Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11](O)=[O:12])[CH:10]=[C:5]2[N:4]=[C:3]1[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=1.S(Cl)(Cl)=O.[CH2:28]([O:30][C:31]([CH2:33][CH2:34][NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:32])[CH3:29].C(N(CC)CC)C>ClCCl.O1CCCC1>[C:36]1([N:35]([CH2:34][CH2:33][C:31]([O:30][CH2:28][CH3:29])=[O:32])[C:11]([C:9]2[CH:10]=[C:5]3[N:4]=[C:3]([CH2:14][CH2:15][C:16]4[CH:17]=[CH:18][C:19]([C:22]#[N:23])=[CH:20][CH:21]=4)[N:2]([CH3:1])[C:6]3=[N:7][CH:8]=2)=[O:12])[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CCOC(=O)CCNc1ccccc1
Reactant: Cn1c(CCc2ccc(C#N)cc2)nc2cc(C(=O)O)cnc21
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CCN(C(=O)c1cnc2c(c1)nc(CCc1ccc(C#N)cc1)n2C)c1ccccc1
Reaction time: 1 h

Procedure:
A solution of 2.0 g (6.5 mmol) of 3-methyl-2-[2-(4-cyanophenyl)ethyl]imidazo[4,5-b]pyridine-6-carboxylic acid in 100 ml dichloromethane was mixed with 20 ml thionyl chloride and refluxed for 2 hours. After the liquid components had been distilled. off, the crude product was taken up twice more in dichloromethane and the solvent was distilled off each time. The crude acid chloride thus obtained (2 g) was suspended in 100 ml of tetrahydrofuran and mixed with 1.2 g (6.5 mmol) of N-(2-ethoxycarbonylethyl)aniline. Then within 5 minutes 0.73 g (7.2 mmol) of triethylamine were added dropwise. After 1 hour's stirring, the solvent was distilled off in vacuo, the residue was taken up in ethyl acetate, the organic phase was washed with water and dried with sodium sulfate. After distillation of the solvent and flash chromatography (silica gel; dichloromethane to dichloromethane/ethanol=49:1), the desired compound was isolated as a brownish oil.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[C:15](=[O:21])[CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:22]([O:24][CH3:25])=[O:23])=[CH:3]1.C([O-])(=O)C>CC(C)=O>[OH:1][C@@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[C:15](=[O:21])[CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:22]([O:24][CH3:25])=[O:23])=[CH:3]1
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=C[C@@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: CC(=O)[O-]
Solvent: CC(C)=O
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Yield: 29.3 %

Procedure:
This crude ester (about 600 mg.) was dissolved in acetone (50 ml.) and pH 5 acetate buffer was added. The solution was refluxed for 45 minutes, then concentrated by evaporation under reduced pressure, diluted with water and extracted with chloroform. The organic solution was dried over sodium sulphate and evaporated to an oil which was purified by preparative TLC and recrystallisation of the main band from acetone/petrol to give title compound (176 mg.) as off-white prisms, m.p. 121°-125°, [α]D + 215°.
Reaction SMILES: OC1C(=O)NN=C(CCC2C=CC=CC=2)C=1.C([O:24][C:25]1[N:26]=[N:27][C:28](/[CH:39]=[CH:40]/[C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][C:42]=2[C:51]([F:54])([F:53])[F:52])=[CH:29][C:30]=1[O:31]CC1C=CC=CC=1)C1C=CC=CC=1>>[F:54][C:51]([F:52])([F:53])[C:42]1[CH:43]=[C:44]([C:47]([F:48])([F:50])[F:49])[CH:45]=[CH:46][C:41]=1[CH2:40][CH2:39][C:28]1[CH:29]=[C:30]([OH:31])[C:25](=[O:24])[NH:26][N:27]=1
Reactant: FC(F)(F)c1ccc(/C=C/c2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c(C(F)(F)F)c1
Agent: O=c1[nH]nc(CCc2ccccc2)cc1O
Product: O=c1[nH]nc(CCc2ccc(C(F)(F)F)cc2C(F)(F)F)cc1O
Yield: 31 %

