Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH2:22][C:21](=O)[N:11]3[CH2:12][CH2:13][CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[CH:10]3[CH2:9]2)C=CC=CC=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:45])=CC=1>CN(P(N(C)C)(N(C)C)=O)C>[S:45]=[C:21]1[N:11]2[CH2:12][CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH:10]2[CH2:9][NH:8][CH2:22]1
Reactant: O=C1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC2c3ccccc3CCCN12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: S=C1CNCC2c3ccccc3CCCN12
Reaction time: 3 h

Procedure:
A mixture of 2-(triphenylmethyl)-4-oxo-1,2,3,4,6,7,8,12b-octahydropyrazino-[2,1-a][2]benzazepine (0.66 g) and Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide) (0.29 g) in HMPA (10 ml) was heated to 80° under a nitrogen atmosphere. The mixture was stirred at this temperature for 3 hr, cooled and partitioned between water and diethyl ether. The organic layer was washed with water and evaporated to a yellow foam. This residue was dissolved in acetone (20 ml), cooled to 0° and concentrated hydrochloric acid (0.5 ml) added. After stirring at room temperature for 30 min the mixture was evaporated and the residue partitioned between dilute hydrochloric acid and chloroform. The aqueous fraction was basified with sodium carbonate and extracted with chloroform. This chloroform fraction was washed with brine, dried (K2CO3) and evaporated to give the title compound as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[C:22]4[C:28]([C:29]5[CH:30]=[N:31][N:32]([CH2:34][CH2:35][C:36]6[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=6)[CH:33]=5)=[CH:27][N:26](C(OC(C)(C)C)=O)[C:23]4=[N:24][CH:25]=3)=[CH:16][C:15]=2[NH:49][S:50]([CH3:53])(=[O:52])=[O:51])[CH2:10][CH2:9]1)=O)(C)(C)C.CO.[ClH:56]>C(OCC)C>[ClH:56].[CH2:34]([N:32]1[CH:33]=[C:29]([C:28]2[C:22]3[C:23](=[N:24][CH:25]=[C:20]([C:17]4[CH:18]=[CH:19][C:14]([N:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[C:15]([NH:49][S:50]([CH3:53])(=[O:52])=[O:51])[CH:16]=4)[CH:21]=3)[NH:26][CH:27]=2)[CH:30]=[N:31]1)[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc4c(c3)c(-c3cnn(CCc5ccccc5)c3)cn4C(=O)OC(C)(C)C)cc2NS(C)(=O)=O)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CS(=O)(=O)Nc1cc(-c2cnc3[nH]cc(-c4cnn(CCc5ccccc5)c4)c3c2)ccc1N1CCNCC1
Yield: 68 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 5-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-(methylsulfonamido)phenyl)-3-(1-phenethyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (21 mg, mmol) was deprotected in methanol/HCl in diethyl ether (2/1 ml) to afford 11 mg (68% yield) of the titled compound. 1H NMR (CD3OD, 300 MHz): δ 8.859-8.853 (d, 1H), 8.736-8.73 (d, 1H), 8.37 (s, 1H), 8.33 (s, 1H), 8.00 (s, 1H), 7.867-7.861 (d, 1H), 7.66-7.63 (dd, 1H), 7.53-7.50 (d, 1H), 7.27-7.12 (m, 5H), 4.63-4.61 (t, 2H), 3.51-3.47 (t, 4H), 3.50-3.24 (m, 9H). MS: m/z=542.3 (M+1), HPLC: 98.49% in method B.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[S:23][C:24]3[C:29]([N:30]=2)=[CH:28][CH:27]=[C:26]([C:31]2([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH2:33][CH2:32]2)[N:25]=3)=[C:18]([F:40])[CH:17]=1>COCCOC>[F:40][C:18]1[CH:17]=[C:16]([CH2:15][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])[CH:21]=[CH:20][C:19]=1[C:22]1[S:23][C:24]2[C:29]([N:30]=1)=[CH:28][CH:27]=[C:26]([C:31]1([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:32][CH2:33]1)[N:25]=2
Reactant: Fc1cc(CBr)ccc1-c1nc2ccc(C3(c4ccccc4)CC3)nc2s1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1)C(=O)OCC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a slurry of NaH (0.55 g, 14 mmol) in 40 mL DME under nitrogen was added diethyl malonate (2.1 mL, 14 mmol) slowly dropwise. After addition of 1 mL, the reaction mixture was warm, so cooled to 0° C. and continued addition. To the resulting clear solution was added a slurry of 2-(4-(bromomethyl)-2-fluorophenyl)-5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridine (3.00 g, 6.8 mmol) as a solid. After 1 h, the reaction mixture was quenched with sat'd aq. Ammonium chloride and DCM, and the aq. Layer was extracted with DCM, and the combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel chromatography, 40 g, 0-30% EA/hexanes. Product containing fractions were combined and concentrated and triturated with hexanes to give diethyl 2-((3-fluoro-4-(5-(1-phenyl-cyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)malonate as an off-white solid. MS (ESI) m/z: calculated: 518.2; Observed: 519.1 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C(N(CC)[C:16](Cl)=[S:17])C.Cl>C1(C)C=CC=CC=1>[N:1]([C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1)=[C:16]=[S:17]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CCN(CC)C(=S)Cl
Agent: Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(N=C=S)cc1
Yield: 74.5 %

