Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[Br:13])[C:6]([C:14]2[C:15](=[O:29])[NH:16][C:17](=[O:28])[C:18]=2[C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)=[CH:5]1)[CH:2]=[CH2:3]>CO>[CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[Br:13])[C:6]([CH:14]2[CH:18]([C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:21][CH:20]=3)[C:17](=[O:28])[NH:16][C:15]2=[O:29])=[CH:5]1)[CH:2]=[CH2:3]
Reactant: C=CCn1cc(C2=C(c3c[nH]c4ccccc34)C(=O)NC2=O)c2cccc(Br)c21
Solvent: CO
Product: C=CCn1cc(C2C(=O)NC(=O)C2c2c[nH]c3ccccc23)c2cccc(Br)c21

Procedure:
(±)-Trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1H-indol-3-yl)pyrrolidine-2,5-dione may be prepared by reacting 1-allyl-7-bromo-1H-indole with (COCl)2 (oxalyl chloride) and sodium methoxide in a polar aprotic solvent such as dichloromethane to yield (1-allyl-7-bromo-1H-indol-3-yl)-oxo-acetic acid methyl ester, which is subsequently reacted with 2-(1H-indol-3-yl)-acetamide and tBuOK (potassium tert-butoxide) in THF to yield 3-(1-allyl-7-bromo-1H-indol-3-yl)-4-(1H-indol-3-yl)-pyrrole-2,5-dione. Reduction of the 3-(1-allyl-7-bromo-1H-indol-3-yl)-4-(1H-indol-3-yl)-pyrrole-2,5-dione by Mg in refluxing methanol, as in Example 2 procedure C, yields 3-(1-allyl-7-bromo-1H-indol-3-yl)-4-(1H-indol-3-yl)-pyrrolidine-2,5-dione, which is treated with 9-BBN (9-borabicyclo[3.3.1]nonane) and Pd(PPh3)4 (tetrakis(triphenylphosphine)palladium) to yield (±)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1H-indol-3-yl)pyrrolidine-2,5-dione.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:17]([OH:19])=O)[N:10]([CH2:12][C:13]([F:16])([F:15])[F:14])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][O:21][CH2:22][CH2:23][N:24]([CH3:32])[C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][N:26]=1>>[CH3:20][O:21][CH2:22][CH2:23][N:24]([CH3:32])[C:25]1[N:26]=[CH:27][C:28]([NH:31][C:17]([C:9]2[N:10]([CH2:12][C:13]([F:14])([F:15])[F:16])[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:8]=2)=[O:19])=[CH:29][CH:30]=1
Reactant: COCCN(C)c1ccc(N)cn1
Reactant: O=C(O)c1cc(-c2ccccc2)nn1CC(F)(F)F
Product: COCCN(C)c1ccc(NC(=O)c2cc(-c3ccccc3)nn2CC(F)(F)F)cn1

Procedure:
With a procedure similar to example 16 above, 5-phenyl-2-(2,2,2-trifluoro-ethyl)-2H-pyrazole-3-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 5-phenyl-2-(2,2,2-trifluoro-ethyl)-2H-pyrazole-3-carboxylic acid and N2-(2-methoxy-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C21H22F3N5O2 (m/e) 433, obsd 434 (M+H). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: S1C2C=CC=CC=2N=C1S.[Cl:11][C:12]1[CH:28]=[CH:27][C:15]([CH2:16][CH2:17][O:18][C:19]2[C:24]([O:25]C)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1>CC(N(C)C)=O.C([O-])(O)=O.[Na+]>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][CH2:17][O:18][C:19]2[C:24](=[O:25])[NH:23][CH:22]=[CH:21][N:20]=2)=[CH:27][CH:28]=1
Reactant: COc1nccnc1OCCc1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: Sc1nc2ccccc2s1
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=c1[nH]ccnc1OCCc1ccc(Cl)cc1
Temperature: 135 °C
Reaction time: 6 h
Yield: 47.8 %

