Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[N:8]([CH3:34])[C:9]([CH2:22][NH:23][S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])(=[O:26])=[O:25])=[CH:10][C:11](=[O:21])[C:12]=1[O:13]CC1C=CC=CC=1)=[O:6])([CH3:3])[CH3:2].C1(S(C(N)C2N(C)C(C(O)=O)=C(O)C(=O)C=2)(=O)=O)C=CC=CC=1>>[CH:1]([NH:4][C:5]([C:7]1[N:8]([CH3:34])[C:9]([CH2:22][NH:23][S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])(=[O:26])=[O:25])=[CH:10][C:11](=[O:21])[C:12]=1[OH:13])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)c1c(OCc2ccccc2)c(=O)cc(CNS(=O)(=O)c2ccccc2Cl)n1C
Agent: Cn1c(C(N)S(=O)(=O)c2ccccc2)cc(=O)c(O)c1C(=O)O
Product: CC(C)NC(=O)c1c(O)c(=O)cc(CNS(=O)(=O)c2ccccc2Cl)n1C
Yield: 19.2 %

Procedure:
6-[(2-Chloro-benzenesulfonylamino)-methyl]-3-hydroxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid isopropylamide (18-03) (38.0 mg, 19.24%, purified by Prep-HPLC) was synthesized as an off white solid from 3-benzyloxy-6-[(2-chloro-benzenesulfonylamino)-methyl]-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid isopropylamide (17-03) (240.0 mg, 0.477 mmol) following the procedure described for 6-(benzene sulfonyl amino-methyl)-3-hydroxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (14-01).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:14][CH3:15])[CH:9]=2)[N:4]=1.S(Cl)([Cl:19])(=O)=O.O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:14][CH3:15])[C:9]=2[Cl:19])[N:4]=1
Reactant: COc1ccc2nc(OC)cc(C)c2c1
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(C)c2c(Cl)c(OC)ccc2n1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A 500 ml, four-necked round bottom flask equipped with a mechanical stirrer, condenser, thermowatch and addition funnel was charged with 2,6-dimethoxy-4-methylquinoline (9) (17.9 g, 0.09 moles) and glacial acetic acid (120 ml). The resulting solution was heated to 60° C., then a solution containing sulfuryl chloride (13.4 g, 0.01 moles) and glacial acetic acid (40 ml) was added over 20 minutes. Reaction temperature was held between 60-65° C. during this addition. The resulting solution was stirred for 1 hour at 60-65° C., then additional sulfuryl chloride (3.8 g, o,028 moles) in glacial acetic acid (10 ml) was added. The mixture was stirred an additional 30 minutes, then it was poured into 300 ml of water. The slurry was cooled to 5° C., the product removed by suction filtration, washed with water and air dried. Yield was 18.4 g (86%); mp=97-100° C.; purity by HPLC=89.7 area %.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]([CH3:25])[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:11][CH:10]=2)O1.Br[C:28]1[C:29]2[C:30]3[CH:52]=[C:51]([CH3:53])[S:50][C:31]=3[C:32](=[O:49])[N:33]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:34]=2[C:35]([CH3:40])=[CH:36][C:37]=1[O:38][CH3:39]>>[CH3:39][O:38][C:37]1[CH:36]=[C:35]([CH3:40])[C:34]2[N:33]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:46])([CH3:47])[CH3:48])[C:32](=[O:49])[C:31]3[S:50][C:51]([CH3:53])=[CH:52][C:30]=3[C:29]=2[C:28]=1[C:9]1[CH:10]=[CH:11][C:12]([C@@H:15]([CH3:25])[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:13][CH:14]=1
Reactant: COc1cc(C)c2c(c1Br)c1cc(C)sc1c(=O)n2COCC[Si](C)(C)C
Reactant: C[C@@H](CNC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: COc1cc(C)c2c(c1-c1ccc([C@@H](C)CNC(=O)OC(C)(C)C)cc1)c1cc(C)sc1c(=O)n2COCC[Si](C)(C)C
Yield: 37.9 %

