Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:27])([CH3:26])[C@@H:11]([O:18][Si:19]([CH3:25])([CH3:24])[C:20]([CH3:23])([CH3:22])[CH3:21])/[CH:12]=C/C(OC)=O)(=[O:7])=[O:6].O=O.[O:30]=[O+][O-].CSC>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:26])([CH3:27])[C@@H:11]([O:18][Si:19]([CH3:25])([CH3:24])[C:20]([CH3:22])([CH3:21])[CH3:23])[CH:12]=[O:30])(=[O:6])=[O:7]
Reactant: O=[O+][O-]
Reactant: COC(=O)/C=C/[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)COS(=O)(=O)CCCCl
Agent: O=O
Solvent: ClCCl
Solvent: CSC
Product: CC(C)(COS(=O)(=O)CCCCl)[C@H](C=O)O[Si](C)(C)C(C)(C)C
Yield: 52 %

Procedure:
Following the general procedure for the preparation of aldehydes from alkenes of Description 11, methyl (2E)(4S)-6-[(3-chloropropyl)sulfonyloxy]-5,5-dimethyl-4-(1,1,2,2-tetramethyl-1-silapropoxy)hex-2-enoate (15a) (2.4 g, 5.4 mmol) dissolved in 25 mL of dichloromethane (DCM) was treated with a mixture of oxygen and ozone (O2/O3). Upon completion of the reaction, 2 mL (1.59 g, 27.2 mmol) of dimethyl sulfide (DMS) was added. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:3) as eluent to provide 1.1 g (52% yield) of the title compound (15b) as a colorless oil. Rf=0.75 (EtOAc/Hxn=1:2). 1H NMR (400 MHz, CDCl3): δ=0.07 (s, 3H), 0.10 (s, 3H), 0.96 (s, 9H), 1.06 (s, 3H), 1.09 (s, 3H), 2.30-2.37 (m, 2H), 3.28-3.32 (m, 2H), 3.69-3.73 (m, 3H), 4.01 (d, J=9.6 Hz, 1H), 4.12 (d, J=9.6 Hz, 1H), 9.62 (d, J=2.4 Hz, 1H) ppm. MS (ESI) m/z 409.13 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[N:8]=[CH:7]1)([CH3:5])[CH:3]=O.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH3:1][C:2]([N:6]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[N:8]=[CH:7]1)([CH3:5])[CH2:3][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC(C)(C=O)n1cnc([N+](=O)[O-])c1
Reactant: C1CCNC1
Product: CC(C)(CN1CCCC1)n1cnc([N+](=O)[O-])c1

Procedure:
2-Methyl-2-(4-nitro-imidazol-1-yl)-propionaldehyde was reacted with pyrrolidine to provide the title compound: H1 NMR (400 MHz, CDCl3) 1.56 (s, 6H), 1.61 (m, 4H), 2.35 (m, 4H), 2.70 (m, 4H), 7.60 (s, 1H), 7.92 (s, 1H); MS m/z 239.2 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:28]=[CH:27][C:6]([C:7]([CH:9]([CH:13]2[C:26]3C=CC=C[C:21]=3[O:20][C:19]3[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=3)C([O-])=O)=[O:8])=[CH:5][CH:4]=1)#[N:2]>CS(C)=O.O>[O:20]1[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH:13]([CH2:9][C:7]([C:6]2[CH:27]=[CH:28][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[O:8])[CH:26]=[CH:21]1
Reactant: N#Cc1ccc(C(=O)C(C(=O)[O-])C2c3ccccc3Oc3ccccc32)cc1
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc(C(=O)CC2C=COc3ccccc32)cc1
Temperature: 190 °C

Procedure:
2-(4-Cyanobenzoyl)-2-(9H-xanthen-9-yl)acetate (8.1 g, 20.4 mmol) was dissolved in dimethylsulfoxide (100 ml),water (0.74 ml) was added and the resulting solution heated at 190° C., under N2 for 45 min. The cooled yellow solution was diluted with water and then extracted with ethyl acetate, washing with water then drying over magnesium sulphate, filtration and evaporation in vacuo gave 4-[2-(4H-benzopyran-4-yl)acetyl]benzonitrile as a yellow solid, m.p. 111° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N:9]([CH3:14])[C:10](=[O:13])[CH:11]=[CH2:12])=[CH:4][N:3]=1.[NH2:15][CH:16]([CH3:20])[CH2:17][O:18][CH3:19].C(N(CC)CC)C>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4].C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]2[C:5]([N:9]([CH3:14])[C:10](=[O:13])[CH2:11][CH2:12][N:15]2[CH:16]([CH3:20])[CH2:17][O:18][CH3:19])=[CH:4][N:3]=1
Reactant: COCC(C)N
Reactant: C=CC(=O)N(C)c1cnc(Cl)nc1Cl
Agent: [Ti+4]
Agent: CC[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(C)N1CCC(=O)N(C)c2cnc(Cl)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.8 %

