Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[N:20]=[N:19]3)=[CH:14][CH:13]=2)=[N:4][CH:3]=1.[NH2:29][C:30]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)=[O:31]>CN(C=O)C.O1CCOCC1.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:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:21]1[N:20]=[N:19][N:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:5]3[C:6]4[N:7]([CH:8]=[CH:9][N:10]=4)[C:2]([C:35]4[CH:36]=[CH:37][C:32]([C:30]([NH2:29])=[O:31])=[CH:33][CH:34]=4)=[CH:3][N:4]=3)=[CH:13][CH:14]=2)[CH:22]=1
Reactant: Brc1cnc(Nc2ccc(-n3cc(-c4ccccn4)nn3)cc2)c2nccn12
Reactant: NC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(-c2cnc(Nc3ccc(-n4cc(-c5ccccn5)nn4)cc3)c3nccn23)cc1

Procedure:
In the same way as described for Compound 178, step 4, using (5-bromo-imidazo[1,2-a]pyrazin-8-yl)-[4-(4-pyridin-2-yl-[1,2,3]triazol-1-yl)-phenyl]-amine (40 mg, 0.0923 mmol), 4-(aminocarbonyl)phenylboronic acid (30.5 mg, 0.185 mmol) 1.5 M Na2CO3 (0.492 mL, 0.738 mmol), and Pd(PPh3)4 (26.7 mg, 0.023 mmol) in (2:1) DMF-dioxane (1.5 mL). The crude material is purified by Isolute FlashSilicaII Cartridge chromatography eluting with 98:2 DCM:NH3 (7M in MeOH) followed by 97:3 DCM:NH3 (7M in MeOH). The title compound is obtained as a white solid (23.5 mg, 54%). LCMS: Rt 2.67 min (95%) m/z (ES+) 474 (M+H)+; 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 7.41-7.47 (1H, d), 7.53 (1H, d), 7.66 (1H, br s), 7.81 (1H, s), 7.84-7.90 (2H, d), 7.96-8.07 (3H, m), 8.08-8.20 (5H, m), 8.36-8.44 (2H, d), 8.70 (1H, d), 9.30 (1H, s), 10.15 (1H, s).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[CH:23][N:22]=[N:21]4)[O:16][C:15]3=[O:25])=[CH:10][C:9]=2[F:26])=[CH:4][CH2:3]1.[CH2:27]([S:29](Cl)(=[O:31])=[O:30])[CH3:28]>>[CH2:27]([S:29]([N:2]1[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[CH:23][N:22]=[N:21]4)[O:16][C:15]3=[O:25])=[CH:10][C:9]=2[F:26])=[CH:4][CH2:3]1)(=[O:31])=[O:30])[CH3:28]
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(C2=CCNCC2)c(F)c1
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Product: CCS(=O)(=O)N1CC=C(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)CC1

Procedure:
(5R)-3-(4-(1,2,5,6-Tetrahydropyridin-4-yl)-3-fluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)-oxazolidin-2-one hydrochloride (380 mg, 1 mM) was), was treated with ethanesulfonyl chloride essentially as in Example 77 to give the desired product (21 mg) after chromatography. MS (ESP): 436 (MH+) for C19H22FN5O4S
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[C:10](Cl)[C:11]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13][C:12]=2[N:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:32][N:33]1[CH:37]=[C:36]([CH2:38][NH2:39])[CH:35]=[N:34]1>CN(C)C(=O)C>[CH2:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][C:11]2[C:10]([NH:39][CH2:38][C:36]3[CH:35]=[N:34][N:33]([CH3:32])[CH:37]=3)=[N:9][C:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:23][C:12]=2[CH2:13][CH2:14]1)=[O:19])[CH3:22]
Reactant: Cn1cc(CN)cn1
Reactant: CCOC(=O)N1CCc2nc(Cc3ccccc3)nc(Cl)c2CC1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCc2nc(Cc3ccccc3)nc(NCc3cnn(C)c3)c2CC1

