Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[CH:9]=2)=[O:4].[NH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27].C[O-].[Na+]>>[OH:15][C:14]1[C:13]2[C:8](=[CH:9][C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[CH:11][CH:12]=2)[CH:7]=[N:6][C:5]=1[C:3]([NH:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:4]
Reactant: COC(=O)c1ncc2cc(Oc3ccccn3)ccc2c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2cc(Oc3ccccn3)ccc2c1O
Yield: 76.9 %

Procedure:
A mixture of 4-hydroxy-7-(pyridin-2-yloxy)-isoquinoline-3-carboxylic acid methyl ester (24 mg), 3-amino-propionic acid (29 mg) and NaOMe (0.48 mL, 0.5 M solution in MeOH) was microwaved at 130° C. for 1 h; then cooled, concentrated, residue was dissolved in water, acidified with 2 M HCl; solids were collected via filtration, washed with water and air dried to give the desired product (22 mg). LC MS ESI: 354 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH:17]3[C:22](=[O:23])[NH:21][C:20]4[CH:24]=[C:25]([N+:28]([O-])=O)[CH:26]=[CH:27][C:19]=4[O:18]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>CO.O1CCCC1.[Pd]>[NH2:28][C:25]1[CH:26]=[CH:27][C:19]2[O:18][CH:17]([CH2:16][CH2:15][CH2:14][N:11]3[CH2:12][CH2:13][N:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:9][CH2:10]3)[C:22](=[O:23])[NH:21][C:20]=2[CH:24]=1
Reactant: O=C1Nc2cc([N+](=O)[O-])ccc2OC1CCCN1CCN(c2ccc(F)cc2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc2c(c1)NC(=O)C(CCCN1CCN(c3ccc(F)cc3)CC1)O2
Yield: 98.2 %

Procedure:
In a mixture of methanol (80 ml) and tetrahydrofuran (20 ml) was dissolved 2-{3-[4-(4-fluorophenyl)-1-piperazinyl]propyl}-6-nitro-2H-1,4-benzoxazin-3(4H)-one (2.03 g). To the solution was added 10% Pd - C (50% wet, 0.6 g) to conduct catalytic reduction. After the absorption of hydrogen finished, the catalyst was filtered off, and the filtrate was concentrated. The residue was crystallized from ethanol to give 1,85 g (98.2%) of 6-amino-2-{3-[4-(4-fluorophenyl)-1-piperazinyl]propyl}-2H-1,4-benzoxazin-3(4H)-one, m.p. 158°-159° C.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[C:8](Br)=[N:9][C:10]([Br:13])=[N:11][CH:12]=1)(=[O:3])[CH3:2].[CH:15]1([C:18]2[NH:22][N:21]=[C:20]([NH2:23])[CH:19]=2)[CH2:17][CH2:16]1.CCN(C(C)C)C(C)C>CC(O)C>[C:1]([O:4][CH2:5][CH2:6][C:7]1[C:8]([NH:23][C:20]2[CH:19]=[C:18]([CH:15]3[CH2:17][CH2:16]3)[NH:22][N:21]=2)=[N:9][C:10]([Br:13])=[N:11][CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCc1cnc(Br)nc1Br
Reactant: Nc1cc(C2CC2)[nH]n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(=O)OCCc1cnc(Br)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 60 °C
Reaction time: 16 h
Yield: 53.2 %