Procedure:
N-(2,4-dichloropyrimidin-5-yl)-N-methyl-prop-2-enamide (Intermediate 113; 318 mg, 1.37 mmol), 2-Amino-1-methoxypropane (152 μl, 1.44 mmol), Triethylamine (382 μl, 2.74 mmol), Titanium Tetra-ethoxide (29 μl, 0.137 mmol) and DCM (5 mL) were combined and stirred at room temperature for 1 hr, heated to 40° C. for 3 hrs, cooled to room temperature, washed with water and gravity filtered through a PTFE. The organic solution was purified by chromatographic separation on silica eluting with a shallow gradient (25 column volumes) of 10-50% Ethyl Acetate/iso-hexane. Product containing fractions were combined and evaporated to give the title compound as a clear gum (54 mg, 18%).
Reaction SMILES: [CH3:1]I.C(=O)([O-])[O-].[K+].[K+].O.[C:10]12([N:20](C)[C:21]3[C:22]([NH2:27])=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[CH2:11]1)[CH2:17]2>CN(C=O)C>[C:10]12([NH:20][C:21]3[C:22]([NH:27][CH3:1])=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:17][CH:16]3[CH2:18][CH:12]([CH2:13][CH:14]([CH2:15]3)[CH2:19]1)[CH2:11]2
Reactant: CN(c1ccccc1N)C12CC3CC(CC(C3)C1)C2
Reactant: CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CNc1ccccc1NC12CC3CC(CC(C3)C1)C2
Reaction time: 4.5 h

Procedure:
Methyl iodide (0.564 ml) was added to a mixture of intermediate 11 (2 g) and potassium carbonate (1.75 g) in dry DMF (8 ml) at 23° under nitrogen. After 4.5 h, the mixture was poured into water (100 ml) and extracted with EA (2×100 ml). The combined extracts were washed with water and saturated brine then dried and evaporated. The residue was chromatographed with hexane- EA (8:1 to 6:1 to 4:1) as eluent to give a 70:30 mixture of the title compound with N-adamantan-1-yl-N-methylbenzene-1,2-diamine (904 mg) as a yellow solid, m.p. 68°-76° dec.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([CH2:13]OS(C)(=O)=O)[C@@H:10]([OH:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([SH:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[H-].[Na+]>CN(C=O)C.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([CH2:13][S:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:10]([OH:19])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: SCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](COS(C)(=O)=O)[C@@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C[C@H](CSCc2ccccc2)[C@@H](O)C1
Reaction time: 1 h

Procedure:
(3R,4R)-1-tert-Butoxycarbonyl-3-hydroxy-4-(mesyloxymethyl)pyrrolidine (see Example 34, 1.10 g, 3.7 mmol) was dissolved in DMF (2 mL) and added dropwise to a solution of benzyl mercaptan (870 μL, 7.4 mmol) and NaH (270 mg, 60% oil dispersion, 6.8 mmol) In DMF (10 mL) and stirred at room temp. for 1 h. The reaction was diluted with toluene, washed with water then brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography to afford (3R,4S)-1-tert-butoxycarbonyl-3-hydroxy-4-(benzylthiomethyl)pyrrolidine as a syrup. Without further characterisation, the product was dissolved in MeOH (5.0 mL) and cHCl (1.0 mL) and concentrated in vacuo to afford (3R,4S)-3-hydroxy-4-(benzylthiomethyl)pyrrolidine hydrochloride (53) as a syrup (730 mg, 76% overall yield for two steps). 1H NMR (D2O) δ 7.40-7.27 (m, 5H), 4.26-4.22 (m, 1H), 3.74 (s, 2H), 3.56 (dd, J=12.4, 7.2 Hz, 1H), 3.37 (dd, J=12.8, 5.2 Hz, 1H), 3.21 (dd, J=12.8, 3.0 Hz, 1H), 3.07 (dd, J=12.4, 5.5 Hz, 1H), 2.61-2.52 (m, 1H), 2.47-2.34 (m, 2H). 13C NMR (D2O) δ 138.7, 129.5, 129.3, 127.9, 73.5, 51.5, 48.5, 45.4, 35.9, 31.8. (MH+) calc for C12H18NOS: 224.1109. Found 224.1102.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1([NH:19][CH:20]=[O:21])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]1)=[O:6].[CH3:22]N(C=O)C.CI>C1COCC1>[CH3:3][O:4][C:5]([C:7]1([N:19]([CH:20]=[O:21])[CH3:22])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:8]1)=[O:6]
Reactant: CN(C)C=O
Reactant: COC(=O)C1(NC=O)CCN(C(=O)OC(C)(C)C)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C1(N(C)C=O)CCN(C(=O)OC(C)(C)C)C1
Reaction time: 1 h