Procedure:
A solution of ethyl 2-benzyl-4-chloro-5,6,8,9-tetrahydro-pyrimido[4,5-d]azepine-7-carboxylate of Step B (50 mg, 0.14 mmol), triethylamine (0.10 ml, 0.72 mmol) and C-(1-Methyl-1H-pyrazol-4-yl)-methylamine (50 mg, 0.45 mmol) in N,N-dimethylacetamide (2.0 ml) was stirred for 18 h at 60° C. The solvent was removed in vacuo and the crude product was deprotected without further purification. LRMS APCI m/z 421 [MH]+.
Reaction SMILES: [CH2:1]([C:3]1([CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([CH2:22]O)[C:17]=2[CH3:24])[O:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][O:4]1)[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[SH:37][C:38]1[NH:39][C:40]2[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=2[N:42]=1>C1COCC1>[CH2:1]([C:3]1([CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([CH2:22][S:37][C:38]3[NH:42][C:41]4[CH:43]=[CH:44][CH:45]=[CH:46][C:40]=4[N:39]=3)[C:17]=2[CH3:24])[O:12][CH2:11][C:6]2([O:7][CH2:8][CH2:9][O:10]2)[CH2:5][O:4]1)[CH3:2]
Reactant: CCC1(CCOc2ccnc(CO)c2C)OCC2(CO1)OCCO2
Reactant: Sc1nc2ccccc2[nH]1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC1(CCOc2ccnc(CSc3nc4ccccc4[nH]3)c2C)OCC2(CO1)OCCO2
Reaction time: 0.5 h
Yield: 52.7 %

Procedure:
To a THF (10 ml) solution of the (4-(2-(8-ethyl-1,4,7,9-tetraoxaspiro[4.5]dec-8-yl)ethoxy)-3-methylpyridin-2-yl)methanol (560 mg, 1.65 mmol) obtained in the step (4g), triethylamine (0.48 ml, 3.44 mmol) was added at room temperature and thereafter, methanesulfonyl chloride (0.19 ml, 2.45 mmol) was added while cooling in an ice salt bath and stirred under the same conditions for 30 minutes. After the ice salt bath was removed, 2-mercaptobenzimidazole (248 mg, 1.65 mmol) was added and stirred at room temperature for 22 hours. After the reaction mixture was concentrated, NH silica gel was added to the residue and dried. The crude substance was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate=1/0, 1/1-0/1 gradient) and a desired fraction(s) was concentrated. The obtained foamy product was dissolved in chloroform and diethyl ether was added thereto. The resulting solid was collected by filtration to obtain the title compound (410 mg, yield: 52.7%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[C@@H:4]2[O:14][C@H:3]12.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][NH:23][C:22](=[O:25])[C:21]=2[CH:26]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][N:23]=[C:22]([O:25][C@@H:4]3[C:5]4[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=4)[O:11][C:2]([CH3:1])([CH3:15])[C@H:3]3[OH:14])[C:21]=2[CH:26]=1
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H]2O[C@@H]21
Reactant: O=c1[nH]oc2ccc(Cl)cc12
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](Oc2noc3ccc(Cl)cc23)[C@@H]1O

Procedure:
Following the procedure in Example 1, using (S,S)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and 5-chloro-benzo[d]isoxazol-3-one (prepared by literature known method) as starting materials, the title compound was prepared as a white solid.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([OH:15])=O)=[N:5]1)([CH3:3])[CH3:2].[NH2:16][C@H:17]1[CH2:22][N:21]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@H:20]([CH2:30][CH2:31][OH:32])[CH2:19][CH2:18]1.C(N(CC)C(C)C)(C)C.C(P(=O)(OCC)OCC)#N>CN(C)C=O>[CH2:23]([N:21]1[C@H:20]([CH2:30][CH2:31][OH:32])[CH2:19][CH2:18][C@H:17]([NH:16][C:13]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=2)=[O:15])[CH2:22]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)n1nc(C(=O)O)c2ccccc21
Reactant: N[C@@H]1CC[C@H](CCO)N(Cc2ccccc2)C1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1nc(C(=O)N[C@H]2CC[C@@H](CCO)N(Cc3ccccc3)C2)c2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 57.1 %