Procedure:
A mixture of benzo[d]thiazole-2-thiol (1.264 g, 7.56 mmol), 2-(4-chlorophenethoxy)-3-methoxypyrazine (1.00 g, 3.78 mmol) and NaHCO3 (1.587 g, 18.89 mmol) in DMA (10 mL) was stirred at 135° C. for 6 hours. After cooling to RT, the mixture was diluted with a solution of saturated NaHCO3 (55 ml) and was then extracted with EtOAc (60 ml). The EtOAc layer was dried over Na2SO4 and concentrated. The crude product was purified by silica gel chromatography employing a solvent gradient (hexane to 100% EtOAc) to elute 3-(4-chlorophenethoxy)pyrazin-2(1H)-one (477 mg, 1.808 mmol, 47.9% yield) as off-white solid. 1H NMR (400 MHz, chloroform-d) δ ppm 7.27-7.31 (2H, m), 7.19-7.25 (2H, m), 6.95 (1H, d, J=4.27 Hz), 6.89 (1H, d, J=4.52 Hz), 4.54 (2H, t, J=7.53 Hz), 3.14 (2H, t, J=7.40 Hz).
Reaction SMILES: [C:1]1([C:7]2([C:10]3[N:15]=[C:14]4[S:16][C:17]([C:19]5[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=5)=[N:18][C:13]4=[CH:12][CH:11]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:27]1[CH2:30][CH:29]([C:31]([OH:33])=[O:32])[CH2:28]1>>[C:1]1([C:7]2([C:10]3[N:15]=[C:14]4[S:16][C:17]([C:19]5[CH:20]=[CH:21][C:22]([CH2:23][N:27]6[CH2:30][CH:29]([C:31]([OH:33])=[O:32])[CH2:28]6)=[CH:25][CH:26]=5)=[N:18][C:13]4=[CH:12][CH:11]=3)[CH2:8][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)cc1
Reactant: O=C(O)C1CNC1
Product: O=C(O)C1CN(Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)cc2)C1

Procedure:
Reaction of 4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzaldehyde (38.9 mg, 0.109 mmol) and azetidine-3-carboxylic acid (55 mg, 0.546 mmol) according to Reference R and the general procedure for reductive amination to give 1-(4-(5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridin-2-yl)benzyl)azetidine-3-carboxylic acid as a white solid. MS (ESI) m/z: Calculated: 441.2; Observed: 442.1 (M++1).
Reaction SMILES: O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:39][CH2:40][CH2:41][N:42]([CH2:63][CH:64]([O:82][C:83](=[O:97])[CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH2:89][CH2:90][CH2:91][CH2:92][CH2:93][CH2:94][CH2:95][CH3:96])[CH2:65][O:66][C:67](=[O:81])[CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH3:80])[CH2:43][CH2:44][O:45][Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1.C(Cl)Cl>[OH:45][CH2:44][CH2:43][N:42]([CH2:63][CH:64]([O:82][C:83](=[O:97])[CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH2:89][CH2:90][CH2:91][CH2:92][CH2:93][CH2:94][CH2:95][CH3:96])[CH2:65][O:66][C:67](=[O:81])[CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH3:80])[CH2:41][CH2:40][OH:39]
Reactant: CCCCCCCCCCCCCC(=O)OCC(CN(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)OC(=O)CCCCCCCCCCCCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCC(=O)OCC(CN(CCO)CCO)OC(=O)CCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
Another batch of XV was prepared as follows: tetrabutyl ammonium fluride trihydrate (0.50 g, 1.60 mmol) was added to an ice-cooled solution of XIV (0.43 g, 0.40 mmol) in THF (3 mL) under N2 atmosphere. The reaction mixture was allowed to warm up to room temperature. After stirring overnight at room temperature, the reaction mixture was diluted with CH2Cl2 (30 mL) and sequentially washed with 5% NaHCO3 (10 mL), water (10 mL) and saturated aqueous NaCl (10 mL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, elution with 2% methanol in CHCl3) furnished XV (172 mg, 72%) as a wax. NMR spectra coordinates are as follows: 1H NMR (CDCl3): δ 5.24-5.14 (m, 1H), 4.35 (dd, J=12.0, 3.2 Hz, 1H), 4.10 (dd, J=12.4, 6.4 Hz, 1H), 3.60 (t, J=5.2 Hz, 4H), 2.77-2.66 (m, 6H), 2.38-2.26 (m, 4H), 1.66-1.54 (m, 4H), 1.36-1.18 (m, 40H), 0.87 (t, J=6.0 Hz, 6H).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[Cl:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[N:36]=[CH:35][CH:34]=[C:33]2[NH:40][NH2:41]>>[Cl:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[N:36]=[CH:35][CH:34]=[C:33]2[N:40]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)(=[O:21])=[O:22])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:41]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(=O)(=O)N3CCCC3)c2)ccc1=O
Reactant: NNc1ccnc2ccc(Cl)cc12
Product: O=c1ccn(-c2cccc(S(=O)(=O)N3CCCC3)c2)nc1-c1ccnn1-c1ccnc2ccc(Cl)cc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-[3-(pyrrolidine-1-sulfonyl)-phenyl]-1H-pyridazin-4-one (A-29) and (6-chloro-quinolin-4-yl)-hydrazine according to the method described for example 91. MS: M=533.1 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.[CH2:20]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[CH2:21][CH3:22]>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11]([N:26]3[CH2:27][CH2:28][N:23]([CH2:20][CH2:21][CH3:22])[CH2:24][CH2:25]3)=[O:12])[C:4]=2[CH:3]=1
Reactant: CCCN1CCNCC1
Reactant: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Product: CCCN1CCN(C(=O)N2Cc3ccccc3Oc3ccc(Cl)cc32)CC1
Yield: 88.4 %