Procedure:
Sodium hydride (60% in oil) (10 mg, 0.25 mmol) was added to a solution of 3-Formylamino-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (2T) (50 mg, 0.183 mmol) in THF (3 ml). DMF (1 ml) was added and stirred for 1 hour. Methyl iodide (0.1 ml, 1.60 mmol) was added and the reaction was stirred overnight. The solvent was evaporated and the residue extracted with EtOAc (50 ml), washed with H2O (20 ml), dried over MgSO4, filtered and solvent evaporated yielding a residue which chromatographed on silica gel eluting with 3% MeOH/MeCl2 yielding 3T (50 mg, 94%). LCMS (MH 287) Retention time=2.77 minutes.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:14]2[O:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=2)=[N:5][N:6]([CH3:13])[C:7]=1[N:8]=[CH:9]OCC)#[N:2].[NH3:22]>C(O)C>[NH2:22][C:1]1[N:2]=[CH:9][N:8]=[C:7]2[N:6]([CH3:13])[N:5]=[C:4]([C:14]3[O:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=3)[C:3]=12
Reactant: N
Reactant: CCOC=Nc1c(C#N)c(-c2ccc([N+](=O)[O-])o2)nn1C
Solvent: CCO
Product: Cn1nc(-c2ccc([N+](=O)[O-])o2)c2c(N)ncnc21

Procedure:
A mixture of 20.0 grams of 4-cyano-5-ethoxymethyleneamino-1-methyl-3-(5-nitro-2-furyl)-pyrazole, 200 milliliters of ethanol and 100 millilitres of concentrated aqueous ammonia solution (S.G., 0.88) was heated at reflux for one hour and cooled. The crystalline solid precipitated was collected, washed with water and dried. Recrystallisation from dimethylformamide gave 4-amino-1-methyl-3-(5-nitro-2-furyl)-1H-pyrazolo[3,4-d]pyrimidine having decomposition point 305° C.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pt]=O>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: Nc1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 99 %

Procedure:
A suspension of 16.0 g (64.1 mmole) of 4-(4'-chlorophenoxy) nitrobenzene and 75% Pt, 161 mg of platinum oxide (641 μmole, 1 mole %) in 200 ml of ethanol was stirred vigorously under hydrogen until hydrogen uptake ceased (about 4 hours). The suspension was filtered through celite and the solution was evaporated to dryness to obtain 13.94 g (99.3%) of the desired product as a pale brown solid.
Reaction SMILES: O.[CH3:2][N:3]([CH3:17])[CH2:4][C@H:5]([C:14]([OH:16])=O)[NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[CH3:18][CH:19]([CH3:34])[CH2:20][CH2:21][NH:22][C:23](=[O:33])[C@H:24]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[NH2:25]>O1CCCC1>[CH3:17][N:3]([CH3:2])[CH2:4][C@H:5]([C:14]([NH:25][C@H:24]([C:23]([NH:22][CH2:21][CH2:20][CH:19]([CH3:34])[CH3:18])=[O:33])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:16])[NH:6][C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8]
Reactant: CN(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)CCNC(=O)[C@@H](N)Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CCNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](CN(C)C)NC(=O)OC(C)(C)C