Procedure:
Prepared as described for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[(E)-2-[2,4-bis(trifluoromethyl)phenyl]-ethenyl]pyridazine (Intermediate 72) in 31% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=O)[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH:59]1[CH2:65][CH2:64][CH2:63][C@H:60]1[CH2:61][OH:62]>C(Cl)Cl.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:19][CH2:20][CH:21]([C:24]([N:59]3[CH2:65][CH2:64][CH2:63][C@H:60]3[CH2:61][OH:62])=[O:26])[CH2:22][CH2:23]2)=[O:17])=[CH:27][CH:28]=1
Reactant: O=C(O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Reactant: OC[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(c1cc2ccccc2n1Cc1ccc(Cl)cc1)N1CCC(C(=O)N2CCC[C@H]2CO)CC1
Reaction time: 8 h

Procedure:
1-(1-(4-chlorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carboxylic acid (100 mg, 0.252 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (97 mg, 0.504 mmol), and 1-Hydroxybenzotriazole (68 mg, 0.504 mmol) were dissolved in 3.0 mL of DCM. The reaction was allowed to stir for 10 minutes before N,N-Diisopropylethylamine (88 μL, 0.504 mmol) and L-prolinol (49.5 μL, 0.504 mmol) were added. The reaction was allowed to stir overnight. The reaction was diluted with water and ethyl acetate. The layers were separated and the organic layer was washed with another aliquot of water. The ethyl acetate layer was washed with saturated citric acid, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude material was purified in silica gel using the gradient 100% DCM to 5% 7M NH3 in methanol diluted with 95% DCM. After purification, pure white solid was obtained. Yield: 118 mg (White solid)
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([O:22][CH3:23])[C:14]([Br:24])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrC1C(OC)=C(C(CSC2C=CC=C([Cl:45])C=2)=CC=1)C(OCC)=O>>[Br:24][C:14]1[C:15]([O:22][CH3:23])=[C:16]([C:11]([CH2:10][S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[C:5]([Cl:45])[CH:6]=2)(=[O:9])=[O:8])=[CH:12][CH:13]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)c1c(CSc2cccc(Cl)c2)ccc(Br)c1OC
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1OC
Product: CCOC(=O)c1c(CS(=O)(=O)c2cccc(Cl)c2)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 61, starting from ethyl 3-bromo-6-(3-chlorophenylthiomethyl)-2-methoxybenzoate (Intermediate 79).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:21]([N:23]1[CH2:94][CH2:93][CH2:92][C@H:24]1[C:25]([NH:27][C@H:28]([C:36]([NH:38][C@H:39]([C:46]([NH:48][C@H:49]([C@H:54]([CH2:56][C:57]([N:59]([CH2:61][C:62]([NH:64][C@H:65]([C:72]([NH:74][C@H:75]([C:88]([O:90][CH3:91])=[O:89])[CH2:76][CH2:77][CH2:78][CH2:79][NH:80]C(OC(C)(C)C)=O)=[O:73])[CH2:66][C:67]1[N:71]=[CH:70][NH:69][CH:68]=1)=[O:63])[CH3:60])=[O:58])[OH:55])[CH2:50][CH:51]([CH3:53])[CH3:52])=[O:47])[CH2:40][C:41]1[N:45]=[CH:44][NH:43][CH:42]=1)=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:26])=[O:22])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:20])[NH2:19])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].C(OC(C)C)(C)C>C(O)(C(F)(F)F)=O>[NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:21]([N:23]1[CH2:94][CH2:93][CH2:92][C@H:24]1[C:25]([NH:27][C@H:28]([C:36]([NH:38][C@H:39]([C:46]([NH:48][C@H:49]([C@H:54]([CH2:56][C:57]([N:59]([CH2:61][C:62]([NH:64][C@H:65]([C:72]([NH:74][C@H:75]([C:88]([O:90][CH3:91])=[O:89])[CH2:76][CH2:77][CH2:78][CH2:79][NH2:80])=[O:73])[CH2:66][C:67]1[N:71]=[CH:70][NH:69][CH:68]=1)=[O:63])[CH3:60])=[O:58])[OH:55])[CH2:50][CH:51]([CH3:53])[CH3:52])=[O:47])[CH2:40][C:41]1[N:45]=[CH:44][NH:43][CH:42]=1)=[O:37])[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:26])=[O:22])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:19])[NH2:20])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9]
Reactant: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)CN(C)C(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)CCCNC(=N)N
Solvent: CC(C)OC(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](CCCCN)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)CN(C)C(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)CCCNC(=N)N
Reaction time: 0.42 h