Procedure:
The title compound of Example 2 (1.0 g, 3.4 mmol) was combined with 1-propylpiperazine (0.44 g, 3.4 mmol) and the reaction was carried out by the method of Example 4. Following chromatographic purification, 1.16 g of the title product was obtained as a white solid.
Reaction SMILES: Br[CH2:2][CH:3](OCC)OCC.Br.C(=O)(O)[O-].[Na+].[Br:16][C:17]1[C:18]([NH2:25])=[N:19][C:20]([CH3:24])=[C:21]([Br:23])[N:22]=1>>[Br:23][C:21]1[N:22]=[C:17]([Br:16])[C:18]2[N:19]([CH:2]=[CH:3][N:25]=2)[C:20]=1[CH3:24]
Reactant: Cc1nc(N)c(Br)nc1Br
Reactant: CCOC(CBr)OCC
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1c(Br)nc(Br)c2nccn12
Temperature: 25 °C

Procedure:
A mixture of 2-bromo-1,1-diethoxyethane (3.21 mL, 20.7 mmol) and 48% aqueous hydrobromic acid (1.0 mL) was stirred at reflux for 2 h. The reaction was then cooled to room temperature and treated with sodium bicarbonate until gas evolution ceased. The mixture was filtered and the filtrate diluted with ethanol (15 mL). To this mixture, 3,5-dibromo-6-methylpyrazin-2-amine VII (3.00 g, 11.2 mmol) was added and the reaction stirred at reflux for 16 h. After this time, the reaction was cooled to room temperature and concentrated under reduced pressure to a volume of approximately 10 mL. The suspension was filtered and the filter cake washed with cold ethanol (5 mL). The filter cake was then taken into water (50 mL) and the pH was adjusted to ˜8 with potassium carbonate. The resulting suspension was filtered and the filter cake dried to a constant weight under vacuum to provide 6,8-dibromo-5-methylimidazo[1,2-a]pyrazine VIII: 1H NMR (400 MHz, CDCl3) δ: 7.90 (s, 1H), 7.72 (s, 1H), 2.74 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[S:5][CH:6]=1.[I:13][CH3:14]>C(O)C>[I-:13].[CH3:14][N+:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:4]2[S:5][CH:6]=[C:2]([CH3:1])[N:3]=2)[CH:8]=1
Reactant: CI
Reactant: Cc1csc(-c2cccnc2)n1
Solvent: CCO
Product: Cc1csc(-c2ccc[n+](C)c2)n1
Product: [I-]

Procedure:
8.3 g of [3-(4-methylthiazol-2-yl)-pyridine] and 4.5 cm3 of iodomethane in 30 cm3 of ethanol are left in darkness for 10 days. After filtering, 14.6 g of product is obtained which is recrystallized from ethanol. M.p.=184°-186° C.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][N:5]1[C:14](=[O:15])[N:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:7]2=[N:6]1.C1(C)C=CC(S([Cl:25])(=O)=O)=CC=1>>[Cl:25][CH2:2][CH2:3][CH2:4][N:5]1[C:14](=[O:15])[N:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:7]2=[N:6]1
Reactant: O=c1n(CCCO)nc2n1CCCCC2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: O=c1n(CCCCl)nc2n1CCCCC2