Procedure:
Following General Procedure B, (R)-tert-butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propylcarbamate (0.12 g, 0.33 mmol) was reacted with 9-bromo-8-methoxy-2,6-dimethyl-5-((2-(trimethylsilyl)ethoxy)methyl)thieno[2,3-c]quinolin-4(5H)-one (0.12 g, 0.33 mmol) to afford the desired product (78 mg, 45%) as a solid: ESI MS m/z 623 [C34H46N2O5SSi+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4](OC)=[N:5][S:6](=[O:8])[N:7]=1.[N:11]1([CH2:17][C:18]2[CH:19]=[N:20][N:21]([O:23][CH2:24][CH2:25][CH2:26][NH2:27])[CH:22]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>CO>[CH3:1][NH:2][C:3]1[C:4]([NH:27][CH2:26][CH2:25][CH2:24][O:23][N:21]2[CH:22]=[C:18]([CH2:17][N:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[CH:19]=[N:20]2)=[N:5][S:6](=[O:8])[N:7]=1
Reactant: CNC1=NS(=O)N=C1OC
Reactant: NCCCOn1cc(CN2CCCCC2)cn1
Solvent: CO
Product: CNC1=NS(=O)N=C1NCCCOn1cc(CN2CCCCC2)cn1
Reaction time: 12 h
Yield: 74.1 %

Procedure:
2.4 g of 4-methylamino-3-methoxy-1,2,5-thiadiazole 1-oxide and 3.5 g of 3-(4-piperidinomethylpyrazol-1-yloxy)propylamine are dissolved in 50 ml of methanol, and the solution is left to stand at room temperature for 12 hours. The solution is then evaporated down and the residue is chromatographed over neutral Al2O3 (activity level III), using methylene chloride/3% strength methanol as the mobile phase. 4 g of the title compound are obtained, the product being crystallized from ethyl acetate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([S:28]C(=O)N(C)C)=[CH:24][CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Br[CH2:37][C:38]([O:40][CH3:41])=[O:39]>CO.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([S:28][CH2:37][C:38]([O:40][CH3:41])=[O:39])=[CH:24][CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C(=O)Sc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)cc1
Reactant: COC(=O)CBr
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)CSc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)cc1
Temperature: 25 °C
Yield: 82.7 %

Procedure:
Dissolve 3-(tert-butoxycarbonyl)-7-chloro-6-(4-dimethylcarbamoylthio-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (270 mg, 0.5 mmol) in methanol (20 mL). Add potassium hydroxide (308 mg, 5.5 mmol) and heat the mixture for 3 h at 65° C. Add methyl bromoacetate (0.52 mL, 5.5 mmol) and heat at 65° C. for 3 h. Cool the mixture to room temperature and dilute with EtOAc. Wash the organic phase with water, dry over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (4:1) to obtain the desired intermediate as an oil (203 mg, 75%).
Reaction SMILES: CO[C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[CH:26]1([NH2:29])[CH2:28][CH2:27]1>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:29][CH:26]4[CH2:28][CH2:27]4)=[O:25])=[CH:5][N:6]=3)=[C:16]([CH3:17])[O:15][N:14]=2)=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2C)nc1
Reactant: NC1CC1
Product: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)NC2CC2)cn1
Yield: 81 %

Procedure:
As described for example 117, 6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (108 mg, 0.3 mmol) was converted, using cyclopropylamine instead of 2,2,2-trifluoroethylamine, to the title compound (93 mg, 81%) which was obtained as a white solid. MS: m/e=384.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:3]=1[CH2:4][P:5](=[O:12])([O:9]CC)[O:6]CC.Br[Si](C)(C)C.O>ClCCl.CO>[F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:3]=1[CH2:4][P:5](=[O:6])([OH:9])[OH:12]
Reactant: CCOP(=O)(Cc1c(F)cccc1F)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: O=P(O)(O)Cc1c(F)cccc1F
Reaction time: 6 h
Yield: 76.1 %