Procedure:
82.5 g of ethyl p-aminobenzoate was dissolved in 500 ml of toluene, to the solution was added 83.4 g of N,N-diethylthiocarbamoyl chloride and the mixture was refluxed by heating for 8 hours. After cooling with ice, 100 ml of concentrated hydrochloric acid was added to the reaction mixture and then the toluene layer was separated and washed with water. The toluene was distilled off under reduced pressure and the residual oily product was crystallized from methanol to obtain 77.1 g of ethyl p-isothiocyanatobenzoate. Yield: 74.5%. Melting Point: 52° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[C:4]([F:9])[C:3]=1[N+:10]([O-:12])=[O:11].C(=O)([O-])[O-].[K+].[K+].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>CS(C)=O.CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:5]=[C:4]([F:9])[C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1F
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1c(F)cc(N2CCOCC2)cc1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 39 %

Procedure:
1,3,5-Trifluoro-2-nitro-benzene (5.30 g, 0.0299 mol) and Potassium carbonate (4.96 g, 0.0359 mol) were mixed in Dimethyl sulfoxide (40.0 mL) and Morpholine (2.74 mL, 0.0314 mol) was added. The reaction was stirred at room temperature for 48 hours and then diluted with EtOAc and washed twice with water. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-40% EtOAc/hex as the eluting solvent gave 4-(3,5-Difluoro-4-nitro-phenyl)-morpholine (2.85 g, 39%) as a yellow solid. MP=112-114° C.; LCMS=245 (M+H); HNMR (CDCl3, 400 MHz) δ 6.45-6.37 (m, 2H), 3.86 (t, 4H, J=4.5 Hz), 3.33 (t, 4H, J=4.5 Hz); F19 NMR (CDCl3, 400 MHz) δ −115.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C.[Cl:21][C:22]1[C:23]([C:32]2[N:37]3[N:38]=[CH:39][N:40]=[C:36]3[N:35]=[C:34]([CH3:41])[CH:33]=2)=[N:24][CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1.O>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:41][C:34]1[CH:33]=[C:32]([C:23]2[C:22]([Cl:21])=[CH:27][C:26]([C:28]([F:29])([F:31])[F:30])=[CH:25][N:24]=2)[N:37]2[N:38]=[CH:39][N:40]=[C:36]2[N:35]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(-c2ncc(C(F)(F)F)cc2Cl)n2ncnc2n1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: FC(F)(F)c1cnc(-c2cc(CBr)nc3ncnn23)c(Cl)c1
Reaction time: 8 h
Yield: 13.7 %

