Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[CH:14][CH:13]=[N:12][C:11]=2[NH:16][C@H:17]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(NC(=O)C2C=CC=NC=2NC2CC(C)(C)NC(C)(C)C2)C=CC=1.[CH2:51](Cl)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.BrCCO>>[CH2:51]([N:19]1[CH2:20][CH2:21][CH2:22][C@@H:17]([NH:16][C:11]2[N:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[O:23])[CH2:18]1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: O=C(Nc1cccc(Cl)c1)c1cccnc1N[C@H]1CCCNC1
Reactant: ClCc1ccccc1
Agent: CC1(C)CC(Nc2ncccc2C(=O)Nc2cccc(Cl)c2)CC(C)(C)N1
Agent: OCCBr
Product: O=C(Nc1cccc(Cl)c1)c1cccnc1N[C@@H]1CCCN(Cc2ccccc2)C1
Yield: 64.4 %

Procedure:
The title compound was prepared in the same manner as in Example 21, with the exception that (S)—N-(3-chlorophenyl)-2-(3-piperidylamino)nicotinamide of Example 20-A, instead of N-(3-chlorophenyl)-2-(2,2,6,6-tetramethylpiperidin-4-ylamino)nicotinamide, and benzylchloride, instead of 2-bromoethanol, were used in the same molar amounts (Yield: 64.4%). 1H NMR (CDCl3) δ 8.33 (d, 1H), 8.24 (d, 1H), 7.83 (s, 1H), 7.74 (s, 1H), 7.68 (d, 1H), 7.47-7.13 (m, 7H), 6.53-6.46 (m, 1H), 4.39-4.27 (m, 1H), 2.69 (d, 1H), 2.53-2.34 (m, 3H), 1.85-1.58 (m, 6H) ppm.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[CH:27]1([CH2:30][C:31](O)=[O:32])[CH2:29][CH2:28]1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:31](=[O:32])[CH2:30][CH:27]3[CH2:29][CH2:28]3)[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: O=C(O)CC1CC1
Agent: Cl
Product: O=C(CC1CC1)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, light yellow solid (74 mg, 73%), MS (ISP) m/z=409.4 [(M+H)+], mp 165° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 2-cyclopropyl-acetic acid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][O:6][NH:7][C:8](=[O:23])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.[C:27]([CH2:29][CH2:30][CH2:31][C:32]#[CH:33])#[N:28]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:27]([CH2:29][CH2:30][CH2:31][C:32]#[C:33][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][O:6][NH:7][C:8](=[O:23])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)#[N:28]
Reactant: O=C(NOCc1cccc(I)c1)c1ccccc1NCc1ccncc1
Reactant: C#CCCCC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Product: N#CCCCC#Cc1cccc(CONC(=O)c2ccccc2NCc2ccncc2)c1

Procedure:
The same procedure was used as described for the preparation of example 365, but without addition of tetrabutylammonium iodide. Starting materials: N-(3-Iodo-benzyloxy)-2-[(pyridin-4-ylmethyl)-amino]-benzamide (see example 361) and 5-cyano-1-pentyne (Aldrich).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[O:13][C:14](Br)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[O:13][C:14]([C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([C:19]([F:30])([F:29])[F:18])[CH:25]=3)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1ccc(Br)o1
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: O
Solvent: COCCOC
Product: O=C(N[C@H]1CN2CCC1CC2)c1ccc(-c2cccc(C(F)(F)F)c2)o1

Procedure:
Prepared by a method analogous to that described in Example 1 from (R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromofuran-2-carboxamide) and 3-trifluoromethylphenylboronic acid, using tetrakis(triphenylphosphine)palladium(0) and sodium carbonate in a mixture of 1,2-dimethoxyethane and water. The compound was purified by reverse phase HPLC on a Waters Bondapak® C18 column using a gradient of acetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent. The product-containing fractions were then evaporated and the residue dissolved in methanol. Excess hydrogen chloride solution (1M in diethyl ether) was added and the solution was evaporated. After drying under vacuum, the hydrochloride salt of the title compound was obtained as a colourless solid; MS (ES+) 365 (MH+).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]1[CH2:20][CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:18][C:17](=[O:27])[CH2:16][CH2:15]1.N1C=CC=CC=1.[Br:34]Br>C(Cl)Cl>[Br:34][CH:16]1[CH2:15][CH:14]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH3:7])[CH2:20][CH:19]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:18][C:17]1=[O:27]