Procedure:
To a stirred solution of 1-isopropyl-1H-indazole-3-carboxylic acid (235 mg, 1.15 mmol), 2-[cis-5-amino-1-benzylpiperidin-2-yl]ethanol (322 mg, 1.37 mmol, step 8 of Example 1), N,N-diisopropylethylamine (177 mg, 1.37 mmol) in N,N-dimethylformamide (3 mL) was added diethyl cyanophosphonate (223 mg, 1.37 mmol) at room temperature. After stirring at room temperature for 20 h, the mixture was concentrated under reduced pressure. The resulting residue was chromatographed on a column of silica gel eluting with dichloromethane/methanol/25% ammonium hydroxide (10:1:0.2) to give 276 mg (52%) of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][CH:2]([C:4]1([CH2:8][NH2:9])[CH2:7][CH2:6][CH2:5]1)C.CO.C(N(CC)CC)C.C[O:20][C:21](=O)[C@H:22]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH2:23]>N>[NH2:23][CH:22]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:21]([NH:9][CH2:8][C:4]1([CH2:2][NH2:1])[CH2:5][CH2:6][CH2:7]1)=[O:20]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(N)C1(CN)CCC1
Agent: N
Solvent: CO
Solvent: CCN(CC)CC
Product: NCC1(CNC(=O)C(N)Cc2ccccc2)CCC1
Yield: 38.7 %

Procedure:
3.6 g (31.5 mmol) of 1 was mixed with 100 mL of methanol, followed by adding triethyl amine to adjust pH to 9-10 to obtain a first reaction solution. 5.1 g (28.7 mmol) of 2 was mixed with 100 mL of methanol to obtain a second reaction solution. The second reaction solution was added dropwisely into the first reaction solution to obtain a reaction mixture. The reaction mixture was subjected to reflux reaction at 60-70° C. for 19 hours, followed by evaporation to obtain a crude product. The crude product was dissolved in ammonia, followed by extracting with chloroform and water and evaporating to obtain a product of 2.9 g (11.1 mmol, 38.6%) of a light-yellow oil 3. The analytic data of the product are as follows: 1H-NMR (D2O, 400 MHz), δ(ppm): 7.29-7.15 (m, 5H, Ar), 3.57 (t, 1H, J=3, H2NCH), 3.20-2.95 (m, 2H, NHCH2), 2.89-2.76 (m, 2H, CH2Ar), 2.21-2.05 (m, CH2NH2), 1.69-1.66 (m, 2H, CH2CH2CH2), 1.52-1.45 (m, 4H, CH2CH2CH2); 13C-NMR (D2O, 100 MHz), δ(ppm): 176.88, 137.37, 129.38, 128.90, 127.11, 56.60, 45.82, 43.99, 42.36, 40.90, 26.59, 26.51, 14.27; ESI-MS (m/z): calcd. 261.36, found 262.18 [M+H]+; Anal. Calcd (Found) for C15H23N3O.HCl: C, 60.94 (60.49); H, 8.43 (8.12); N, 14.53 (14.11).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([C:15]#[N:16])[CH:11]=3)[C:6]=2[C:5](=[O:17])[C:4]2[CH:18]=[CH:19][C:20]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:21][C:3]1=2.[N:29]1([S:34](N2C=C[N+](C)=C2)(=[O:36])=[O:35])[CH:33]=[CH:32][N:31]=[CH:30]1>>[N:29]1([S:34]([N:25]2[CH2:26][CH2:27][CH:22]([C:20]3[CH:19]=[CH:18][C:4]4[C:5](=[O:17])[C:6]5[C:7]6[C:12](=[CH:11][C:10]([C:15]#[N:16])=[CH:9][CH:8]=6)[NH:13][C:14]=5[C:2]([CH3:28])([CH3:1])[C:3]=4[CH:21]=3)[CH2:23][CH2:24]2)(=[O:36])=[O:35])[CH:33]=[CH:32][N:31]=[CH:30]1
Reactant: CC1(C)c2cc(C3CCNCC3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: C[n+]1ccn(S(=O)(=O)n2ccnc2)c1
Product: CC1(C)c2cc(C3CCN(S(=O)(=O)n4ccnc4)CC3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Yield: 22.2 %

Procedure:
According to the method disclosed in Journal of Organic Chemistry, 2003, page 115, 6,6-dimethyl-11-oxo-8-piperidin-4-yl-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound B3-13-2, 10 mg, 0.027 mmol) was reacted with 3-(imidazole-1-sulfonyl)-1-methyl-3H-imidazol-1-ium (19 mg, 2 eq.). After removing the solvent, the residues were purified by liquid chromatography to obtain the title compound (3 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])[N:5]=[C:4]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])[N:3]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C(N1CCOCC1)C>[CH3:15][C:14]([NH:13][C:4]1[N:5]=[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:7]=[C:2]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[N:3]=1)([CH3:17])[CH3:16]
Reactant: CC(C)(C)Nc1cc(Cl)nc(NC(C)(C)C)n1
Reactant: C1CNCCN1
Agent: CCN1CCOCC1
Product: CC(C)(C)Nc1cc(N2CCNCC2)nc(NC(C)(C)C)n1
Reaction time: 25 h
Yield: 64 %