Procedure:
In the manner described in Reference Example 10-3), 2-(3-hydroxypropyl)-2,5,6,7,8,9-hexahydro-3H-1,2,4-triazolo-[4,3-a]azepin-3-one was treated with p-toluenesulfonyl chloride to obtain the entitled compound as an oily substance.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-])=O>[Pd].C(O)C>[F:1][CH:2]([F:13])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:10]
Reactant: O=[N+]([O-])c1ccccc1OC(F)F
Agent: [Pd]
Solvent: CCO
Product: Nc1ccccc1OC(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 74424 %

Procedure:
A mixture of 1-difluoromethoxy-2-nitrobenzene (8.21 g, 43.4 mmol) and 10% palladium on carbon (1.1 g) in 100 mL of ethanol was stirred under a hydrogen atmosphere at room temperature for approximately 24 hours. The mixture was filtered and the filtrate was concentrated to give 2-difluoromethoxyaniline (5.14 g, 32.3 mol) as an oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.F[B-](F)(F)F.[N:29]1(OC(N(C)C)=[N+](C)C)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=N1.C(N(CC)C(C)C)(C)C.NCC1C=CC=CN=1>CN(C=O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:31][CH2:32][C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][N:29]=2)=[O:21])=[CH:17][N:16]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: NCc1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCc2ccccn2)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.5 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64 mmol) in DMF (2 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (228 mg, 0.71 mmol), N,N-diisopropyl ethyl amine (552 μL, 3.22 mmol) and 2-(aminomethyl)pyridine (0.77 mmol). The resulting reaction mixture was stirred for 12 h at ambient temperature. After dilution with ethyl acetate (20 mL) it was washed with water (20 mL) and aqueous sodium carbonate (saturated, 40 mL). The organic layer was dried over sodium sulfate and concentrated. Purification by chromatography ((SiO2, heptane:ethyl acetate:methanol=50:50:0 to 0:95:5) afforded the title compound (191 mg, 74%) which was obtained as a white solid. MS: m/e=401.2 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:3][CH2:2]1.[NH2:20][C@@H:21]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:22][OH:23]>>[OH:23][CH2:22][C@@H:21]([NH:20][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[CH2:24][CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)C[C@H](N)CO
Reactant: O=C(O)c1ccc(N2CCCC2)c(OCC2CC2)n1
Product: CC(C)C[C@@H](CO)NC(=O)c1ccc(N2CCCC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid and (2S)-2-amino-4-methyl-1-pentanol (CAN 7533-40-6) as starting materials, MS (LC/MS): 362.2 [M+H]+.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH2:13]([S:17]([N:20]1[CH2:25][CH2:24][CH2:23][CH:22]([C:26]([OH:28])=O)[CH2:21]1)(=[O:19])=[O:18])[CH2:14][CH2:15][CH3:16].[CH:29]([O:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1)([CH3:31])[CH3:30]>N1C=CC=CC=1>[CH2:13]([S:17]([N:20]1[CH2:25][CH2:24][CH2:23][CH:22]([C:26]([NH:37][C:36]2[CH:35]=[CH:34][C:33]([O:32][CH:29]([CH3:31])[CH3:30])=[CH:39][CH:38]=2)=[O:28])[CH2:21]1)(=[O:18])=[O:19])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCS(=O)(=O)N1CCCC(C(=O)O)C1
Reactant: CC(C)Oc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: CCCCS(=O)(=O)N1CCCC(C(=O)Nc2ccc(OC(C)C)cc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 43 %