Reactant: Cc1ccccc1C1CCC(=O)NC(c2ccccc2)C1
Reactant: BrBr
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccccc1C1CC(Br)C(=O)NC(c2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 46.5 %

Procedure:
To a 250 mL round-bottomed flask equipped with addition funnel and nitrogen inlet were added 3.5 grams (16.8 mol) phosphorus pentachloride and 25 mL dry methylene chloride. The mixture was cooled with stirring to 0° C., and a solution of 4.7 grams (16.8 mmol) 5-(2-methlphenyl)-7-phenyl-2,3,4,5,6,7-hexahydroazepin-2-one and 2.7 mL (33.6 mmol) pyridine in 50 mL methylene chloride was added drop wise over 20 minutes. The reaction was stirred 5 minutes at 0° C., then 1.9 mL (37.0 mmol) bromine in 5 mL methylene chloride was added drop wise over 5 minutes. The reaction was stirred 5 minutes at 0° C., then 1.8 hours at room temperature. The reaction was evaporated, taken up in 40 mL of 1:1 tetrahydrofuran: water, and stirred for 1.2 hours. The reaction was then poured into water and extracted into ethyl acetate. The organic layer was washed with aqueous sodium bisulfite solution and brine, dried over sodium sulfate, and evaporated to an oil. At this point, a little of the desired monobrominated product can be recovered by chromatography, as described below; the remainder, mostly dibromo adduct, is treated an follows. The oil was taken up in 20 mL methylene chloride and 20 mL ethanol, and hydrogenated under 42 p.s.i. hydrogen in the presence of 0.70 grams 10% palladium-on-carbon and 7 drops of quinoline for 1 hour. Tlc showed mostly desired monobromo product at Rf=0.5, with a little dibromo precursor at Rf=0.7 and starting lactam at Rf=0.15, in 1/1-ethyl acetate/hexane. The reaction was filtered through Celite with ethanol and methylene chloride, evaporated, and chromatographed on silica gel using 2/1-hexane/ethyl acetate as eluent to afford 2.8 grams (46%) of a foam, a mixture of diastereomers.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH:14]([CH:15]=O)[CH:13]2[CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10]3)[CH:5]=[CH:6][C:7]=1[Cl:8].C1(=O)NC(=O)C=C1.ClC1C=C(C=CC=1Cl)N.Cl.[NH2:41][OH:42].N1C=CC=CC=1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH:14]([CH:15]=[N:41][OH:42])[CH:13]2[CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10]3)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CC2C(C=O)C2(c2ccc(Cl)c(Cl)c2)C1
Reactant: NO
Agent: Cl
Agent: Nc1ccc(Cl)c(Cl)c1
Agent: O=C1C=CC(=O)N1
Solvent: CCO
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CC2C(C=NO)C2(c2ccc(Cl)c(Cl)c2)C1
Yield: 73 %

Procedure:
To a solution of tert-butyl 1-(3,4-dichlorophenyl)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (200 mg, 0.56 mmol, prepared from maleimide and 3,4-dichloroaniline according to the methods described in WO 2009141412 and WO 2008074716), in ethanol (10 mL) under nitrogen atmosphere were added hydroxylamine hydrochloride (78 mg, 1.12 mmol) and pyridine (0.23 mL, 2.86 mmol). The reaction mixture was refluxed for 5 h. After completion of the reaction as confirmed by TLC, the solvent was evaporated. The crude compound was extracted with ethyl acetate (70 mL). The organic layer was separated, washed with 5% HCl (5 mL), water (10 mL), dried over Na2SO4 and concentrated in vacuo to afford crude product which was purified by column chromatography (silica gel, 1:4 EtOAc:Pet Ether) to afford pure tert-butyl 1-(3,4-dichlorophenyl)-6-((hydroxyimino)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (152 mg, 73%) as a viscous oil as a mixture of isomers.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH3:54][C:55]1[O:59][N:58]=[CH:57][C:56]=1[C:60](Cl)=[O:61]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:48][CH2:49][N:50]([C:60]([C:56]2[CH:57]=[N:58][O:59][C:55]=2[CH3:54])=[O:61])[CH2:51][CH2:52]1
