 ml, 0.95 mmol) and DIPEA (0.11 ml, 0.63 mmol) were added to a solution of N-(4-chloro-quinolin-8-yl)-benzenesulfonamide 224 (100 mg, 0.32 mmol) in n-butanol (1 ml) and the reaction was heated in a sealed tube at 100° C. for 16 h. After cooling, the mixture was concentrated in vacuo. The crude residue was purified by column chromatography with chloroform/MeOH (97:3) as the eluent to give the title compound (40 mg, 34%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:17][CH2:16][C@H:15]([S:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C@H:14]2[OH:28])(=O)=O)=CC=1.[N-:29]=[N+:30]=[N-:31].[Li+]>CN(C)C=O>[N:29]([CH2:12][C@@H:13]1[O:17][CH2:16][C@H:15]([S:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C@H:14]1[OH:28])=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(CS[C@H]2CO[C@@H](COS(=O)(=O)c3ccc(C)cc3)[C@@H]2O)cc1
Agent: [Li+]
Solvent: CN(C)C=O
Product: COc1ccc(CS[C@H]2CO[C@@H](CN=[N+]=[N-])[C@@H]2O)cc1
Temperature: 70 °C
Reaction time: 65 h
Yield: 32.6 %

Procedure:
A mixture of 2.0 g of product from Example 324, 0.460 g of lithium azide and 2 ml of N,N-dimethylformamide is stirred at 70° C. for 65 hours. The reaction mixture is concentrated in vacuo. The residue is purified by chromatography (Silica gel: 30% ethyl acetate/hexane). to give 0.454 g of the desired product.
Reaction SMILES: Cl[SiH2:2][Cl:3].[CH3:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH3:11])[NH:6]1.C(N(CC)CC)C.Cl>CCCCCC>[CH3:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH3:11])[N:6]1[SiH2:2][Cl:3]
Reactant: CC1CCCC(C)N1
Reactant: Cl[SiH2]Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CC1CCCC(C)N1[SiH2]Cl
Temperature: -20 °C
Yield: 66 %

Procedure:
In a 2000 ml 3-necked round bottom flask equipped with mechanical stirror and an addition funnel, 1000 ml hexane was added. With the flask was cooled to −20° C. using a dry ice IPA cold bath, 101 g (1.0 mol) dichlorosilane was condensed and dissolved into hexane. With stirring, a mixture of 113 g (1.0 mol) 2,6-dimethylpiperidine and 111 g (1.1 mol) triethylamine was added dropwise to the flask. After the addition was complete, the reaction mixture was stirred at −20° C. for 1 hour, and then let warming up to room temperature. A salt byproduct precipitate of HCl.Et3N was removed by vacuum filtration in a glove bag purging with N2 to prevent the product reacting with the moisture in the air. A GC/MS analysis on the filtrate confirmed the product 2,6-dimethylpiperidinochlorosilane, showing the product with a molecular ion mass of 177 and supporting mass fragment of mass M —CH3 of 162. The solvent hexane was removed by distillation and the product was separated by vacuum distillation. The boiling point was 60° C. at 10 torr. The yield was 66%.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[N+:13]([O-])([OH:15])=[O:14]>C(O)(=O)C>[N+:13]([C:12]1[CH:11]=[C:5]([CH:4]=[CH:3][C:2]=1[OH:1])[C:6]([O:8][CH2:9][CH3:10])=[O:7])([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1ccc(O)cc1
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(O)c([N+](=O)[O-])c1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 20.0 grams (0.12 mole) of ethyl 4-hydroxybenzoate in 200 mL of acetic acid was added a solution of 7.5 mL (excess) of 70% nitric acid in 30 mL of acetic acid. After the reaction mixture stirred for about one hour, it gradually turned orange and warmed to about 40° C. The reaction mixture was stirred for an additional eighteen hours and then was poured into 800 mL of ice-water. The mixture was stirred until the ice melted, and filtered to collect a solid, which was dissolved in ethyl acetate and dried with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure, yielding 22.0 grams of ethyl 3-nitro-4-hydroxybenzoate, mp 70°-71° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([O:22]C(C)(C)C)=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:27]3[CH:32]=[CH:31][C:30]([O:33]C)=[CH:29][CH:28]=3)[S:8][C:7]=2[CH:35]=1.B(Br)(Br)Br>C(Cl)Cl.CO>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([OH:22])=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:27]3[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=3)[S:8][C:7]=2[CH:35]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(/C=C/C(=O)OC(C)(C)C)cc2)cc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=C(O)/C=C/c1ccc(Oc2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cc1
Temperature: 0 °C
Reaction time: 1.67 h
Yield: 50 %