Procedure:
A mixture containing 9.58 g (34.7 mmoles) of 4-chloro-2,6-bis(1,1-dimethylethylamino)pyrimidine, 11.95 g (138.8 mmoles) of piperazine and 150 ml of N-ethylmorpholine is boiled under reflux and nitrogen atmosphere for 25 hours, then the solvent and the excess of piperazine are distilled off under atmospheric pressure. Subsequently, 100 ml of water are added to the residue and the distillation is continued until the head temperature reaches 100° C. After cooling down, the residue is distributed between 200 ml of chloroform and 30 ml of 10% sodium hydroxide solution. After separation the organic phase is washed 4 times with 50 ml of water each, then dried and evaporated. The residue is purified by chromatography on a silica gel column by using a 9:1 mixture of chloroform/methanol as eluent. After evaporating the eluate the residue is recrystallized from hexane to obtain the title compound in a yield of 64%, m.p.: 142°-145° C.
Reaction SMILES: [ClH:1].[C:2]1([C:8](=O)[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=O)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:18]([NH2:22])([NH2:21])(=[O:20])=[O:19]>CO>[ClH:1].[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:9]2[C:8]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:22][S:18](=[O:20])(=[O:19])[N:21]=2)[CH:12]=1
Reactant: NS(N)(=O)=O
Reactant: O=C(C(=O)c1cccnc1)c1ccccc1
Agent: Cl
Solvent: CO
Product: O=S1(=O)N=C(c2ccccc2)C(c2cccnc2)=N1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
Hydrogen chloride gas is bubbled into a solution of 1-phenyl-2-(pyridin-3-yl)ethan-1,2-dione (1.63 g, 7.7 mmol, J. Org. Chem., 1999, 64, 6102) and sulfamide (750 mg, 7.7 mmol) in methanol (10 mL) until the solution begins to reflux. The gas flow is turned off, and the solution stirred at 65° C. for 3 h then cooled to rt. The solid that formed is filtered and dried to give 2.06 g of the product 497. MS: m/z 272 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[C:10]([N+:16]([O-])=O)[CH:9]=2)=[CH:4][CH:3]=1.O.[Cl-].[NH4+]>CO.[Zn]>[NH2:16][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:13]=[CH:12][C:11]=1[CH2:14][CH3:15]
Reactant: CCc1ccc(-c2ccc(Cl)cc2)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1N
Temperature: 25 °C
Yield: 75.3 %

Procedure:
4-(4-chlorophenyl)-1-ethyl-2-nitrobenzene (22.6 g, 86 mmol) is suspended in methanol (250 ml) and the reaction mixture is stirred at room temperature. Water (100 ml) is added, followed by zinc dust (39.0 g, 0.60 mol) and ammonium chloride (13.8 g, 0.26 mol) and the mixture is heated to reflux for 1 hour. The reaction mixture is cooled to room temperature, filtered through diatomaceous earth and the filtrate is evaporated under reduced pressure to remove most of the methanol. The residue is partitioned between ethyl acetate and water and the aqueous phase is re-extracted with ethyl acetate. The organic extracts are combined, washed with water and brine, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure to give 3-amino-4′-chloro-4-ethylbiphenyl (15.0 g) as a colourless solid. The product is used directly without further purification in Step 5.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[C:10]([CH:21]=[C:22]([O:24][CH:25]([CH3:27])[CH3:26])[CH:23]=1)[C:11]([NH:13][C:14]1[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=1)=[O:12].[N:28]1([C:32]([C:34]2[CH:39]=[CH:38][C:37](Br)=[CH:36][N:35]=2)=[O:33])[CH2:31][CH2:30][CH2:29]1>CC(N(C)C)=O>[N:28]1([C:32]([C:34]2[N:35]=[CH:36][C:37]([O:7][C:8]3[CH:9]=[C:10]([CH:21]=[C:22]([O:24][CH:25]([CH3:27])[CH3:26])[CH:23]=3)[C:11]([NH:13][C:14]3[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=3)=[O:12])=[CH:38][CH:39]=2)=[O:33])[CH2:31][CH2:30][CH2:29]1
Reactant: O=C(c1ccc(Br)cn1)N1CCC1
Reactant: Cc1cnc(NC(=O)c2cc(O)cc(OC(C)C)c2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)nc3)cc(OC(C)C)c2)cn1
Temperature: 160 °C
Yield: 32.2 %