Reactant: Cc1oncc1C(=O)Cl
Reactant: Clc1cnc2nc1Nc1ccc(OCCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Solvent: O=C(O)C(F)(F)F
Product: Cc1oncc1C(=O)N1CCC(CCOc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 40 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using 6-chloro-12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and 5-methylisoxazole-4-carbonyl chloride as the starting materials in 40% yield. LCMS for C29H31ClN7O3 (M+H)+: m/z=560.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N:22]1[CH2:26][C@H:25]([OH:27])[C@@H:24]([OH:28])[CH2:23]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[N:29]1[CH:34]=[CH:33][CH:32]=[C:31](B(O)O)[CH:30]=1>>[OH:28][C@@H:24]1[C@@H:25]([OH:27])[CH2:26][N:22]([C:21]2[CH:20]=[CH:19][C:4]([C:5]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=3)=[O:6])=[CH:3][C:2]=2[C:31]2[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=2)[CH2:23]1
Reactant: OB(O)c1cccnc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2C[C@H](O)[C@@H](O)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2C[C@H](O)[C@@H](O)C2)c(-c2cccnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 7 using 3-bromo-4-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 7.1) and pyridin-3-ylboronic acid to afford a yellow solid. UPLC-MS (condition 1) tR=1.67 min, m/z=460.0 [M+H]+, m/z=458.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.73 (d, J=10.76 Hz, 2H) 3.24 (dd, J=10.51, 3.67 Hz, 2H) 3.85 (d, J=2.20 Hz, 2H) 5.03 (br. s, 2H) 6.92 (d, J=8.80 Hz, 1H) 7.33 (d, J=8.31 Hz, 2H) 7.48 (dd, J=7.46, 5.26 Hz, 1H) 7.76-7.83 (m, 2H) 7.83-7.89 (m, 2H) 7.91 (dd, J=8.80, 2.20 Hz, 1H) 8.55 (dd, J=4.77, 1.59 Hz, 1H) 8.62 (d, J=1.47 Hz, 1H) 10.10 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[CH:11]=[CH:10][N:9]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]=2[N:6]=[CH:7][N:8]=1.C([Li])CCC.[I:27]I>O1CCCC1.CCCCCC>[I:27][C:10]1[N:9]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:14])[C:5]2[N:6]=[CH:7][N:8]=[C:3]([O:2][CH3:1])[C:4]=2[CH:11]=1
Reactant: II
Reactant: COc1ncnc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ncnc2c1cc(I)n2S(=O)(=O)c1ccc(C)cc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
To a solution of 4-methoxy-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine [2.23 g, Reference Example 7] in tetrahydrofuran (35 mL) at −78° C. was added drop wise a solution of butyl lithium in hexane (5 mL, 1.6M) under inert atmosphere. The solution was stirred at −70° C. for 1 hour and iodine (2.05 g) was added. The reaction mixture was stirred at −70° C. for another 1 hour, allowed to reach room temperature and partitioned between ethyl acetate and aqueous sodium sulfite solution. The organic phase was separated, then dried over magnesium sulfate and then evaporated under reduced pressure to give the title compound (2.64 g) as an amorphous solid. MS: 430 [MH]+. LCMS (Method B) RT=4.15 minutes.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]2[C:14]([CH2:19][OH:20])=[N:15][C:16]([Cl:18])=[CH:17][C:12]=2[N:11]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:49](Cl)([CH3:51])=[O:50]>C(Cl)Cl>[C:49]([O:20][CH2:19][C:14]1[C:13]2[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:10][N:11]([C:21]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:12]=2[CH:17]=[C:16]([Cl:18])[N:15]=1)(=[O:50])[CH3:51]