Procedure:
A mixture of 2-(2,4-dibromopyrimidin-5-yl)ethyl acetate (650 mg, 2.0 mmol, 1.0 eq), 5-cyclopropyl-1H-pyrazol-3-amine (296 mg, 2.4 mmol, 1.2 eq) and DIPEA (387 mg, 3.0 mmol, 1.5 eq) in propan-2-ol (10 mL) was stirred at 60° C. for 16 h. The mixture was extracted with EtOAc. The combined organic phases were washed (brine), dried (Na2SO4), filtered and concentrated to give a residue, which was purified by silica gel column chromatography (PE/EtOAc=1:2) to give 2-(2-bromo-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-5-yl)ethyl acetate (390 mg, 53%) as a white solid. LC-MS (m/z)=366 [M+H]+
Reaction SMILES: Br[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[CH:25])=[CH:20][CH:19]=1>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[C:25][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: C#Cc1ccc(Br)cc1
Reactant: N#Cc1cnccc1Br
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1cnccc1C#Cc1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of 4-bromo-nicotinonitrile (1.10 g, 6.00 mmol) in DMF (20 ml) are added bis(triphenylphosphine)-palladium(II)-chloride (211 mg, 0.30 mmol), copper(I) iodide (34 mg, 0.18 mmol), triethylamine (1.66 ml, 12.0 mmol) and 1-bromo-4-ethynyl-benzene (1.19 g, 6.6 mmol). The mixture is flushed with nitrogen, heated to 80° C. and stirred in a closed reaction vial at this temperature for 4 hours. The reaction mixture is allowed to cool to room temperature and partitioned between water and dichloromethane. The organic phase is washed with 1 N HCl, dried over sodium sulfate and evaporated under vacuum. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to give 4-(4-bromo-phenylethynyl)-nicotinonitrile as light yellow powder; HPLC/MS 2.09 min (B), [M+H] 283/285.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][C:15]=1[Cl:24]>>[Cl:24][C:15]1[CH:16]=[C:17]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:18]=[CH:19][C:14]=1[CH2:13][N:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CS(=O)(=O)c1ccc(CBr)c(Cl)c1
Reactant: O=Cc1ccc2[nH]ncc2c1
Product: CS(=O)(=O)c1ccc(Cn2ncc3cc(C=O)ccc32)c(Cl)c1

Procedure:
1-(2-Chloro-4-methanesulfonyl-benzyl)-1H-indazole-5-carbaldehyde was prepared from 1H-indazole-5-carbaldehyde and 1-Bromomethyl-2-chloro-4-methanesulfonyl-benzene following General Procedure A.
Reaction SMILES: [ClH:1].[N:2]1([CH2:8][CH2:9][CH2:10][C:11](=O)[CH3:12])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.N[N:16]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH2:20][CH2:19][C:18]2[CH:27]=[CH:28][CH:29]=[CH:30][C:17]1=2.[OH-].[NH4+]>C(O)(C)C>[ClH:1].[N:2]1([CH2:8][CH2:9][C:10]2[C:30]3[C:17]4=[C:18]([CH:27]=[CH:28][CH:29]=3)[CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:16]4[C:11]=2[CH3:12])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: NN1c2ccccc2CCc2ccccc21
Reactant: CC(=O)CCCN1CCCCC1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(C)O
Product: Cc1c(CCN2CCCCC2)c2cccc3c2n1-c1ccccc1CC3
Yield: 39.7 %

Procedure:
A solution of 5-piperidino-2-pentanone hydrochloride (3.4g.) and 5-amino-10,11-dihydro-5H-dibenz[b,f]azepine hydrochloride (4.2g.) in isopropyl alcohol (50 ml.) was warmed on a steam bath in a nitrogen atmosphere for thirty minutes, cooled and treated with concentrated ammonium hydroxide. The resulting mixture was extracted with ether and the ether extract was washed with water and dried. The resulting solution in ether of the free base 2-(2-piperidinoethyl)-1-methyl-6,7-dihydroindolo[1,7-ab][1]benzazepine was treated with ethanolic hydrogen chloride. The precipitate was collected and a suspension thereof in acetone-isopropyl alcohol was heated, cooled, filtered and recrystallized from methyl alcohol to give 2-(2-piperidinoethyl)-1-methyl-6,7-dihydroindolo[1,7-ab][1]benzazepine hydrochloride (2.5g.), m.p. 291°-293°C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.Br[CH2:11][CH2:12][CH2:13][Cl:14]>>[Cl:14][CH2:13][CH2:12][CH2:11][N:2]1[NH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[NH:1]1
Reactant: ClCCCBr
Reactant: c1ccc2[nH]nnc2c1
Product: ClCCCN1Nc2ccccc2N1
Yield: 36.3 %