Procedure:
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (57.5 mg, 0.3 mmol) was added to a pyridine (5 mL) solution of the compound (50 mg, 0.2 mmol) synthesized in (1) and 4-isopropoxyaniline (0.061 mg, 0.4 mmol), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and, after addition of ethyl acetate, washed once with 1N-sodium hydroxide solution, and once with saturated brine. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was then purified using silica gel column chromatography to obtain the title compound (33 mg, 43%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[NH3:17]>>[N:6]1([CH2:5][C:4]2[CH:11]=[CH:12][C:13]([N+:14]([O-:16])=[O:15])=[C:2]([NH2:17])[CH:3]=2)[CH:10]=[CH:9][N:8]=[CH:7]1
Reactant: O=[N+]([O-])c1ccc(Cn2ccnc2)cc1F
Reactant: N
Product: Nc1cc(Cn2ccnc2)ccc1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
Potassium carbonate (1.18 g, 8.54 mmol) was added to a stirred solution of 4-(bromomethyl)-2-fluoro-1-nitrobenzene (2.0 g, 8.55 mmol) and imidazole (584 mg, 8.58 mmol) in acetonitrile (40 mL), the mixture stirred at room temperature for 3.5 h, the solvent removed under reduced pressure, and the residue partitioned between water and EA. The aqueous layer was extracted three times with EA, then the combined EA layers were extracted three times with 1M hydrochloric acid. The pH of the combined aqueous layers was adjusted to 8 with 5M aqueous sodium hydroxide, and the resulting milky solution was extracted three times with EA. The EA layers were combined, washed with brine, and dried over magnesium sulfate. Filtration and concentration gave 1-(3-fluoro-4-nitrobenzyl)-1H-imidazole (914 mg), which contained about 15% of a bis-alkylated imidazole byproduct. 1-(3-Fluoro-4-nitrobenzyl)-1H-imidazole (914 mg) was treated with an ethanolic ammonia solution (2M NH3, 55 mL) in a sealed tube heated to 80° C. for 2 days. After cooling, the solvent was removed to give 5-[(1H-imidazol-1-yl)methyl]-2-nitrobenzeneamine (1.0 g) as an orange solid. 5-[(1H-Imidazol-1-yl)methyl]-2-nitrobenzeneamine (1.0 g, 4.77 mmol) was dissolved in a 10% solution of dimethylformamide in ethanol (44 mL), and 10% palladium on carbon (130 mg, 0.12 mmol) was added. The solution was degassed and stirred under a hydrogen atmosphere using a balloon for 1 day. Following degassing, the solution was diluted with MeOH and filtered through diatomaceous earth, giving 4-[(1H-imidazol-1-yl)methyl]benzene-1,2-diamine (1.08 g) as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].C(N(CC)CC)C.[C:38]1(=[O:45])[O:44][C:42](=[O:43])[CH2:41][CH2:40][CH2:39]1>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([NH:30][C:38](=[O:45])[CH2:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43])=[CH:28][CH:29]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: O=C1CCCC(=O)O1
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(N)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(NC(=O)CCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.6 %

Procedure:
To a solution of 2-(4-aminobenzyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (139 mg) in tetrahydrofuran (5 ml) were added triethylamine (0.084 ml), glutaric anhydride (51 mg), and the mixture was stirred at room temperature for 24 hrs. The solvent was evaporated under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure and isopropyl ether was added to the obtained residue and the mixture was crystallized. The obtained crystals were collected by filtration and dried under reduced pressure at 50° C. to give the title compound (131 mg, 76%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[S:6][C:7]([Cl:10])=[CH:8][CH:9]=1)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15](/[CH:18]=[N:19]/[NH:20][C:21](=[NH:23])[NH2:22])=[CH:14][CH:13]=1>C(O)C>[Cl:11][C:12]1[CH:13]=[CH:14][C:15](/[CH:18]=[N:19]/[N:20]2[CH:2]=[C:3]([C:5]3[S:6][C:7]([Cl:10])=[CH:8][CH:9]=3)[N:22]=[C:21]2[NH2:23])=[CH:16][CH:17]=1
Reactant: N=C(N)N/N=C/c1ccc(Cl)cc1
Reactant: O=C(CBr)c1ccc(Cl)s1
Solvent: CCO
Product: Nc1nc(-c2ccc(Cl)s2)cn1/N=C/c1ccc(Cl)cc1
Reaction time: 10 h
Yield: 72 %