Reactant: CC(=O)Cl
Reactant: OCc1nc(Cl)cc2c1c(OCc1ccccc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OCc1nc(Cl)cc2c1c(OCc1ccccc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of (3-(benzyloxy)-6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)methanol (2.443 g, 4.59 mmol) and DIPEA (3.0 ml, 17.18 mmol) in DCM (25 ml) was charged with AcCl (0.70 ml, 9.84 mmol). Stirred at RT for 45 min. Diluted with DCM, washed organics with 2N HCl, dried over MgSO4, filtered, concentrated in vacuo and obtained (3-(benzyloxy)-6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)methyl. MS: [M+H]+ m/z 574.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([CH:20]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]3)=[O:19])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]([CH:20]3[CH2:24][CH2:23][NH:22][CH2:21]3)=[O:19])[CH2:16][CH2:17]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C(=O)C2CCNC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of tert-butyl 3-[(4-{[(3,4-dichlorophenyl)amino]carbonyl}piperazin-1-yl)carbonyl]pyrrolidine-1-carboxylate (3.485 g, 7.39 mmol) in DCM (30 ml) was added TFA (30 ml). The reaction was allowed to stir at ambient temperature for 1 hour. The solvents were then removed in vacuo, residue partitioned between DCM and 2M NaOH, extracted twice and the combined organics dried (Na2SO4), filtered and evaporated to dryness to give the product, N-(3,4-dichlorophenyl)-4-(pyrrolidin-3-ylcarbonyl)piperazine-1-carboxamide, as a pale yellow foam (2.745 g, 7.39 mmol, 100%).
Reaction SMILES: [NH2:1][C@H:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=2[F:19])=[C:7]([CH3:20])[N:6]([CH2:21][C:22]2[C:27]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:25]=[CH:24][C:23]=2[F:32])[C:5]1=[O:33].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:47][CH2:48][CH2:49][N:50]1[C:54](=[O:55])[C:53]2=[CH:56][CH:57]=[CH:58][CH:59]=[C:52]2[C:51]1=[O:60].C(OCC)(=O)C>CN(C=O)C>[C:51]1(=[O:60])[N:50]([CH2:49][CH2:48][CH2:47][NH:1][C@H:2]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:3][N:4]2[C:9](=[O:10])[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=3[F:19])=[C:7]([CH3:20])[N:6]([CH2:21][C:22]3[C:27]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:25]=[CH:24][C:23]=3[F:32])[C:5]2=[O:33])[C:54](=[O:55])[C:53]2=[CH:56][CH:57]=[CH:58][CH:59]=[C:52]12
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: COc1cccc(-c2c(C)n(Cc3c(F)cccc3S(C)(=O)=O)c(=O)n(C[C@H](N)c3ccccc3)c2=O)c1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cccc(-c2c(C)n(Cc3c(F)cccc3S(C)(=O)=O)c(=O)n(C[C@H](NCCCN3C(=O)c4ccccc4C3=O)c3ccccc3)c2=O)c1F
Temperature: 80 °C
Yield: 68.1 %

Procedure:
To a solution of compound 6d (4.0 g, 7.2 mmol) in anhydrous DMF (8 mL) was added sodium carbonate (0.76 g, 7.2 mmmol) and N-(3-bromopropyl)phthalimide (2.4 g, 9.0 mmmol). The reaction mixture was heated to 80° C. under nitrogen for 4 hr. The reaction mixture was cooled and partitioned between dichloromethane and water. The organic layer was washed with saturated aqueous sodium bicarbonate solution and brine, dried with sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane, 50% ethyl acetate in hexane and then ethyl acetate to yield 6e as a pale yellow solid (3.6 g, 4.9 mmol, 67%). MS (CI) m/z 743.1 (M+H+), tR=2.539 min. (method 4). 1H NMR (CDCl3): δ 1.62–1.70 (m, 2H), 2.26 (s, 1.5H), 2.27 (s, 1.5H), 2.29–2.33 (m, 1H), 2.40–2.48 (m, 1H), 3.51 (s, 1.5H), 3.52 (s, 1.5H), 3.54–3.74 (m, 2H), 3.90 (s, 1.5H), 3.91 (s, 1.5H), 3.93–4.26 (m, 3H), 5.60 (brs, 2H), 6.80–6.89 (m, 1H), 6.99 (dd, 1H), 7.11–7.36 (m, 8H), 7.42–7.49 (m, 1H), 7.71–7.75 (m, 2H), 7.84–7.89 (m, 1H), 7.95 (d, J=8.4 Hz, 1H).