Procedure:
312 mg of N-bromosuccinimide and 13 mg of azobisisobutylonitrile (AIBN) were added to a solution having 500 mg of 7-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine dissolved in 3 mL of carbon tetrachloride, followed by stirring overnight under reflux with heating. After completion of the reaction, water was added to the reaction liquid, followed by extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=7/3) to obtain 86 mg of the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25]([CH2:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:27])=[O:26]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:32]4[CH:31]=[CH:30][C:29]([CH2:28][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:34][CH:33]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Reactant: CS(=O)(=O)Cc1ccc(B(O)O)cc1
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(CS(C)(=O)=O)cc4)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and [4-[(methylsulfonyl)methyl]phenyl]boronic acid following a procedure analogous to that described in Example 28. LC (method 10): tR=1.60 min; Mass spectrum (ESI+): m/z=473 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]([CH2:14][C:15](O)([CH2:21][CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(S(F)(F)[F:30])CC>ClCCl>[CH2:1]([N:8]([CH2:14][C:15]([F:30])([CH2:21][CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CCOC(=O)C(O)(CC)CN(Cc1ccccc1)C1CCCC1
Solvent: ClCCl
Product: CCOC(=O)C(F)(CC)CN(Cc1ccccc1)C1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
To ethyl 2-((benzyl(cyclopentyl)amino)methyl)-2-hydroxybutanoate (2.9 g, 9.1 mmol) in 30 ml of dichlormethane at −78° C., was added DAST (2.4 ml, 18 mmol) dropwise. The reaction mixture was gradually warmed up to room temperature and stirred for 1 h. It was then diluted to dichloromethane, washed by NaHCO3, brine and water. Organic extract dried and concentrated to a residue, which was purified on silica gel column chromatographically (Hex/EtOAc=40:1 to 20:1) to give 2.2 g product (75%) as light yellow liquid. [M+H] calc'd for C19H28FNO2, 322; found 322.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:17][CH2:16][C:15]3[C:14]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=4)=[N:13][C:12](S(C)(=O)=O)=[N:11][C:10]=3[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:33][N:34]([CH2:36][CH2:37][NH2:38])[CH3:35].O>CS(C)=O>[Cl:1][C:2]1[C:3]([N:8]2[CH2:17][CH2:16][C:15]3[C:14]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=4)=[N:13][C:12]([NH:38][CH2:37][CH2:36][N:34]([CH3:35])[CH3:33])=[N:11][C:10]=3[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CCN
Reactant: CS(=O)(=O)c1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(c1ncccc1Cl)C2
Solvent: O
Solvent: CS(C)=O
Product: CN(C)CCNc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(c1ncccc1Cl)C2
Yield: 40.7 %

Procedure:
The solution of 7-(3-chloropyridin-2-yl)-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2-(methylsulfonyl)pyrido[3,4-d]pyrimidin-4-amine from Example 25 (50 mg, 0.1 mmol) and unsym-dimethylethylenediamine (100 mg, 1.1 mmol) in DMSO was irradiated by microwave at 150° C. for 10 min. The reaction mixture was poured into water and extracted by ethyl acetate. Solids between two phases were filtered out and this solid was dissolved in methanol and undissolved solid was filtered out. Filterate was concentrated to yield the product as beige powder (20 mg, 41%).
Reaction SMILES: CO[C:3]([CH2:5][C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[O:7])=[O:4].CO[C:15]1[CH2:16][CH2:17][CH2:18][N:19]=1>C(N(CC)CC)C>[OH:7][C:6]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:18]2[N:19]([CH2:15][CH2:16][CH2:17]2)[C:3](=[O:4])[CH:5]=1
Reactant: COC(=O)CC(=O)CC(=O)OC
Reactant: COC1=NCCC1
Solvent: CCN(CC)CC
Product: COC(=O)c1c(O)cc(=O)n2c1CCC2
Reaction time: 72 h
Yield: 74.8 %