Procedure:
By the method of part A of Example 1, in two runs, and using tetrahydrofuran instead of acetone as solvent 3-dimethylamino-N2 -(t-butoxycarbonyl)-D-alanine monohydrate (1.00 g., 716 mg.) was condensed with N-(3-methylbutyl)-L-phenylalaninamide (part D of Example 1, 1.05 g., 760 mg.). The products (2.06 g., 1.21 g.) were combined and purified by reverse phase high pressure liquid chromatography on octadecylsilated silica gel using ammonium acetate (0.2%) in methanol-water (70:30) as the eluant, affording [3-dimethylamino-N2 -(t-butoxycarbonyl)-D-alanyl]-N-(3-methylbutyl)-L-phenylalaninamide as an oil (1.96 g.).
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:7][C:8]([N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:9])[C:4]([OH:6])=O.[CH:16]1[C:26]2[CH:25]=[CH:24][C:23]3[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=3[C:21](=[C:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[C:20]=2[CH:19]=[CH:18][CH:17]=1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>ClCCl>[CH:16]1[C:26]2[CH:25]=[CH:24][C:23]3[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=3[C:21](=[C:31]3[CH2:32][CH2:33][N:34]([C:4](=[O:6])[CH:3]([NH:7][C:8]([N:10]4[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]4)=[O:9])[CH2:2][OH:1])[CH2:35][CH2:36]3)[C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: C1=Cc2ccccc2C(=C2CCNCC2)c2ccccc21
Reactant: O=C(O)C(CO)NC(=O)N1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC(CO)C(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1)N1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
64.0 mg (0.296 mmol) of 3-hydroxy-2-[(1-piperidinylcarbonyl)amino]propionic acid, 80.9 mg (0.296 mmol) of 4-(5H-dibenzo[a,d][7]annulen-5-ylidene)piperidine and 85.1 mg (0.444 mmol) of 1 -ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride were dissolved in 10 ml of dichloromethane. 0.091 ml (0.651 mmol) of triethylamine was added to the obtained solution, and they were stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue. After washing with saturated aqueous sodium chloride solution, the reaction product was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resultant product was purified by the silica gel chromatography (dichloromethane: methanol=9:1) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=[C:4]([CH:11]([C:14](=O)[C:15]([F:18])([F:17])[F:16])[C:12]#[N:13])[CH:3]=1.O=P(Cl)(Cl)[Cl:22].C(N(CC)CC)C>O>[Cl:22][C:14]([C:15]([F:18])([F:17])[F:16])=[C:11]([C:4]1[CH:3]=[C:2]([Cl:1])[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=1)[C:12]#[N:13]
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#CC(C(=O)C(F)(F)F)c1cc(Cl)c2c(c1)OCO2
Solvent: O
Solvent: CCN(CC)CC
Product: N#CC(=C(Cl)C(F)(F)F)c1cc(Cl)c2c(c1)OCO2
Temperature: 90 °C
Yield: 79.5 %

Procedure:
2-(7-chloro-1,3-benzodioxol-5-yl)-4,4,4-trifluoro-3-oxo-butanenitrile (23.9 g, 82 mmol) was treated with POCl3 (62.0 g, 0.41 mol) and then triethylamine (11.4 mL, 82 mmol) was added. The reaction mixture was heated for 3 h at 80-100° C. and then carefully poured into warm water. The product was then extracted ethyl acetate, washed with water and brine, dried, filtered and concentrated to give the title compound (20.2 g; 80%) and used for the next step directly.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:23]([O-])=O)[CH:8]=2)[N:3]=1>[Pd].C(O)C.ClCCl>[CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:23])[CH:8]=2)[N:3]=1
Reactant: Cc1cc(N2CCC(c3ccccc3)C2)c2cc([N+](=O)[O-])ccc2n1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc(N2CCC(c3ccccc3)C2)c2cc(N)ccc2n1

Procedure:
2-Methyl-6-nitro-4-(3-phenylpyrrolidin-1-yl)quinoline (0.29 g; see Preparation 7 above) and palladium on carbon (10%, 0.2 g) in ethanol (10 mL) and dichloromethane (4 mL) was stirred under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered and concentrated to give the title compound as a thick yellow oil, which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.B1([C:18]2[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=2)OCCCO1.C(=O)(O)[O-].[Na+]>COCCOC.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>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=2)[CH:19]=1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: c1cncc(B2OCCCO2)c1
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: COCCOC
Product: Nc1ccc(-c2cccnc2)cc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 105.6 %