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]1[CH:10]=[C:9]([CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:8]=[CH:7][N:6]=1)=O.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:17][O:16][C:14]([CH2:13][CH2:12][CH2:11][C:9]1[CH:8]=[CH:7][N:6]2[CH:1]=[N:3][CH:4]=[C:5]2[CH:10]=1)=[O:15]
Reactant: COC(=O)CCCc1ccnc(CNC=O)c1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)CCCc1ccn2cncc2c1

Procedure:
2-(N-formylaminomethyl)-4-(3-methoxycarbonylpropyl)pyridine (33 mg) is dissolved in 1 ml of toluene and heated at 90° with phosphorus oxychloride (44 mg) for 18 hours under nitrogen. The solvent is evaporated and the residue is suspended in methylene chloride, cooled to 0° and made basic with saturated ammonium hydroxide solution. The aqueous phase is extracted with methylene chloride (4×15 ml) which is dried over sodium sulfate and evaporated to yield 7-(3-methoxycarbonylpropyl)imidazo[1,5-a]pyridine as an oil, after purification by preparative thin layer chromatography (silica gel, 3:1 ethyl acetatemethanol); NMR (CDCl3) 3.70 (s, 3 1 H), 6.45 (q, 1 H), 7.2 (s, 1 H), 7.32 (s, 1 H), 7.90 (d, l H), 8.08 (s, 1 H); IR (CH2Cl2) 1730 cm-1.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[CH3:11].[CH2:12]([CH:14]([C:17]1[C:18]2[N:19]([C:24](I)=[C:25]([CH3:27])[N:26]=2)[N:20]=[C:21]([CH3:23])[CH:22]=1)[CH2:15][CH3:16])[CH3:13]>C1COCC1.[Zn]>[CH2:12]([CH:14]([C:17]1[C:18]2[N:19]([C:24]([C:2]3[C:10]4[C:5](=[N:6][CH:7]=[CH:8][CH:9]=4)[S:4][C:3]=3[CH3:11])=[C:25]([CH3:27])[N:26]=2)[N:20]=[C:21]([CH3:23])[CH:22]=1)[CH2:15][CH3:16])[CH3:13]
Reactant: Cc1sc2ncccc2c1Br
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Agent: [Zn]
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3c(C)sc4ncccc34)c(C)nc12
Temperature: 100 °C
Yield: 10.4 %

Procedure:
382 mg of 3-Bromo-2-methyl-thieno[2,3-b]pyridine (1.67 mmol) is placed into the vial with 2.5 ml of Reiki Zn, suspension in THF (1.75 mmol) and capped and heated at 100° C. for 2 h. The excess Zinc is allowed to settle down and the solution is transferred to the vial containing 200 mg of 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.58 mmol) and 41 mg of PdCl2(pddf) (0.05 mmol) in 3 ml of dry THF. The vial is capped with a Teflon cap and heated at 80° C. for 2 days. The reaction mixture is quenched with sat. NH4Cl and extracted by CH2Cl2, dried over Na2SO4 and evaporated. The crude product is applied onto a silica-gel chromatography column (Hexane:AcOEt=8:1) to give 22 mg of the title compound. Yield 4%. mass spectrum (m/e): 365 (M+1).