Procedure:
To a solution of (E)-tert-butyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)-benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (40 mg, 0.08 mmol) in DCM (2.5 mL) at 0° C. was added BBr3 (1.0 M in DCM, 0.33 mL, 0.33 mmol) dropwise, a solid immediately precipitated from the solution. The resulting mixture was stirred at 0° C. for 100 min after which the reaction was quenched by addition of sat. aq. NaHCO3 (4 mL) solution and a white precipitate was observed. The aqueous layer was then extracted with 5% MeOH/EtOAc (4×12 mL) and the combined organic layers were passed through a phase separator to remove water and concentrated in vacuo to afford the crude product which was dissolved in MeOH (2 mL) and purified by reverse phase HPLC (neutral condition, 3% 1-propanol in 1-100% CH3CN/H2O) to afford (E)-3-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (17.5 mg, 0.04 mmol, 53% yield). LC/MS (m/z, MH+): 405.0790.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[CH:25]=[N:24][C:23]([CH2:26][NH:27][CH3:28])=[CH:22][N:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].C([O:33][C:34]([CH3:39])([CH3:38])[C:35](Cl)=[O:36])(=O)C.C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[N:21]=[CH:22][C:23]([CH2:26][N:27]([CH3:28])[C:35](=[O:36])[C:34]([OH:33])([CH3:38])[CH3:39])=[N:24][CH:25]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: CNCc1cnc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)cn1
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1cnc(CN(C)C(=O)C(C)(C)O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.2 %