Procedure:
Benzotriazole (303 mg, 2.54 mmol) and 1-bromo-3-chloro propane (437 mg, 2.77 mmol) were used according to the method of Example 291, Step A to yield 2-(3-chloropropyl)-1H-1,2,3-benzotriazole (182 mg, 37%). The title compound was prepared according to Example 286, Step C as a yellow oil (20 mg, 40%) from (8aS,12aR)-6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole (30 mg, 0.12 mmol) and 2-(3-chloropropyl)-1H-1,2,3-benzotriazole (48 mg, 0.24 mmol). 1H NMR (CDCl3) δ1.84-1.94 (m, 3H), 1.99-2.20 (m, 2H), 2.25-2.52 (m, 5H), 2.64-2.72 (m, 1H), 2.74-2.82 (m, 1H), 2.88-3.00 (m, 1H), 3.02-3.18 (m, 2H), 3.22-3.28 (m, 1H), 3.51-3.61 (m, 1H), 3.74-3.85 (m, 1H), 4.80 (t, 2H, J=6.7 Hz), 6.61 (t, 1H, J=7.5 Hz), 6.92 (dd, 2H, J=6.6, 24.9 Hz), 7.35-7.41 (m, 2H), 7.83-7.85 (m, 2H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][NH:13][CH3:14])[CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.[C:15]1([C:25](Cl)=[O:26])[C:24]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=2[CH:18]=[CH:17][CH:16]=1.O>C(Cl)Cl.[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:9][CH2:10][OH:11])[CH2:12][N:13]([CH3:14])[C:25]([C:15]2[C:24]3[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=3[CH:18]=[CH:17][CH:16]=2)=[O:26])=[CH:6][CH:7]=1
Reactant: CNCC(CCO)c1ccc(Cl)cc1
Reactant: O=C(Cl)c1cccc2c1CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CN(CC(CCO)c1ccc(Cl)cc1)C(=O)c1cccc2c1CCCC2
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 90.4 %

Procedure:
To a stirred cooled (0° C.) mixture of 3-(4-chloropenyl)-N-methyl-4-amino-1-butanol (0.706 g, 3.30 mmol) in DCM (25 mL) and 1N NaOH (4.13 mL) was added dropwise a solution of 5,6,7,8-tetrahydro-1-naphthalenecarbonyl chloride (0.643 g, 3.30 mmol) in DCM (10 mL). The mixture was stirred at 0° C. for 2.5 h, H2O and DCM were added and the mixture was extracted with DCM (2×20 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. Purification by chromatography (0%, 50%, 100% EtOAc in Et2O) provided the title compound (1.11 g, 90%) as a solid. MS m/z 372 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:45])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:31]([O:33]CC)=[O:32])([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27])[CH2:14][C:13](=[O:36])[NH:12][CH:11]3[C:37]3[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=3[CH3:44])[C:5]2=[CH:4][CH:3]=1.O[Li].O.O>CO>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:45])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:31]([OH:33])=[O:32])([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27])[CH2:14][C:13](=[O:36])[NH:12][CH:11]3[C:37]3[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=3[CH3:44])[C:5]2=[CH:4][CH:3]=1
Reactant: CCCC(CCC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)OCC
Agent: [Li]O
Solvent: CO
Solvent: O
Product: CCCC(CCC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Temperature: 25 °C
Yield: 92.6 %