Procedure:
Triethylamine (0.5 mL, 3.6 mmol) was added to a mixture of dimethyl 1,3-acetonedicarboxylate (16.3 mL, 111 mmol) and 5-methoxy-3,4-dihydro-2H-pyrrole (10 g, 101 mmol), and the reaction stirred for 72 h. The white solid was collected by filtration, rinsed with ether, and dried under vacuum to give 15.8 g (75%) of compound 1a. 1H NMR (400 MHz, DMSO-d6): δ 11.11 (s, 1H), 5.54 (s, 1H), 3.94 (t, 2H, J=7.6 Hz), 3.80 (s, 3H), 3.36 (t, 2H, J=7.6 Hz), 2.02-2.11 (m, 2H). MS (ES) [m+H] calc'd for C10H11NO4, 210. found 210.
Reaction SMILES: [S:1]1([C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=[O:6])[NH:4]1)(=[O:3])=[O:2].[Na].[OH2:14]>CN(C)C=O>[O:3]=[S:1]1(=[O:2])[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:5](=[O:6])[N:4]1[CH2:9][CH2:8][CH2:7][C:12](=[O:14])[CH3:11]
Reactant: O=C1NS(=O)(=O)c2ccccc21
Reactant: O
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(=O)CCCN1C(=O)c2ccccc2S1(=O)=O
Temperature: 170 °C

Procedure:
A mixture of the above ketal (3.2 gm, 15 mmol) and sodium saccharin (3.1 gm, 14 mmol) in dimethylformamide (15 mL) was heated at 170° C. for 5 hours. The cooled reaction mixture was poured into water and the crude product extracted into ethyl acetate. The dried extract was evaporated and the crude product was chromotographed on a column of silica gel eluting with a gradient of 20-40% EtOAc/hexane to give crystalline 1,1-dioxido-2-(4-oxo-pentyl)-1,2-benzisothiazol-3(2H)-one, melting point 90-93° C.
Reaction SMILES: Br[CH2:2][CH:3]([N:10]1[C:14]2[CH:15]=[C:16]([F:20])[C:17]([F:19])=[CH:18][C:13]=2[N:12]=[C:11]1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[OH:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:11]2[N:10]([CH:3]([CH:4]3[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]3)[CH2:2][O:28][C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)[C:14]3[CH:15]=[C:16]([F:20])[C:17]([F:19])=[CH:18][C:13]=3[N:12]=2)=[CH:22][CH:23]=1
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3)n(C(CBr)C3CCCCC3)c2cc1F
Reactant: Oc1ccncc1
Product: Fc1cc2nc(-c3ccc(Cl)cc3)n(C(COc3ccncc3)C3CCCCC3)c2cc1F

Procedure:
The title compound was prepared in analogy to Example 35 from 1-(2-bromo-1-cyclohexyl-ethyl)-2-(4-chloro-phenyl)-5,6-difluoro-1H-benzoimidazole (Ex. 34, int.) and 4-hydroxypyridine after a reaction time of 3 days at room temperature. White solid (32%). MS (Turbo Spray): m/z=468.2 [M+H].
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1.[NH2:29][CH:30]([CH2:33][OH:34])[CH2:31][OH:32]>>[OH:32][CH2:31][CH:30]([CH2:33][OH:34])[NH:29][C:3]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:26])[CH3:27])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:16][CH2:17]2)=[O:11])=[CH:6][CH:5]=1)=[O:28]
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)cc1
Reactant: NC(CO)CO
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NC(CO)CO)cc2)CC1
Yield: 79 %

Procedure:
By the same procedure as described in the example 31, synthesis was carried out starting with 4-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoic acid methyl ester and using 2-amino-1,3-propanediol. Then, the product was recrystallized using ethyl acetate and ether to give the desired compound.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([F:13])[C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[CH:3]=1.[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[F:13][C:7]1[C:8]([CH3:12])=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[CH:3]=[C:2]2[C:22]1[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=1
Reactant: COC(=O)c1cc(Br)c2ccc(C)c(F)c2n1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2cnn(C)c2)c2ccc(C)c(F)c2n1
Temperature: 100 °C
Yield: 73.7 %