Procedure:
To a cold (5° C.) solution of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-({5-[(methylamino)methyl]pyrazin-2-yl}methyl)pyridin-2(1H)-one (0.24 g, 0.52 mmol) in DMF (2.0 ml), was added 2-acetoxyisobutyryl chloride (0.093 g, 0.56 mmol), followed by the addition of triethylamine (0.072 g, 0.71 mmol). The mixture was stirred at room temperature for an additional 2 h and concentrated in vacuo. The residue was partitioned between water (5.0 mL) and EtOAc (15.0 mL). The EtOAc extract was washed with water, dried (Na2SO4), and concentrated to dryness. The resulting material (0.2 g) was stirred with 1M. LiOH (0.5 mL, MeOH/Water 1:1 v/v) at room temperature for 3 h, cooled, acidified with trifluoroacetic acid and the product was purified by reverse-phase HPLC using 10-90% CH3CN/Water gradient (60 min) at a flow rate of 70 mL/min. The appropriate fractions (m/z=551 M+H) were combined and freeze dried to give a white powder. This was partitioned between 5% NaHCO3 (10 mL) and EtoAc (15 mL). The organic layer was washed with water, dried (Na2SO4), and concentrated to dryness to afford the title compound (0.075 g) as a white powder: 1H NMR (CD3OD/400 MHz) δ 8.59 (s, 1H), 8.41 (br, 1H), 7.60 (m, 2H), 7.01 (m, 2H), 6.52 (s, 1H), 5.45 (s, 2 h), 5.29 (s, 2H),
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([C:12]([OH:14])=O)[C:4](=[O:11])[N:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2.C(N1C=CN=C1)([N:17]1C=CN=C1)=O.N>CN(C)C=O>[CH:1]1[CH:2]=[C:3]([C:12]([NH2:17])=[O:14])[C:4](=[O:11])[N:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2
Reactant: O=C(O)c1ccc2ccccn2c1=O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: CN(C)C=O
Product: NC(=O)c1ccc2ccccn2c1=O
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
To a suspension of 4H-quinolizin-4-one-3-carboxylic acid (2.27 g) in dry N,N-dimethylformamide (22.7 ml) was added 1,1'-carbonyldiimidazole (2.92 g). The resulting suspension was heated to 100° C. and kept for 30 minutes. After cooling to room temperature the resulting solution was treated with dry ammonia and stirred for 20 minutes. The crystals separated was collected by filtration and washed with water to give 4H-quinolizin-4-one-3-carboxamide (1.94 g). mp. 230°-232° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([N:33]([CH3:41])[CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])=[O:32])=[CH:27][CH:26]=3)[CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:14]([CH3:42])[C:13]=2[CH:43]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH2:1]([NH:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([C:31]([N:33]([CH3:41])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:32])=[CH:29][CH:30]=3)[CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)=[C:14]([CH3:42])[C:13]=2[CH:43]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(NCc4ccccc4)cc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)oc2ccc(NCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
To a mixture of ethyl 3-[{[4-({[5-(benzylamino)-3-methyl-1-benzofuran-2-yl](cyclohexyl)methyl}amino)phenyl]carbonyl}(methyl)amino]-propanoate (354 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 1.5 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (310 mg, 92%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[CH:7]([N:22]([CH2:34][CH:35]=[CH2:36])[S:23]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH:8]([CH2:19]C=C)[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2]>ClCCl.[Ru]>[C:1]([O:5][C:6]([CH:7]1[CH:8]([C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[CH2:19][CH:36]=[CH:35][CH2:34][N:22]1[S:23]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)(=[O:24])=[O:25])=[O:37])([CH3:3])([CH3:2])[CH3:4]
Reactant: C=CCC(C(=O)OCc1ccccc1)C(C(=O)OC(C)(C)C)N(CC=C)S(=O)(=O)c1ccc(OC)cc1
Agent: [Ru]
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2CC=CCC(C(=O)OCc3ccccc3)C2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
2-Al lyl-3-[allyl-(4-methoxy-benzenesulfonyl)-amino]-succinic acid 1-benzyl ester 4-tert-butyl ester (5.5 g, 10.4 mmol) are solved in 40 ml Dichloromethane and deoxygenated and flushed with Argon three times. The catalyst (RuCl2(PCy3)2═—Ph) (100 mg, 0.12 mmol) is added and the reaction is deoxygenated and flushed with Argon one more time. The reaction solution is stirred for 7 h at room temperature. Another (90 mg, 0.11 mmol) of the Ruthenium catalyst are added and the reaction is stirred over night. Evaporation of the solvent followed by flash-chromatography, Hexane/Ethylacetate (3:1) afforded the product: 1H NMR (CDCl3 400 Mhz), ppm: 7.81 (d, 2H), 7.37 (m, 5H), 6.93 (d, 2H), 5.60 (m, 2H), 5.10 (m, 3H), 4.18 (dd, 1H), 4.05 (dd, 1H), 3.88 (s, 3H), 3.20 (ddd, 1H), 2.68 (m, 2H), 1.32 (s, 9H).
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](Cl)(=[O:20])=[O:19].[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][NH2:29]>C(N(CC)CC)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](=[O:20])(=[O:19])[NH:29][CH2:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=1
Reactant: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)Cl)c2)N1C
Reactant: NCc1ccccn1
Agent: Br
Solvent: CCN(CC)CC
Product: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)NCc3ccccn3)c2)N1C

Procedure:
8.8 g of 4-(4-chloro-3-chlorosulfonylphenyl)-3-methyl-2-methylimino-1,3-thiazolidine-4-ol-hydrobromide were reacted with 3.0 g of 2-picolyl amine and 5 g of triethyl amine as prescribed in Example 76 and the end product precipitating as crystals was filtered off. Melting point: 166° C (decomposition).
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[CH3:24][CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=2)[CH2:27][CH2:26]1>CN(C=O)C>[CH3:24][CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([NH:36]/[C:4](=[C:11]3\[C:12](=[O:23])[NH:13][C:14]4[C:19]\3=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=4)/[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:37][CH:38]=2)[CH2:27][CH2:26]1
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: CC1CCN(Cc2ccc(N)cc2)CC1
Solvent: CN(C)C=O
Product: CC1CCN(Cc2ccc(N/C(=C3\C(=O)Nc4ccc([N+](=O)[O-])cc43)c3ccccc3)cc2)CC1