Procedure:
Diethyl 2,6-difluorobenzylphosphonate (2.00 g, 7.57 mmol) was dissolved in dry dichloromethane (20 mL). Bromotrimethylsilane (3.3 mL, 25 mmol) was added via syringe. The reaction was capped with a greased glass stopper and allowed to stir for 6 hours. The volatiles were removed under reduced pressure to yield a yellow oil. This was dissolved in 10:1 methanol:water (20 mL) and allowed to stir overnight. After removing the solvents, recrystallization in acetonitrile yielded a white crystalline solid (1.199 g, 76% yield). 1H NMR (400.14 MHz, DMSO) δ 7.29 (m), 7.04 (m, 2H), 2.96 (d, J=20.99 Hz, 2H). 31P {1H} NMR (161.97 MHz, DMSO): δ 19.51. Analysis calculated (found) %: C 40.40 (40.64), H 3.39 (3.34).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][NH2:17].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][NH:17][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: NCc1cccc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(F)cc1NCc1cccc(Cl)c1
Yield: 94.5 %

Procedure:
2,4-Difluoronitrobenzene (2.9 g, 18.1 mmol), 3-chlorobenzylamine (2.6 g, 18.1 mmol) and N,N-diisopropylethylamine (2.4 g, 18.1 mmol) were stirred in acetonitrile (25 mL) at room temperature for 2 hours. The solvent was evaporated and the crude mixture was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated in vacuo to collect the title compound (4.8 g, 95% yield). 1H NMR (400 MHz, CDCl3): δ 8.55 (s, 1H), 8.25 (dd, 1H), 7.32-7.21 (m, 4H), 6.41 (m, 2H), 4.50 (d, 2H).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:30][CH3:31])[C:25](OCC)=[O:26])[C:5]1=[O:32])[CH:2]=[CH2:3].[BH4-].[Li+]>CCOCC>[CH2:1]([C@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:30][CH3:31])[CH2:25][OH:26])[C:5]1=[O:32])[CH:2]=[CH2:3]
Reactant: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(=O)OCC)C1=O
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Product: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO)C1=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 256 mg (0.54 mmol) of (S)-ethyl 2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butanoate (Example 9, Step B) in Et2O (5.5 mL) was added lithium borohydride of 90% purity (17.6 mg, 0.809 mmol) at 0° C. After being stirred at 0° C. for 10 min, the reaction was quenched (ice cold 10% citric acid), extracted (2×EtOAc) and washed (sat. aq. NaCl solution). The combined organic layers were washed with sat. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification by chromatography on silica gel (eluent 30% to 50% EtOAc/Hexanes, a gradient elution) provided the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][C:5]([OH:7])=O.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>O.CN(C=O)C>[CH3:8][C:2]([CH3:1])([CH3:9])[CH2:3][CH2:4][C:5]([N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:7]
Reactant: CC(C)(C)CCC(=O)O
Reactant: C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)CCC(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4,4-Dimethylvaleric acid (348 g), piperidine (291 mL) and DMF (1.7 L) were mixed. To the mixture were added HOBt.H2O (450 g) and WSC.HCl (563 g) at ice temperature. After the mixture was stirred at RT overnight, water (1.7 L) was added to the reaction mixture at ice temperature and the mixture was extracted with toluene (500 mL, and 400 mL×2). The organic layer was washed with aqueous 10 w/v % sodium carbonate (1 L) and water (1 L), then concentrated in vacuo to give the title compound (508 g) as a crude product.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH2:5])=[O:4].[CH3:6][N:7]([C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[N:8]([CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1)[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].N1C=CC=CC=1>C1C=CC=CC=1>[CH3:6][N:7]([C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[N:8]([CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](=[O:25])[NH:5][C:3]([NH:2][CH3:1])=[O:4])=[CH:22][CH:21]=1)[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: CN(C(=O)OCc1ccccc1)N(Cc1ccc(C(=O)Cl)cc1)C(=O)OCc1ccccc1
Reactant: CNC(N)=O
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CNC(=O)NC(=O)c1ccc(CN(C(=O)OCc2ccccc2)N(C)C(=O)OCc2ccccc2)cc1