Procedure:
Cesium carbonate (489 mg, 1.5 mmol) was added to a solution of 3-hydroxy-5-[(1-methylethyl)oxy]-N-(5-methylpyrazin-2-yl)benzamide (144 mg, 0.5 mmol) and 2-(azetidin-1-ylcarbonyl)-5-bromopyridine (181 mg, 0.75 mmol) and bromotris(triphenylphosphine)copper (93 mg, 0.1 mmol) in DMA (5 mL) and the stirred mixture heated at 160° C. in a microwave reactor for 4 hours. The mixture was cooled to RT and ambient pressure, partitioned between water (75 mL) and ethyl acetate (50 mL), the organic layer washed with brine, dried (MgSO4) and evaporated in vacuo. The residue was chromatographed on silica, eluting with 75% ethyl acetate in isohexane, to give the desired compound (crystallised from ether) (72 mg). 1H NMR δ (CDCl3): 1.3 (d, 6H), 2.3 (m, 2H), 2.5 (s, 3H), 4.2 (t, 2H), 4.5 (m, 1H), 4.65 (t, 2H), 6.7 (s, 1H), 7.05 (s, 1H), 7.2 (s, 1H), 7.3 (d, 1H), 8.0 (br, 2H), 8.3 (br, 2H) and 9.45 (s, 1H). m/z 448 (M+H)+. Mpt (melting onset) 125.7° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.[CH2:10]([CH2:12][NH2:13])[OH:11].CO>C(OCC)(=O)C>[NH2:9][C:4]1[N:5]=[C:6]([CH3:8])[N:7]=[C:2]([NH:13][CH2:12][CH2:10][OH:11])[CH:3]=1
Reactant: NCCO
Reactant: Cc1nc(N)cc(Cl)n1
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1nc(N)cc(NCCO)n1
Temperature: 250 °C
Yield: 39.7 %

Procedure:
A mixture of 6-chloro-2-methylpyrimidin-4-ylamine (717 mg, 5.0 mmol) and ethanolamine (0.602 mL, 10.0 mmol) were heated at 250° C. in a microwave for 30 seconds. After cooling, the residue was dissolved in ethyl acetate, containing a small amount of methanol and was washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a white solid (334 mg, 40% yield). 1H NMR (400 MHz, DMSO-d6): δ 6.45 (br s, 1H), 5.98 (br s, 2H), 5.25 (s, 1H), 3.47 (t, J=6.0 Hz, 2H), 3.23-3.14 (m, 2H), 2.12 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([OH:14])=O)[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.C([N:17](CC)CC)C.COC(Cl)=O.O>CC(C)=O.CC1C=CC(CCN)=CC=1>[N:8]1[C:9]2[C:4](=[CH:3][CH:2]=[CH:11][C:10]=2[C:12]([NH2:17])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cc(Cl)cc2cccnc12
Agent: COC(=O)Cl
Agent: Cc1ccc(CCN)cc1
Solvent: O
Solvent: CC(C)=O
Product: NC(=O)c1cccc2cccnc12

Procedure:
5.2 g of 6-chloro-quinoline-8-carboxylic acid in 150 ml of acetone were combined, while stirring and cooling with ice, with 2.8 g of triethylamine and 2.6 g of chloroformic acid methyl ester. The whole was stirred for about 10 minutes, a solution of 3.4 g of 2-(4-methylphenyl)-ethylamine in 50 ml of 2-(4-methylphenyl)-ethyl-amine in 50 ml of acetone was added and the mixture was again stirred for 1 hour at room temperature. Then, water was added, the precipitate was filtered off with suction, treated with a dilute ammonia solution, undissolved matter was filtered off and recrystallized from dilute methanol. The 6-chloro-N-(2-<4-methylphenyl>-ethyl)-quinoline-8-carboxylic acid amide so obtained was found to melt at 102°-104° C.
Reaction SMILES: Cl.[F:2][CH2:3][C:4]([C:8]1[CH:9]=[C:10]([NH:20][C:21]([NH:23][C:24]2[C:25]([CH3:36])=[N:26][C:27]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:28][CH:29]=2)=[O:22])[N:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:12]=1)([CH2:6][F:7])[CH3:5].[F:37][C:38]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[C:39]=1[C:40](Cl)=[O:41].C(N(CC)CC)C>C(Cl)Cl>[F:37][C:38]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[C:39]=1[C:40]([N:33]1[CH2:32][CH2:31][N:30]([C:27]2[N:26]=[C:25]([CH3:36])[C:24]([NH:23][C:21]([NH:20][C:10]3[N:11]([C:13]4[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=4)[N:12]=[C:8]([C:4]([CH2:6][F:7])([CH3:5])[CH2:3][F:2])[CH:9]=3)=[O:22])=[CH:29][CH:28]=2)[CH2:35][CH2:34]1)=[O:41]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Cc1ccc(-n2nc(C(C)(CF)CF)cc2NC(=O)Nc2ccc(N3CCNCC3)nc2C)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C(C)(CF)CF)cc2NC(=O)Nc2ccc(N3CCN(C(=O)c4c(F)cccc4F)CC3)nc2C)cc1