Procedure:
Prepared analogously to Example 89 from 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-(4-methylpiperidinomethyl)-aniline in DMF.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][O:11][CH:12]([O:15][CH3:16])[CH2:13][NH2:14].CC(O)=O.[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:14][CH2:13][CH:12]([O:15][CH3:16])[O:11][CH3:10])=[CH:4][CH:3]=1
Reactant: COC(CN)OC
Reactant: O=Cc1ccc(Br)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(CNCc1ccc(Br)cc1)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To an ice-cold solution of 4-bromo-benzaldehyde (10 g, 0.05 mol) and 2,2-dimethoxy-ethylamine (6.8 g, 0.06 mol) in MeOH (200 mL) was added AcOH (2 mL), and the reaction mixture was stirred at RT for 1 h. The reaction mixture was cooled to 0° C. and NaBH4 (6.2 g, 0.15 mol) was added portionwise. The reaction mixture was stirred at RT for 10 h. After completion, The resulting reaction mixture was concentrated under reduced pressure and 10% aqueous NaOH was added. The mixture was extracted with EtOAc, the organic layer separated, dried over Na2SO4, and concentrated under reduced pressure. Purification was done by column chromatography using 100-200 mesh silica gel eluting with 5-15% EtOAc in hexanes to afford N-(4-bromobenzyl)-2,2-dimethoxyethanamine (10 g, 67%) as a pale yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[N:16][C:17]([CH:21]([CH3:23])[CH3:22])=[C:18](O)[N:19]=2)=[N:6]1.P(Cl)(Cl)(Cl)=O.[NH3:33]>C(#N)C>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[N:16][C:17]([CH:21]([CH3:23])[CH3:22])=[C:18]([NH2:33])[N:19]=2)=[N:6]1
Reactant: N
Reactant: CC(C)c1nnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CC(C)c1nnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
900 mg (5.138 mmol) of 3-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6-isopropyl-1,2,4-triazin-5-ol were admixed with 12 ml of phosphoryl chloride and stirred overnight at RT. The reaction mixture was diluted with 50 ml of dry acetonitrile and, with ice-cooling, stirred into 173 ml of concentrated aqueous ammonia solution (25% strength). The reaction mixture was stirred for 2 h at RT and for 6 h at 50° C. After cooling, concentration on a rotary evaporator was carried out.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C@@H:22]2[CH2:26][C@H:25]([F:27])[CH2:24][N:23]2[C:28]([O:30]CC2C=CC=CC=2)=O)[N:8](C)[C:9](=[O:20])[C:10]=1[O:11][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4].[C:38](OC(=O)C)(=O)C>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]([C:5]1[C:10]([O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:9]([OH:20])[N:8]=[C:7]([C@@H:22]2[CH2:26][C@H:25]([F:27])[CH2:24][N:23]2[C:28](=[O:30])[CH3:38])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc([C@@H]2C[C@H](F)CN2C(=O)OCc2ccccc2)n(C)c(=O)c1OC(=O)c1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1nc([C@@H]2C[C@H](F)CN2C(C)=O)nc(O)c1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl-5-(benzoyloxy)-2-{(2S,4S)-1-[(benzyloxy)carbonyl]-4-fluoropyrrolidin-2-yl}-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate, dissolved in ethyl acetate was treated with Pd/C 10% (10% w/w) and acetic anhydride (1 eq.) and submitted under H2 atmosphere at room temperature. The reaction mixture was stirred at room temperature for 18 hours and then the suspension was filtered over celite to give the title compound as a 7:3 mixture of rotamers by NMR.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]2[N:21]([CH2:22][CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[N:20]=[C:19]([O:32][CH2:33][CH2:34][OH:35])[C:18]=2[C:36]2[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=2)(=[O:15])=[O:14])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].[Cl:43][C:44]1[CH:45]=[N:46][C:47](S(C)(=O)=O)=[N:48][CH:49]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CCOCC.CN(C=O)C>[C:3]([C:7]1[CH:8]=[CH:9][C:10]([S:13]([NH:16][C:17]2[N:21]([CH2:22][CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[N:20]=[C:19]([O:32][CH2:33][CH2:34][O:35][C:47]3[N:48]=[CH:49][C:44]([Cl:43])=[CH:45][N:46]=3)[C:18]=2[C:36]2[CH:37]=[CH:38][C:39]([CH3:42])=[CH:40][CH:41]=2)(=[O:14])=[O:15])=[CH:11][CH:12]=1)([CH3:4])([CH3:5])[CH3:6]
Reactant: Cc1ccc(-c2c(OCCO)nn(CCO[Si](C)(C)C(C)(C)C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: CS(=O)(=O)c1ncc(Cl)cn1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(OCCOc3ncc(Cl)cn3)nn(CCO[Si](C)(C)C(C)(C)C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.9 %