Procedure:
To a solution of 4-bromo-2-nitroaniline (4.8 g, 22 mmol) in DME (100 mL) was added pyridine-3-boronic acid 1,3-propanediol cyclic ester (4 g, 24 mmol), sodium bicarbonate (45 mL, 1M), and tetrakis(triphenylphosphine)palladium (0.05 eq). The resulting mixture was heated at 90° C. for 8 hours then cooled to room temperature. The solids were collected, washed with water, 5% EtOAc in Hexane and dried to afford the title compound (5 g). 1H NMR (CDCl3) δ 8.8 (d, 1H), 8.55 (m, 1H), 8.35 (d, 1H), 7.85 (dd, 1H), 7.65 (dd, 1H), 7.35 (m, 1H), 6.95 (d, 1H), 6.25 (br s, 2H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][C:6]1[C:7]2[CH:13]=[CH:12][S:11][C:8]=2[NH:9][CH:10]=1)[CH3:3].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CC([O-])(C)C.[K+]>C1COCC1>[CH3:1][N:2]([CH2:4][CH2:5][C:6]1[C:7]2[CH:13]=[CH:12][S:11][C:8]=2[N:9]([S:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:22])=[O:21])[CH:10]=1)[CH3:3]
Reactant: CN(C)CCc1c[nH]c2sccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)CCc1cn(S(=O)(=O)c2ccccc2)c2sccc12

Procedure:
A mixtue of N,N-dimethyl-2-(6H-thieno[2,3-b]pyrrol-4-yl)ethylamine (0.2 mmol), benzenesulfonyl chloride (0.22 mmol) and KOt-Bu (0.22 mmol) in THF is shaken at ambient temperatures for 8 h and concentrated in vacuo. The resultant residue is dissolved in a mixture of DMSO, methanol and water and purified by preparative HPLC1 to afford the title product, [M+H] 335, retention time (RT) 1.42 min. 1 Gilson Preparative HPLC conditions: Gilson Preparative HPLC system; YMC Pro C18, 20 mm×50 mm ID, 5 uM column; 2 mL injection; Solvent A: 0.02% TFA/water; Solvent B: 0.02% TFA/acetonitrile; Gradient: Time 0: 95% A; 2 min: 95% A; 14 min: 10% A, 15 min: 10% A, 16 min: 95% A; Flow rate 22.5 mL/min; Detection: 254 nm DAD.
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Br:14])[CH:5]1[CH2:15][C:16]([O:18]C)=O)(=[O:3])[CH3:2].C([N:23]1C=CC2C(=CC=CC=2Br)C1CC(OC)=O)(=O)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCCl>[Br:14][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[CH2:12][CH2:13][N:4]1[C:1](=[O:3])[CH2:2][NH:23][C:16](=[O:18])[CH:15]=[C:5]12
Reactant: COC(=O)CC1c2cccc(Br)c2CCN1C(C)=O
Reactant: COC(=O)CC1c2cccc(Br)c2C=CN1C(C)=O
Agent: CC[SiH](CC)CC
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1C=C2c3cccc(Br)c3CCN2C(=O)CN1
Temperature: 25 °C

Procedure:
methyl 2-(2-acetyl-5-bromo-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate. A stirred solution of methyl 2-(2-acetyl-5-bromo-1,2-dihydroisoquinolin-1-yl)acetate (147 g, 453 mmol), triethylsilane (388 g, 3333 mmol) and trifluoroacetic acid (266 mL, 3446 mmol) in 1,2-dichloroethane (1100 mL) was stirred at 80° C. for 3 h. The reaction mixture was cooled to rt and the solvent was evaporated under reduced pressure. The remaining volatile components were evaporated under high vacuo and 40° C. bath temperature. To the resulting yellow residue saturated aqueous NaHCO3 (500 mL) was added while stirring and the mixture was extracted with DCM (3×400 mL). The organic layer was washed with saturated aqueous NaHCO3 (300 mL) and brine (300 mL). The organic layer was treated with charcoal, then dried with sodium sulfate, filtered through a pad of Hyflo and the solvent was removed under reduced pressure. The crude product was crystallized from diethyl ether (300 mL) to yield the title compound as white crystals (90 g). UPLC-MS: MS 326.0/328.0 (M+H+); UPLC rt 0.94 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[F:19][C:20]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:21]=1[CH2:22][NH2:23]>>[F:19][C:20]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:21]=1[CH2:22][NH:23][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][N:17]=[CH:18][C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: NCc1ccc(F)cc1F
Product: O=C(NCc1ccc(F)cc1F)c1ccncc1Nc1ccc(I)cc1F