Procedure:
77 mg of H-Arg-Arg-Pro-Phe-His-Sta-Sar-His-Lys(Boc)-OMe (from Example 17) are dissolved in 0.4 ml of 95% strength TFA and left to stand for 25 minutes. By adding 5 ml of diisopropyl ether and filtering off the precipitate, H-Arg-Arg-Pro-Phe-His-Sta-Sar-His-Lys-OMe is obtained in the form of an amorphous, hygroscopic powder; Rf (D)=0.04; Rf (M)=0.04; Rf (O)=0.05.
Reaction SMILES: C[Si](C)(C)C#CCP(=O)(OCC)OCC.[N+:16]([C:19]1[C:20]([N:25]2[CH2:30][CH2:29][C:28](=[CH:31][C:32]#[CH:33])[CH2:27][CH2:26]2)=[N:21][CH:22]=[CH:23][CH:24]=1)([O-:18])=[O:17].I[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1>>[N+:16]([C:19]1[C:20]([N:25]2[CH2:30][CH2:29][C:28](=[CH:31][C:32]#[C:33][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)[CH2:27][CH2:26]2)=[N:21][CH:22]=[CH:23][CH:24]=1)([O-:18])=[O:17]
Reactant: Ic1ccccn1
Reactant: C#CC=C1CCN(c2ncccc2[N+](=O)[O-])CC1
Agent: CCOP(=O)(CC#C[Si](C)(C)C)OCC
Product: O=[N+]([O-])c1cccnc1N1CCC(=CC#Cc2ccccn2)CC1

Procedure:
The title compound was obtained as described for the Compound of Example 1, reacting Compound 1c with 2-iodopyridine instead of 2-bromo-6-methylpyridine. The crude was purified by flash chromatography (EtOAc—Petroleum Ether 1:1) affording the title compound.
Reaction SMILES: [N:1]([CH2:4][C@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1)[OH:6])=[N+]=[N-].[BH4-].[Na+].C(O)(C)C>CO>[NH2:1][CH2:4][C@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1)[OH:6]
Reactant: [N-]=[N+]=NC[C@@H](O)c1cccc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CO
Product: NC[C@@H](O)c1cccc(Cl)c1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of (S)-2-Azido-1-(3-chlorophenyl)-ethanol (5.14 g, 0.026 mol), NaBH4 (1.97 g, 0.052 mol) and isopropyl alcohol (100 mL) was stirred at 80° C. for 24 h. The solvent was evaporated, the residue was separated on SiO2 (15 g) CHCl3-MeOH (0 to 30%). Colorless oil, 3.70 g (0.021 mol, 83%). The material was reacted with Boc2O in dichloromethane and NEt3 and analyzed by chiral SFC using a CHIRALPAK AD-H column, 30% MeOH and determined to be 91% ee. LCMS [M+H]+ 172.4
Reaction SMILES: [C:1](I)([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].I[C:16]1[CH:21]=[C:20]([CH3:22])[C:19](I)=[CH:18][C:17]=1[CH3:24].ClCCl.O>CS(C)=O.[Cu]>[F:2][C:1]([F:3])([C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([C:1]([F:3])([F:2])[C:4]([F:5])([F:6])[C:7]([F:8])([F:9])[C:10]([F:13])([F:12])[F:11])=[CH:18][C:17]=1[CH3:24])[C:4]([F:6])([F:5])[C:7]([F:9])([F:8])[C:10]([F:13])([F:12])[F:11]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Reactant: Cc1cc(I)c(C)cc1I
Agent: [Cu]
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1cc(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(C)cc1C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.9 %