Procedure:
Stir 1-[5-(2-Fluoro-1-fluoromethyl-1-methyl-ethyl)-2-p-tolyl-2H-pyrazol-3-yl]-3-(2-methyl-6-piperazin-1-yl-pyridin-3-yl)-urea hydrochloride (0.85 mmol, 0.5 g), 2,6-difluorobenzoyl chloride (0.85 mmol, 0.1 mL) and triethylamine (2.6 mmol, 0.4 mL) in 5 mL of CH2Cl2 at room temperature overnight. Add water and extract in CH2Cl2. Wash organic layer with saturated aq. sodium chloride solution. Dry over anhydrous sodium sulfate and concentrate under reduced pressure. Subject residue to silica gel chromatography eluting with using hexanes/ethyl acetate (20%-70%). MS(ES): m/z=624 [M+H].
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:12]2[C:7](=[CH:8][C:9]([Cl:14])=[CH:10][C:11]=2[Cl:13])[NH:6][C@@H:5]([C:15]([O:17]C)=[O:16])[CH2:4]1.C(N(CC)CC)C.[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[I-].[Na+]>CN(C=O)C>[CH2:26]([NH:2][C@@H:3]1[C:12]2[C:7](=[CH:8][C:9]([Cl:14])=[CH:10][C:11]=2[Cl:13])[NH:6][C@@H:5]([C:15]([OH:17])=[O:16])[CH2:4]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)[C@H]1C[C@H](N)c2c(Cl)cc(Cl)cc2N1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)[C@H]1C[C@H](NCc2ccccc2)c2c(Cl)cc(Cl)cc2N1
Temperature: 25 °C
Reaction time: 90 h

Procedure:
To a solution of trans-4-amino-5,7-dichloro-2-methoxycarbonyl-1,2,3,4-tetrahydroquinoline hydrochloride (0.300 g, 0.96 mmol) in anhydrous DMF (10 ml) was added triethylamine (0.403 ml, 2.89 mmol), benzyl bromide (0.230 ml, 1.92 mmol) and a catalytic quantity of sodium iodide. This mixture was stirred under an atmosphere of nitrogen at room temperature for 90 hours. The solvent was removed in vacuo and the residue obtained was partitioned between distilled water (100 ml) and ethyl acetate (200 ml). The organic layer was washed with saturated sodium hydrogen carbonate (2×100 ml), brine (2×100 ml) and distilled water (2×100 ml), dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatrography on silica gel (using from 10% ethyl acetate in hexane to 50% ethyl acetate in hexane as eluents) to give the title compound as colourless crystals, m.p. 112°-114° C. δ (360 MHz, DMSO), 1.41 (1H, ddd, J=13.4, 12.3 and 3.1 Hz, CHACHBHCCHD), 2.33 (1H, dm, J=13.4 Hz, CHACHBHCCHD), 3.73 (3H, s, CO2CH3), 3.84 (2H, 2 d, J=13.5 Hz, CH2C6H ), 4.13 (1H, m, CHACHBHCCHD), 4.27 (1H, dd, J=12.3 and 2.8 Hz, CHACHBHCCHD), 6.60 (1H, d, J=2.1 Hz, 6-H or 8-H), 6.73 (1H, s, ArNH, 6.78 (1H, d, J=7.69 (1H, d, 2.1 Hz, 6-H or 8-H), 7.28 (3H, m, ArH), 7.37 (2H, m, ArH), 7.69 (1H, m, CHNHCH2); m/e (CI+) 365 (M+1).