Procedure:
A mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-ethoxycarbonyl-1-propyl-butoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (130 mg, 0.198 mmol), LiOH.H2O (1 g, 24.6 mmol), H2O (5 mL) and methanol (15 mL) was refluxed for 2 h. After cooled to room temperature, the solution was concentrated and then the water phase was acidified to “pH” 1-2 by addition of concentrated HCl solution and then extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4 and concentrated to give the title compound as a light yellow solid (115 mg).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Cl[C:25]1[N:26]=[N:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=1>>[Cl:18][C:16]1[CH:15]=[CH:14][C:13]([N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)=[C:12]([C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]2[CH2:2][NH:1][C:25]2[N:26]=[N:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=2)=[O:11])[CH:17]=1
Reactant: FC(F)(F)c1ccc(Cl)nn1
Reactant: C[C@@H]1CCCN(C(=O)c2cc(Cl)ccc2-n2nccn2)[C@@H]1CN
Product: C[C@@H]1CCCN(C(=O)c2cc(Cl)ccc2-n2nccn2)[C@@H]1CNc1ccc(C(F)(F)F)nn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A45 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 3-chloro-6-(trifluoromethyl)pyridazine. MS (ESI) 480 (M+H).
Reaction SMILES: [C:1]([OH:15])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].S(Cl)([Cl:18])=O>C1C=CC=CC=1>[C:1]([Cl:18])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCCC(=O)O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CCCCCCCCCCCCC(=O)Cl

Procedure:
To a benzene solution containing 5.0 g (0.023 mol) of tridecanoic acid was added 25 g of thionyl chloride, followed by refluxing for 5 hours. The excess of thionyl chloride and benzene were removed by distillation to obtain tridecanoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH2:30])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1.[Br:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1>CC(O)=O.CS(C)=O>[Br:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]([NH:30][C:29]2[C:9]([C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[CH:10][C:11]3[CH:16]=[N:15][C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[N:13][C:12]=3[N:28]=2)=[O:40])=[CH:34][CH:33]=1
Reactant: O=C=Nc1ccc(Br)cc1
Reactant: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(N)nc3n2)CC1
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(NC(=O)Nc4ccc(Br)cc4)nc3n2)CC1
Yield: 67.7 %

Procedure:
6-(2,6-Dichlorophenyl)-N2 -[3-(4-methyl-piperazin-1-yl)-propyl]-pyrido[2,3-d]pyrimidine-2,7-diamine (1.0 g) from Example 36 was reacted with 0.44 g of 4-bromophenyl isocyanate according to the general procedure of Example 37 to give 0.97 g of 1-(4-Bromo-phenyl)-3-{6-(2,6-dichlorophenyl)-2-[3-(4-methylpiperazin-1-yl)-propylamino]-pyrido[2,3-d]pyrimidin-7-yl}-urea, ESMS (20/80 MeOH/CH3 CN+0.1% AcOH+DMSO): M+ +H=645; mp 171°-175° C.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[F:23][C:24]([F:47])([F:46])[O:25][C:26]1[CH:45]=[CH:44][C:29]([O:30][CH2:31][CH2:32][NH:33][C:34](=O)[C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[F:23][C:24]([F:47])([F:46])[O:25][C:26]1[CH:45]=[CH:44][C:29]([O:30][CH2:31][CH2:32][NH:33][C:34](=[S:10])[C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[CH:28][CH:27]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(NCCOc1ccc(OC(F)(F)F)cc1)c1c(F)cccc1F
Solvent: Cc1ccccc1
Product: Fc1cccc(F)c1C(=S)NCCOc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Lawesson's reagent (1.94 g) was added to a toluene (20 ml) solution of N-[2-(4-trifluoromethoxyphenoxy)ethyl]-2,6-difluorobenzamide (1.44 g) and the mixture was stirred at room temperature for 3 hours.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[C:10]([NH:11][C:12]2[C:13]3[C:20]([CH3:21])=[C:19]([C:22]([OH:24])=O)[S:18][C:14]=3[N:15]=[CH:16][N:17]=2)=[CH:9][CH:8]=[CH:7][N:6]=1.[NH3:25]>O1CCOCC1>[OH:1][CH2:2][CH2:3][O:4][C:5]1[C:10]([NH:11][C:12]2[C:13]3[C:20]([CH3:21])=[C:19]([C:22]([NH2:25])=[O:24])[S:18][C:14]=3[N:15]=[CH:16][N:17]=2)=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3OCCO)c12
Reactant: N
Solvent: C1COCCO1
Product: Cc1c(C(N)=O)sc2ncnc(Nc3cccnc3OCCO)c12