Procedure:
A solution of C4F9I (0.96 mL, 5.6 mmol) was added dropwise over 10 min to a stirred mixture of 2,5-diiodo-ρ-xylene (0.5 g, 1.4 mmol), copper powder (1.4 g, 22.4 mmol) in DMSO (10 mL) at 130° C. The reaction mixture was subsequently stirred for a further 24 h at this temperature. After cooling to room temperature, it was poured into a beaker containing dichloromethane (30 mL) and water (30 mL). After filtering, the organic layer was separated, washed with water (3×30 mL) and dried over MgSO4. The residue was purified by column chromatography (hexane as eluant) to give the product 8 as a white solid (553 mg, 73%).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[CH3:16][N:17]1[C:21]2[CH:22]=[CH:23][C:24]([CH:26]=O)=[CH:25][C:20]=2[N:19]([CH3:28])[C:18]1=[O:29].C(=O)([O-])[O-]>ClCCl>[CH3:16][N:17]1[C:21]2[CH:22]=[CH:23][C:24]([CH:26]=[N:2][CH2:3][CH2:4][N:5]3[C:6](=[O:15])[C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:13]3=[O:14])=[CH:25][C:20]=2[N:19]([CH3:28])[C:18]1=[O:29]
Reactant: Cn1c(=O)n(C)c2cc(C=O)ccc21
Reactant: NCCN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: Cn1c(=O)n(C)c2cc(C=NCCN3C(=O)c4ccccc4C3=O)ccc21
Temperature: 22 °C
Reaction time: 48 h
Yield: 80.2 %

Procedure:
To a dry flask charged with a stir bar was added 2-(2-amino-ethyl)-isoindole-1,3-dione hydrochloride salt (100 mg, 0.53 mmoles) (Burgess, K.; Ibarzo, J. D.; Linthicum S.; Russell, D. H.; Shin, H.; Shitangkoon, A.; Totani, R.; and Zhang, A.; J. Am. Chem. Soc. 1997, 119, 1556), 1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carbaldehyde (156 mg, 0.68 mmoles), MP-carbonate (254 mg, 0.79 mmoles) (Argonaut Tech), 3 Å sieves (1.2 g) and 4 mL of dichloromethane. The flask was sealed with a plastic cap and the resulting mixture was stirred for 48 hours at 22° C. The mixture was filtered through a nylon disk via syringes, rinsing with dichloromethane and the filtrate was concentrated to give 154 mg of 2-{2-[(1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-ylmethylene)-amino]-ethyl}-isoindole-1,3-dione as a light yellow solid.
Reaction SMILES: N[C:2]1C=C(Br)C=CC=1C(OC)=O.[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[C:16]([N+:23]([O-:25])=[O:24])[CH:15]=1.N12CCCN=C1CCCCC2.IC>CN(C=O)C.O>[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([O:20][CH3:2])=[O:19])=[C:16]([N+:23]([O-:25])=[O:24])[CH:15]=1
Reactant: O=C(O)c1ccc(Br)cc1[N+](=O)[O-]
Reactant: COC(=O)c1ccc(Br)cc1N
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
Methyl 2-amino-4-bromobenzoate. To a stirred solution of 4-bromo-2-nitrobenzoic acid (3.8 g, 15 mmol) in DMF (30 mL) at 0° C. was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (10.0 mL, 75.0 mmol) followed by iodomethane (4.7 mL, 75 mmol). The reaction mixture was stirred 15 min at 0° C., then was allowed to warm to room temperature and was stirred overnight. The mixture was poured into H2O and extracted with EtOAc (2×). The combined organic extracts were washed with H2O (2×), dried (MgSO4), and concentrated in vacuo. The residue was purified by flash chromatography (hexanes/EtOAc) to afford methyl 4-bromo-2-nitrobenzoate as a pale yellow solid (3.52 g, 90%). To a solution of the nitrobenzoate (3.52 g, 13.5 mmol) in 1:1 EtOAc/DCM (30 mL) at room temperature was added SnCl2.2H2O (15 g, 67 mmol). The reaction mixture was allowed to stir overnight. The solvents were evaporated in vacuo, and the residue was partitioned between satd. aq. NaHCO3 and DCM. The layers were separated, and the aqueous layer was further extracted with DCM (2×). The combined organic layers were dried (MgSO4) and concentrated in vacuo to provide the pure aminobenzoate as a white solid (2.89 g, 93%). 1H NMR (400 MHz, CDCl3): 7.70 (d, J=8.6 Hz, 1H), 6.84 (d, J=1.9 Hz, 1H), 6.75 (dd, J=8.6, 1.9 Hz, 1H), 5.78 (br s, 2H), 3.86 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[CH2:22][CH:23](OC)OC)[CH2:10][CH2:9]1)=O)(C)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:21][C:19]1[CH:20]=[C:15]2[C:16]([CH:22]=[CH:23][N:14]2[CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:17][CH:18]=1
Reactant: COC(Cc1ccc(Cl)cc1NC1CCN(C(=O)OC(C)(C)C)CC1)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Clc1ccc2ccn(C3CCNCC3)c2c1
Temperature: 60 °C
Yield: 97 %