Procedure:
Sodium hydride (16 mg, 60% suspension in mineral oil) was added to a stirred solution of 4-(tert-butyl)-N-[1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-(2-hydroxyethoxy)-4-(4-methylphenyl)-1H-pyrazol-5-yl]benzenesulfonamide (105 mg) (Preparation 28) in anhydrous THF (5 ml) at room temperature under a nitrogen atmosphere and the resulting mixture was stirred for 10 minutes at room temperature. DMF (2 ml) was added to the reaction mixture, followed by 5-chloro-2-(methylsulphonyl)pyrimidine (39 mg) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into an aqueous solution of 1.0M citric acid (50 ml) and ether (50 ml) and the aqueous phase was separated. The organic phase was washed with water (30 ml) and then dried over magnesium sulfate, filtered and concentrated under pressure. The orange/brown residue was purified by chromatography on a Biotage Flash 12i cartridge at 10 psi using 20% ethyl acetate/hexane as eluant to give the title compound as a pale yellow oil (90 mg).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)/[C:6](=[C:13](/[NH:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][S:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)(=[O:30])=[O:29])=[CH:23][CH:22]=2)\[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)/[C:5]1=[O:37])(=O)C.[CH3:38][N:39]([CH3:44])[C:40](=[O:43])[CH2:41]Br.CC(C)([O-])C.[K+].[OH-].[Na+]>CS(C)=O.CO>[CH3:38][N:39]([CH3:44])[C:40]([CH2:41][N:27]([C:24]1[CH:25]=[CH:26][C:21]([NH:20]/[C:13](=[C:6]2\[C:5](=[O:37])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:22][CH:23]=1)[S:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:29])=[O:30])=[O:43]
Reactant: CC(=O)N1C(=O)/C(=C(\Nc2ccc(NS(=O)(=O)c3ccccc3)cc2)c2ccccc2)c2ccccc21
Reactant: CN(C)C(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: CN(C)C(=O)CN(c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1)S(=O)(=O)c1ccccc1

Procedure:
Prepared analogously to Examples 1 and 187 from (Z)-1-acetyl-3-[1-(4-phenylsulphonylamino-phenylamino)-1-phenyl-methylidene]-2-indolinone, bromoacetic acid-N,N-dimethylamide and potassium tert.butoxide in DMSO and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [F:1][CH2:2][C@@H:3]([N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25])[CH2:4][C:5]([O:7]CC1C=CC=CC=1)=[O:6]>C(O)C.[Pd]>[F:1][CH2:2][C@@H:3]([N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25])[CH2:4][C:5]([OH:7])=[O:6]
Reactant: O=C(C[C@@H](CF)N1C(=O)c2ccccc2C1=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)C[C@@H](CF)N1C(=O)c2ccccc2C1=O
Reaction time: 1 h

Procedure:
(S)-4-fluoro-3-(1,3-dioxoisoindolin-2-yl)butanoic acid 19-4 (0.20 mmol) was dissolved in ethanol (5 ml). This solution was purged with nitrogen for 10 minutes, then 10% palladium on carbon was added (0.02 mmol of palladium) under an atmosphere of nitrogen. Hydrogen was then bubbled rapidly through the solution, while stirring, for approximately 1 h. The reaction progress was followed with LCMS. The reaction mixture was filtered through celite to remove the palladium. The celite was rinsed twice with methylene chloride. The filtrate was then concentrated to give the crude product. The crude product 19-6 was used for the next reaction step.