Reaction SMILES: Br.Br[CH2:3][C:4]1[N:5]=[C:6]2[C:11](=[N:12][CH:13]=1)[N:10]=[C:9]([NH2:14])[N:8]=[C:7]2[NH2:15].[OH:16][C:17]1[CH:18]=[C:19]([CH2:24][CH2:25][NH2:26])[CH:20]=[CH:21][C:22]=1[OH:23].C(N(C(C)C)C(C)C)C.C(=O)(O)[O-]>CN(C)C(=O)C>[OH:16][C:17]1[CH:18]=[C:19]([CH2:24][CH2:25][NH:26][CH2:3][C:4]2[N:5]=[C:6]3[C:11](=[N:12][CH:13]=2)[N:10]=[C:9]([NH2:14])[N:8]=[C:7]3[NH2:15])[CH:20]=[CH:21][C:22]=1[OH:23]
Reactant: NCCc1ccc(O)c(O)c1
Reactant: Nc1nc(N)c2nc(CBr)cnc2n1
Agent: Br
Agent: O=C([O-])O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(N)c2nc(CNCCc3ccc(O)c(O)c3)cnc2n1
Temperature: 50 °C
Reaction time: 4 h
Yield: 22.6 %

Procedure:
To a solution of 6-bromomethyl-2,4-pteridinediamine hydrobromide (67.3 mg, 0.2003 mmol) in anhydrous N,N dimethylacetamide was added 2-(3,4-dihydroxyphenyl) ethylamine (43.6 mg, 0.23 mmol). Under positive pressure of Argon, iPr2EtN (32.63 ul) was added. The reaction mixture was stirred at 50° C. for 4 hrs and then at Room temperature overnight. The crude product was poured into saturated bicarbonate solution. The resulted precipitate was collected and purified by preparative HPLC. 14.8 mg product was obtained. Yield: 22.6%; 1H NMR (500 MHz, DMSO-d6): δ 2.69242 (b, 4H), 4.03353 (s, 2H), 6.37542–6.39065 (d, J=7.615 Hz, 1H), 6.4851(s, 1H), 6.56632–6.58226 (d, J=7.97 Hz, 1H), 8.80972 (s, 1H); ESI-MS: m/z 328 (M++1)
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([N:10]=[C:11]=[O:12])[CH:6]=[CH:7][C:8]=1[Cl:9].[NH2:15][C:16]([CH3:20])([CH3:19])[C:17]#[N:18]>>[F:14][C:2]([F:13])([F:1])[C:3]1[CH:4]=[C:5]([N:10]2[C:17](=[NH:18])[C:16]([CH3:20])([CH3:19])[NH:15][C:11]2=[O:12])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: CC(C)(N)C#N
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Product: CC1(C)NC(=O)N(c2ccc(Cl)c(C(F)(F)F)c2)C1=N

Procedure:
14.5 g. of 3-trifluoromethyl-4-chlorophenyl-isocyanate and 5.5 g. of α-aminoisobutyronitrile are kept at 100° for 20 minutes. For purification, the viscous oil obtained is chromatographed on 500 g. of silica gel (particle size about 0.06-0.2 mm) using methylene chloride/methanol. The product obtained is crystallized from methylene chloride/petroleum ether. After drying under greatly reduced pressure at 50° for 15 hours, 1-(3-trifluoromethyl-4-chlorophenyl)-5-imino-4,4-dimethyl-2-imidazolidinone, which melts at 148°-149°, is obtained.