Procedure:
After degassing with N2, a mixture of methyl 4-bromo-8-fluoro-7-methylquinoline-2-carboxylate (7-16, 650 mg, 2.18 mmol.), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (544 mg, 2.62 mmol) Pd(dppf)Cl2—CH2Cl2 adduct (89 mg, 0.11 mmol), and K3PO4 (1388 mg, 6.54 mmol) in 1,4-dioxane (12.9 mL) and H2O (1.6 mL) was heated at 100° C. for 20 min under microwave condition. After cooling to room temperature, the reaction mixture was filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc/Hexane (0-100%) to afford methyl 8-fluoro-7-methyl-4-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carboxylate (7-17, 481 mg, 74%). LRMS m/z (M+H)+ 300.3 found, 300.1 require.
Reaction SMILES: [OH:1][C:2]1[CH:44]=[CH:43][C:5]([CH2:6][NH:7][C:8]2[N:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:11]=[C:10]([NH:20][C:21]3[CH:42]=[CH:41][C:24]([C:25]([NH:27][CH2:28][C:29]([CH3:40])([CH3:39])[CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:26])=[CH:23][N:22]=3)[CH:9]=2)=[CH:4][CH:3]=1.[Cl:45][CH2:46][C:47]([CH2:49]Cl)=[CH2:48].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.CCOC(C)=O>[Cl:45][CH2:46][C:47](=[CH2:48])[CH2:49][O:1][C:2]1[CH:44]=[CH:43][C:5]([CH2:6][NH:7][C:8]2[N:13]=[C:12]([O:14][CH2:15][C:16]([F:17])([F:18])[F:19])[N:11]=[C:10]([NH:20][C:21]3[CH:42]=[CH:41][C:24]([C:25]([NH:27][CH2:28][C:29]([CH3:39])([CH3:40])[CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:26])=[CH:23][N:22]=3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: C=C(CCl)CCl
Reactant: CC(C)(CNC(=O)OC(C)(C)C)CNC(=O)c1ccc(Nc2cc(NCc3ccc(O)cc3)nc(OCC(F)(F)F)n2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: C=C(CCl)COc1ccc(CNc2cc(Nc3ccc(C(=O)NCC(C)(C)CNC(=O)OC(C)(C)C)cn3)nc(OCC(F)(F)F)n2)cc1
Yield: 43.7 %

Procedure:
A suspenssion of tert-butyl (3-(6-((6-((4-hydroxybenzyl)amino)-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)amino)nicotinamido)-2,2-dimethylpropyl)carbamate (90 mg), 3-chloro-2-(chloromethyl)prop-1-ene (27.2 mg) and K2CO3 (40.1 mg) in acetone (6 mL) was heated to reflux for 16 hours. The mixture was diluted with EtOAc (200 mL), washed with water (30 mL), brine (30 mL), dried over MgSO4 and concentrated. The residue was purified by preparative HPLC to give desired product tert-butyl 3-(6-(6-(4-(2-(chloromethyl)allyloxy)benzylamino)-2-(2,2,2-trifluoroethoxy)pyrimidin-4-ylamino)nicotinamido)-2,2-dimethylpropylcarbamate (45 mg).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH3:9][C:10]([CH3:14])([CH3:13])[C:11]#[CH:12].O>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:9][C:10]([CH3:14])([CH3:13])[C:11]#[C:12][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5]
Reactant: Nc1cccc(I)c1
Reactant: C#CC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)C#Cc1cccc(N)c1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
1.05 g (1.5 mmol) of bis(triphenylphosphine)palladium(II) chloride and 0.26 g (1.5 mmol) of copper(I) iodide are added to a solution consisting of 5.47 g (25 mmol) of 3-iodoaniline in 40 ml of triethylamine. With ice-cooling, 3.08 g (37.5 mmol) of 3,3-dimethyl-1-butyne are added dropwise such that the temperature remains at 20° C. After the addition has ended, the mixture is stirred at 20° C. for 20 hours. The reaction solution is concentrated under reduced pressure and the residue formed is stirred into 1 l of water. The mixture is then extracted three times with diethyl ether. The combined organic phases are once more washed with water, dried with sodium sulphate and concentrated under reduced pressure. The crude product obtained is purified by silica gel chromatography (mobile phase methylene chloride). This gives 2.70 g (60% of theory) of 3-(3,3-dimethylbut-1-yn-1-yl)aniline having a content of 97% according to HPLC. log P=2.71.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13](=[CH:21]O)[C:14](=O)[CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.S(O)(O)(=O)=O.[NH2:28][C:29]1[NH:30][CH:31]=[CH:32][N:33]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13]2[CH:21]=[N:28][C:29]4[N:33]([C:14]=2[CH2:15]3)[CH:32]=[CH:31][N:30]=4)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Nc1ncc[nH]1
Reactant: O=C1CC2CCCC(C1=CO)N2S(=O)(=O)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Product: O=S(=O)(c1ccc(Cl)cc1)N1C2CCCC1c1cnc3nccn3c1C2