Procedure:
Prepared analogously to example 28.3 using 4-(2-(2-hydroxyethoxy)pyridin-3-ylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylic acid (30.5 mg) and ammonia in dioxane (0.5M; 1.6 ml)
Reaction SMILES: [C:1]([C:3]1[C:4]([O:22][C:23]([F:32])([F:31])[CH:24]([F:30])[O:25][C:26]([F:29])([F:28])[F:27])=[N:5][N:6]([C:8]2[CH:13]=[C:12]([S:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([CH3:20])=[CH:10][C:9]=2[F:21])[CH:7]=1)#[N:2].ClC1C=CC=C(C(OO)=[O:41])C=1>C(Cl)(Cl)Cl>[C:1]([C:3]1[C:4]([O:22][C:23]([F:32])([F:31])[CH:24]([F:30])[O:25][C:26]([F:27])([F:28])[F:29])=[N:5][N:6]([C:8]2[CH:13]=[C:12]([S:14]([CH2:15][C:16]([F:19])([F:18])[F:17])=[O:41])[C:11]([CH3:20])=[CH:10][C:9]=2[F:21])[CH:7]=1)#[N:2]
Reactant: Cc1cc(F)c(-n2cc(C#N)c(OC(F)(F)C(F)OC(F)(F)F)n2)cc1SCC(F)(F)F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1cc(F)c(-n2cc(C#N)c(OC(F)(F)C(F)OC(F)(F)F)n2)cc1S(=O)CC(F)(F)F
Reaction time: 1 h
Yield: 92 %

Procedure:
0.2 g of 4-cyano-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole was dissolved in 10 mL of chloroform, and 93 mg of m-chloroperbenzoic acid (purity: 75%) was added under cooling with ice. After stirring for one hour under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous sodium hydrogen carbonate solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel column chromatography (developing solvent ethyl acetate:hexane=1:2) to obtain 0.19 g of 4-cyano-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([OH:14])=O)[CH:3]=1.[Cl-].[OH:16][C@H:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]1[NH3+:23].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([NH:23][C@@H:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C@@H:17]2[OH:16])=[O:14])[CH:3]=1
Reactant: O=C(O)c1cc(Br)c2ccccc2n1
Reactant: [NH3+][C@@H]1CCCC[C@@H]1O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1CCCC[C@@H]1O)c1cc(Br)c2ccccc2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the 4-bromoquinoline-2-carboxylic acid (A3) (0.10 g, 0.40 mmol) in 2.0 mL, CH2Cl2 was added (cis)-2-hydroxycyclohexanaminium chloride (0.12 g, 0.80 mmol), BOP reagent (0.35 g, 0.80 mmol), and triethylamine (0.16 mL, 1.2 mmol). The reaction mixture was stirred at room temperature for 16 h, diluted with CH2Cl2, washed with water, dried over sodium sulfate, filtered, and concentrated. The resultant residue subjected to silica gel chromatography eluting with 0-60% ethyl acetate in hexanes to afford 4-bromo-N-[(cis)-2-hydroxycyclohexyl]quinoline-2-carboxamide (I1) that gave a mass ion (ES+) of 349.2 (79Br) for M+H+.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:32])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4([C:23]5[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=5[OH:30])[CH2:22][CH2:21]4)[C:14]3=[O:31])[CH:7]=2)[CH2:3][CH2:2]1.Br[CH2:34][CH2:35][Cl:36].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Cl:36][CH2:35][CH2:34][O:30][C:24]1[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:23]=1[C:20]1([NH:19][C:15]2[C:14](=[O:31])[N:13]([C:8]3[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=3[CH3:12])[C:5]([NH:4][CH:1]3[CH2:3][CH2:2]3)=[O:32])[CH:18]=[CH:17][N:16]=2)[CH2:22][CH2:21]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3cc(F)ccc3O)CC2)c1=O
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3cc(F)ccc3OCCCl)CC2)c1=O