Procedure:
N-(2,4-difluorobenzyl)-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.33 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.49 mmol of 2,4-difluorobenzylamine. LC/MS [6.28 min; 484 (M+1)]
Reaction SMILES: N12CCCN=C1CCCCC2.[Cl:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17](=[O:29])[CH:18]([C:26]([OH:28])=[O:27])[C:19](=[O:25])[N:20]2[CH2:23][CH3:24])=[CH:15][C:14]=1[NH:30][N:31]1[C:35]([CH3:36])=[CH:34][CH:33]=[C:32]1[CH3:37].[C:38]([O:44][CH2:45]Cl)(=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40]>C(#N)C>[Cl:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17](=[O:29])[CH:18]([C:26]([O:28][CH2:45][O:44][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40])=[O:27])[C:19](=[O:25])[N:20]2[CH2:23][CH3:24])=[CH:15][C:14]=1[NH:30][N:31]1[C:35]([CH3:36])=[CH:34][CH:33]=[C:32]1[CH3:37]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CCN1C(=O)C(C(=O)O)C(=O)c2cc(Nn3c(C)ccc3C)c(Cl)cc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCN1C(=O)C(C(=O)OCOC(=O)C(C)(C)C)C(=O)c2cc(Nn3c(C)ccc3C)c(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
18 μl of 1,8-diazabicyclo[5.4.0]undec-7-ene were added to a solution of 21 mg of 7-chloro-6-(2,5-dimethylpyrrol-1-ylamino)-1-ethyl-4-oxo-1,4-dihydroquinolonecarboxylic acid (Example 36) in 3 ml of acetonitrile and stirred at room temperature for 30 minutes. Then 36 μl of chloromethyl pivalate were added, and reaction was allowed to take place at room temperature for 5 days. The resulting precipitate was filtered off with suction to afford 3.3 mg of pure product.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=[C:11]2[C:10]([Br:21])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH2:1]([N:8]1[C:12]2=[N:13][C:14]([NH:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[N:15][CH:16]=[C:11]2[C:10]([Br:21])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCN1CCOCC1
Reactant: CS(=O)(=O)c1ncc2c(Br)nn(Cc3ccccc3)c2n1
Product: Brc1nn(Cc2ccccc2)c2nc(NCCN3CCOCC3)ncc12

Procedure:
Prepared as described above in Example 8 starting from 1-benzyl-3-bromo-6-methanesulfonyl-1H-pyrazolo[3,4-d]pyrimidine and N-aminoethylmorpholine to give the title compound (1-benzyl-3-bromo-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-(2-morpholin-4-yl-ethyl)-amine; LC/MS (m/e)=419.2 (MH+), Rt=1.47 min.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[O:8]1[C:12]2([CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)[O:11][CH2:10][CH2:9]1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:15]2[CH2:16][CH2:17][C:12]3([O:11][CH2:10][CH2:9][O:8]3)[CH2:13][CH2:14]2)[CH2:4][CH2:3]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN1CCN(C2CCC3(CC2)OCCO3)CC1
Temperature: 25 °C
Yield: 99.2 %

Procedure:
1-Methyl-piperazine (128.27 g, 105.90 ml, 1.28 mol) was added in one portion to a stirred and cooled (3° C.) solution of 1,4-dioxaspiro[4.5]decan-8-one (200.00 g, 1.28 mol) in 1,2-dichloroethane (2.0 L). Then glacial acetic acid (76.90 g, 73.31 ml, 1.28 mol) was added in one portion followed by solid NaBH(OAc)3 (379.97 g, 1.79 mol) portionwise over 20 min. The reaction was slowly allowed to warm to RT and was stirred overnight. The reaction was quenched by addition of 10% aqueous NaOH (3×450 mL) with stirring over a period of 25 min. An exotherm of ca. 10° C. was observed. The mixture was stirred for 30 min. The organic layer was separated. Aqueous layer was further extracted with CH2Cl2 (3×1 L). Brine (1000 mL) was added to the aqueous layer and extracted with EtOAc (2×1000 mL). The combined organic solutions were dried (MgSO4) and concentrated to afford 4 (305.00 g, 1.27 mol, 99.10% yield) as brown/orange oil. 1H NMR (400 MHz, CDCl3) δ 1.45-1.68 (m, 4H), 1.72-1.90 (m, 4H), 1.99 (s, 3H), 2.45 (s, 2H), 2.56-2.67 (m, 1H), 2.87 (bs, 6H), 3.86-3.95 (m, 4H).