Procedure:
Prepared as described in Example 5 using 9-(4-chlorophenylsulfonyl)-2-(hydroxymethylene)-9-azabicyclo[3.3.1]nonan-3-one which was prepared as described in Example 34 and 2-aminoimidazole sulfate.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15]Cl>C1(C)C=CC=CC=1>[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN(C)CCOc1ccc(C=O)cc1
Yield: 46.6 %

Procedure:
The reaction between 61.0 g (0.50 mole) of 4-hydroxybenzaldehyde, 24.0 g of 50% NaH, and 341 ml of 2.2 N (0.75 mole) 2-dimethylaminoethyl chloride in toluene in a procedure described for Example 2,part A, gives 45.0 g (46%) of colorless product, bp 140°-142°/2 mm. Lit. bp 185°-187°/15 mm.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:35]=[CH:34][C:9]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:21]4[CH:22]=[CH:23][C:24](=[O:27])[CH:25]=[CH:26][C:20]4=[C:19]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:18]=3)[CH2:13][CH2:12]2)=[CH:8][CH:7]=1)=[O:5])C.C(O)C.[OH-].[K+]>O>[C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:21]4[CH:22]=[CH:23][C:24](=[O:27])[CH:25]=[CH:26][C:20]4=[C:19]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:18]=3)[CH2:13][CH2:12]2)=[CH:34][CH:35]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccc(CN2CCN(c3cc(-c4ccccc4)c4ccc(=O)ccn34)CC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(CN2CCN(c3cc(-c4ccccc4)c4ccc(=O)ccn34)CC2)cc1
Temperature: 60 °C
Yield: 53.2 %

Procedure:
To a stirred suspension of 3-[4-(4-ethoxycarbonylbenzyl)-1-piperazinyl]-1-phenyl-7H-pyrrolo[1,2-a]azepin-7-one (1.2 g), prepared as described in Example 20, and ethyl alcohol (30 cc) under an atmosphere of nitrogen, a solution of potassium hydroxide (0.2 g) in distilled water (3 cc) is added at a temperature of about 20° C. in the course of 5 minutes. The reaction mixture is then heated to 60° C. for 4 hours. After the solution is cooled, 1N aqueous potassium hydroxide solution (10 cc) is added and the mixture is washed 3 times with methylene chloride (150 cc in total). The organic phases are combined, dried over anhydrous magnesium sulphate, filtered and evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue is dissolved in methylene chloride (5 cc) and the solution is poured into silica (40 g) contained in a column 1 cm in diameter. Elution is first performed with a mixture of cyclohexane and ethyl acetate (50:50 by volume) (2.5 liters) and the corresponding eluate is rejected. Elution is then performed with methanol (1 liter and the corresponding eluate is evaporated to dryness under reduced pressure (20 mm Hg; 1.7 kPa) at 40° C. After recrystallization in 2-methyl-2-butanol, 3-[4-(4-carboxybenzyl)-1-piperazinyl]-1-phenyl-7H-pyrrolo[1,2-a]azepin-7-one (0.6 g) is obtained in the form of its potassium salt.