Procedure:
N-Cyclopropyl-3-[3-[[1-(5-fluoro-2-hydroxyphenyl)cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide (Example 278d 1.22 g), 1-bromo-2-chloroethane (2.4 mL) and cesium carbonate (9.15 g) were stirred together in acetonitrile (100 mL) at 80° C. under nitrogen for 16 h. The cooled reaction mixture was evaporated to dryness, diluted with water (200 mL) and extracted with dichloromethane (3×100 mL). The combined organics were dried (MgSO4), filtered and evaporated. The residue was triturated with 1:1 iso-hexane:diethyl ether to give the subtitle compound (1.13 g)
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9].[CH3:16][CH:17]([CH3:33])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:22]=1)=[O:19]>>[CH3:16][CH:17]([CH3:33])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]2[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[O:9])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:29][CH2:28]2)[CH:22]=1)=[O:19]
Reactant: O=C(CCCCCCCl)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCC(=O)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 using 7-chloro-1-phenyl-1-heptanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 435.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:18](=[O:19])[N:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C:12]2=[N:11]1.Br[CH2:21][CH2:22][Cl:23].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:21][CH2:22][Cl:23])=[CH:4][C:3]=1[N:10]1[C:18](=[O:19])[N:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C:12]2=[N:11]1
Reactant: ClCCBr
Reactant: O=c1n(-c2cc(O)c(Cl)cc2Cl)nc2n1CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=c1n(-c2cc(OCCCl)c(Cl)cc2Cl)nc2n1CCCC2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
3.0 Parts of 2-(2,4-dichloro-5-hydroxyphenyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-A]pyridin-3(2H)-one prepared as described above in Example 3, 1.4 parts of 1-bromo-2-chloroethane, 1.5 parts of anhydrous potassium carbonate and 20 parts of dry acetonitrile were combined and refluxed for 6 hours followed by stirring for 72 hours at room temperature. The reaction mixture was poured into 200 parts of water. The aqueous suspension of the product was extracted three times with 200 parts of methylene chloride. The organic extracts of the product were dried with anhydrous sodium sulfate. The solvent was stripped from the product at reduced pressure on a rotary evaporator. The resulting dark oil was crystallized from ether yielding 0.2 parts of a light brown solid with m.p. 148°-150°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][CH2:21][C@H:22]4[CH2:27][CH2:26][C@H:25]([NH:28]C(OCC5C=CC=CC=5)=O)[CH2:24][CH2:23]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][CH2:21][C@H:22]4[CH2:27][CH2:26][C@H:25]([NH2:28])[CH2:24][CH2:23]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(N[C@H]1CC[C@H](CNc2ncc3ncnc(Nc4ccc(F)c(Cl)c4)c3n2)CC1)OCc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: N[C@H]1CC[C@H](CNc2ncc3ncnc(Nc4ccc(F)c(Cl)c4)c3n2)CC1

Procedure:
Prepared from 4-[(3-chloro-4-fluorophenyl)amino]-6-(trans-4-(benzyloxycarbonylamino)cyclohexylmethylamino]pyrimido-[5,4-d]pyrimidine by catalytic hydrogenation. Melting point: 166°-169° C.; Rf : 0.53 (silica gel; methylene chloride/methanol/concentrated ammonia=10:1:0.05); Mass spectrum: M+ =401/403 (Cl)