Procedure:
A solution of 2-bromo-1-(5-chloro-2-thienyl)-1-ethanone (1.07 g, 4.49 mmol), 2-[(E)-1- (4-chlorophenyl)methylidene]-1-hydrazinecarboximidamide (1.77 g, 8.98 mmol) was heated in ethanol (10 mL) for 2 h, then the mixture was left at room temperature for additional 10 h. The precipitate filtered, washed with hot water, and recrystallized from ethanol to give N1-[(E)-1-(4-chlorophenyl)methylidene]-4-(5-chloro-2-thienyl)-1H-1,2-imidazolediamine 2 (1.09 g, 72%) as a brown solid.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:10]2[CH:14]=[C:13]([C:15]([NH2:17])=[O:16])[C:12]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[N:11]2)[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)#[N:2].[C:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=O)[CH3:27].C(O)(=O)C.C([BH3-])#N.[Na+]>CO.CN(C=O)C>[C:1]([CH2:3][C:4]1([N:10]2[CH:14]=[C:13]([C:15]([NH2:17])=[O:16])[C:12]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)=[N:11]2)[CH2:9][CH2:8][N:7]([CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH3:27])[CH2:6][CH2:5]1)#[N:2]
Reactant: CC(=O)c1ccccc1
Reactant: N#CCC1(n2cc(C(N)=O)c(Nc3ccc(F)cc3)n2)CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CC(=O)O
Product: CC(c1ccccc1)N1CCC(CC#N)(n2cc(C(N)=O)c(Nc3ccc(F)cc3)n2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1-(4-(cyanomethyl)piperidin-4-yl)-3-((4-fluorophenyl)amino)-1H-pyrazole-4-carboxamide (Intermediate #38-5) (50 mg, 0.11 mmol) in MeOH (0.32 mL) and DMF (0.063 mL) was added acetophenone (41 mg, 0.34 mmol) and acetic acid (0.065 mL, 1.1 mmol). The reaction mixture was allowed to stir at room temperature for 15 minutes. Sodium cyanoborohydride (7 mg, 0.1 mmol) was added and the reaction mixture was allowed to stir for 24 hours at ambient temperature. The mixture was then purified directly by mass-triggered reverse-phase preparative HPLC (MeCN/water, with 0.1% v/v TFA modifier). Desired fractions were identified, combined, and concentrated in vacuo. The residue was dissolved in MeOH and passed through a Si-Carbonate cartridge to afford the title compound as a free base.
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:11])[CH2:6][O:7][CH:8]([OH:10])[CH3:9])([CH3:3])[CH3:2].[CH2:12]=O>[Pd].CO>[CH:1]([N:4]([CH:5]([CH3:11])[CH2:6][O:7][CH:8]([OH:10])[CH3:9])[CH3:12])([CH3:3])[CH3:2]
Reactant: C=O
Reactant: CC(C)NC(C)COC(C)O
Agent: [Pd]
Solvent: CO
Product: CC(O)OCC(C)N(C)C(C)C
Temperature: 80 °C
Yield: 94.4 %

Procedure:
A total of 155 g of 2-(isopropylamino) propoxyethanol, 122 g of 37% aqueous formaldehyde, 5 g of 10% Pd/C and 1 l of methanol were charged to an autoclave, pressured to 1000 psi with H2 and heated at 80° C. for 3 hours. Filtration and distillation of the reaction mixture yielded 159 g of 2-(N-isopropyl-N-methylamino)propoxyethanol with b.p. of 125° C. at 20 mm.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3](=[O:12])/[CH:4]=[CH:5]/[C:6]1[N:7]=[C:8]([CH3:11])[NH:9][CH:10]=1.[H][H].[ClH:16]>CO.[Pd]>[ClH:16].[CH3:13][N:2]([CH3:1])[C:3](=[O:12])[CH2:4][CH2:5][C:6]1[N:7]=[C:8]([CH3:11])[NH:9][CH:10]=1
Reactant: [H][H]
Reactant: Cc1nc(/C=C/C(=O)N(C)C)c[nH]1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1nc(CCC(=O)N(C)C)c[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of (E)-N,N-dimethyl-3-(2-methyl-1H-imidazol-4-yl)-2-propenamide (340 mg) in methanol (10 ml) and HCl-saturated ethanol (2 ml) was added to a previously hydrogen-saturated suspension of 10% palladium on charcoal (50% paste with water) (35 mg) in methanol (10 ml) and the resulting suspension stirred at room temperature under hydrogen for 4 h. The mixture was filtered, concentrated in vacuo to ca. 5 ml and ethyl acetate (ca. 40 ml) was added, precipitating the title compound (275 mg) as white flakes, t.l.c. (System A 89:10:1), Rf 0.14. Addition of further ethyl acetate (40 ml) to the mother liquors precipitated further title compound (31 mg).