Procedure:
To a stirred solution of 1.03 g (2.59 mmol) of 4-[5-chloro-2-(2,2-dimethoxy-ethyl)-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester in 15 mL toluene was added 1.0 g (5.2 mmol) of p-toluenesulfonic acid. The reaction mixture was heated to 60° C. for 20 min, allowed to cool to room temperature and quenched with 100 mL of sat. aqueous NaHCO3 then extracted with EtOAc (3×75 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to afford 590 mg (98%) of the desired product as a pink oil. MS (electrospray): exact mass calculated for C13H15ClN2, 234.09. m/z found, 235.1 [M+H]+. 1H NMR (CDCl3, 400 MHz, a mixture of amide rotamers): 7.52 (d, J=8.34 Hz, 1H), 7.38 (br s, 1H), 7.21 (d, J=3.28 Hz, 1H), 7.06 (dd, J=8.34, 1.77 Hz, 1H), 6.49 (d, J=3.28 Hz, 1H), 4.24 (m, 1H), 3.30 (m, 2H), 2.85 (dt, J=12.38, 2.53 Hz, 2H), 2.08 (m, 2H), 1.94 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[CH:10][C:9]2[C:8](=[O:14])[CH2:7][C:6]([CH3:16])([CH3:15])[CH2:5][C:4]=2[N:3]=1.[CH2:17]([NH:24][CH3:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.O>C(O)C>[CH2:17]([N:24]([CH3:25])[C:2]1[C:11]([C:12]#[N:13])=[CH:10][C:9]2[C:8](=[O:14])[CH2:7][C:6]([CH3:16])([CH3:15])[CH2:5][C:4]=2[N:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CNCc1ccccc1
Reactant: CC1(C)CC(=O)c2cc(C#N)c(Cl)nc2C1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: CN(Cc1ccccc1)c1nc2c(cc1C#N)C(=O)CC(C)(C)C2
Yield: 48.3 %

Procedure:
A solution of 2-chloro-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-quinoline-3-carbonitrile (0.22 g, 0.94 mmol), benzyl(methyl)amine (0.17 g, 1.4 mmol) and triethylamine (0.14 ml, 0.1 g, 1.0 mmol) in ethyl alcohol (3 ml) was heated at reflux for 3 h. Then water (20 ml) was added and the mixture was extracted by dichloromethane. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (CH2Cl2-hexane, 1:1). The product obtained was recrystallized from ethyl alcohol to give the title compound (0.145 g, 48%).
Reaction SMILES: [CH3:1][N:2]([CH3:30])[CH2:3][CH2:4][N:5]([CH2:18][CH2:19][NH:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7].O[CH2:32][CH2:33]N1CCCC1>>[N+:27]([C:24]1[CH:25]=[CH:26][C:21]([NH:20][CH2:19][CH2:18][N:5]([S:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])(=[O:7])=[O:8])[CH2:4][CH2:3][N:2]2[CH2:30][CH2:33][CH2:32][CH2:1]2)=[N:22][CH:23]=1)([O-:29])=[O:28]
Reactant: CN(C)CCN(CCNc1ccc([N+](=O)[O-])cn1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: OCCN1CCCC1
Product: O=[N+]([O-])c1ccc(NCCN(CCN2CCCC2)S(=O)(=O)c2ccccc2[N+](=O)[O-])nc1

Procedure:
Made using the same procedure as for polymer-bound [2-(dimethylamino)ethyl]{2-[(5-nitro(2-pyridyl))amino]ethyl}[(2-nitrophenyl)sulfonyl]amine except that 1-(2-hydroxyethyl)pyrrolidine (4.9 mL, 42 mmol) was used.
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)[NH2:2].[C:12]([CH2:18][C:19]#[N:20])(=O)[C:13]([CH3:16])([CH3:15])[CH3:14]>C1(C)C=CC=CC=1>[NH2:20][C:19]1[N:1]([C:3]2[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=2)[N:2]=[C:12]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:18]=1
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)C(=O)CC#N
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(N)n(-c2ccc(C(=O)O)cc2)n1
Temperature: 25 °C

Procedure:
To a suspension of 2.4 g (16 mmol) 4-hydrazino-benzoic acid in 12 mL toluene, 2.0 g of pivaloyl acetonitrile are added at rt. The suspension is heated to and kept under reflux for 12 h. After completion, the resulting reaction mixture is allowed to cool to rt. The precipitated product is isolated by filtration, washed with cold toluene and dried under high vacuum. [M+1]+=260.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[O:23][CH:24]=[CH:25][CH:26]=2)=[N:10]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH:28]1[C:33]([OH:35])=[O:34]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[O:23][CH:24]=[CH:25][CH:26]=2)[NH:12][C:13]([CH2:20][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH:28]2[C:33]([OH:35])=[O:34])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(CBr)NC(c2ccco2)=NC1c1ccc(F)cc1Br
Reactant: O=C(O)C1COCCN1
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2ccco2)=NC1c1ccc(F)cc1Br
Yield: 37.8 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(furan-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.74 g, 1.53 mmol) (The compound was synthesized according to the procedure as described in WO2010069147) was reacted with morpholine-3-carboxylic acid (0.2 g, 1.53 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (0.31 g, 38%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1I.[OH:29][C:30]1[CH:31]=[C:32]([NH:45][S:46]([C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)(=[O:48])=[O:47])[CH:33]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(P([Pd-4](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)C=CC=CC=1>[NH2:1][C:2]1[C:3]([C:34]2[CH:33]=[C:32]([NH:45][S:46]([C:49]3[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=3)(=[O:48])=[O:47])[CH:31]=[C:30]([OH:29])[CH:35]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: COc1ccc(S(=O)(=O)Nc2cc(O)cc(B3OC(C)(C)C(C)(C)O3)c2)cc1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3I)n(-c3ccccc3)c(=O)c12
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc(S(=O)(=O)Nc2cc(O)cc(-c3c(N)ncnc3N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c2)cc1
Yield: 28 %

Procedure:
(S)-2-(1-((6-Amino-5-iodopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (70 mg, 0.14 mmol) was treated with N-(3-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-methoxybenzenesulfonamide (87 mg, 0.21 mmol), 2M sodium carbonate (216 μl, 0.43 mmol) and tetrakis(triphenylphosphino)palladium(0) (8 mg, 0.01 mmol) according to the method described in Example 3 to give 25 mg (27% yield) of the title compound as a solid. Purity 100%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1.[N:12]([O-])=O.[Na+].[ClH:16]>O>[ClH:16].[NH:1]([C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH2:11])=[O:10])=[CH:6][CH:7]=1)[NH2:12]
Reactant: NC(=O)Cc1ccc(N)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(CC(N)=O)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred suspension of 2-(4-aminophenyl)acetamide (19.5 g) in concentrated hydrochloric acid (43 ml) was added an ice cold solution of sodium nitrite (9.43 g) in water (25 ml) at such a rate that the temperature of the mixture remained between -5° and +5° C. When the addition was complete the solution was stirred at 0° C. for 15 min. This was then added to a stirred solution of stannous chloride (146.3 g) in concentrated hydrochloric acid (86 ml) at -10° C. The mixture was stirred for 30 min., poured into ice cold ethanol (750 ml) and the suspension was stirred for a further 30 min. Collection of the solid by filtration and washing with ethanol followed by ether gave the title compound as a white powder (20.6 g). This material was 62% pure but was contaminated with sodium chloride. It was used in the next stage without further purification.