Procedure:
7.4 g. of methyl urea, 46.7 g. of 4-[(2-methyl-1,2-dicarbobenzoxy-hydrazino)-methyl]-benzoyl chloride, 8 g. of pyridine and 200 ml. of benzene were mixed and refluxed for 8 hours. After cooling down, the mixture was poured onto water and extracted with an ether/methylene chloride mixture. The extract was washed with water, with 1 N hydrochloric acid and again with water, dried over sodium sulfate and freed of the solvent by distillation. The residue crystallized upon triturating with methanol. The crystals were filtered off and dried, yielding 1-methyl-2-[4-(4-methyl-allophanoyl)-benzyl]-1,2-dicarbobenzoxy-hydrazine melting at 141°-142°. 25 g. thereof were dissolved in 50 ml. of glacial acetic acid and to it were added 100 ml. of a 33% solution of hydrobromic acid in glacial acetic acid. After 4 hours standing, the crystals formed were filtered off, washed with glacial acetic acid and ether, and recrystallized from methanol, yielding 1-methyl-2-[4-(4-methyl-allphanoyl)benzyl]-hydrazine hydrobromide of melting point 183°-183.5°.
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[CH2:14]([O:21][C:22]1[CH:23]=[C:24]([OH:28])[CH:25]=[CH:26][CH:27]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>C1COCC1>[CH2:14]([O:21][C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=1)[O:28][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cccc(OCc2ccccc2)c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1cccc(OCc2ccccc2)c1

Procedure:
43.459 ml tert-butyl-chloro-dimethyl-silane were added at rt to a solution of 17 g imidazole and 25 g 3-benzyloxy-phenol in 400 ml THF. After 3 hours water was added to the reaction mixture and the mixture was then extracted with methylene chloride. The organic phase was extracted three times with water, dried over sodium sulfate and concentrated in vacuo. The residue was solved in methylene chloride and filtered over Alox (neutral) and concentrated.
Reaction SMILES: [CH:1]1([N:7]([P:10]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])=[O:11])[CH:8]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH:1]1([N:7]([P:10]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])=[O:11])[CH:8]=[S:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOP(=O)(OCC)N(C=O)C1CCCCC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOP(=O)(OCC)N(C=S)C1CCCCC1

Procedure:
A mixture of 0.359 g (1.4 mmol) of N-(cyclohexyl)diethylphosphonoformamide, 0.276 g (0.7 mmol) of Lawesson Reagent in 10 ml toluene was refluxed for 5.5 h. The resulting mixture was subjected to VLC (vacuum liquid chromatography) using gradient eluants [from 5% ethyl acetate in petroleum ether to ethyl acetate/petroleum ether (40:60) to give N-cyclohexyl diethylphosphonothioformamide as a yellow solid, 0.327 g (85.8%, isolated yield). NMR (CDCl3): 3P −1.66. 1H, 1.18–2.01 (m, 16H), 4.17 (m, 4H), 4.34 (m, 1H), 8.89 (br. s, 1H).
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[C:6]2[N:7]([C:11]([C:15]3[N:19]4[N:20]=[C:21]([CH3:29])[CH:22]=[C:23]([CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[C:18]4=[N:17][C:16]=3[CH3:30])=[C:12]([CH3:14])[N:13]=2)[CH:8]=[CH:9][CH:10]=1)C.Cl>CC(C)=O>[CH2:25]([CH:24]([C:23]1[C:18]2[N:19]([C:15]([C:11]3[N:7]4[CH:8]=[CH:9][CH:10]=[C:5]([CH:4]=[O:3])[C:6]4=[N:13][C:12]=3[CH3:14])=[C:16]([CH3:30])[N:17]=2)[N:20]=[C:21]([CH3:29])[CH:22]=1)[CH2:27][CH3:28])[CH3:26]
Reactant: CCOC(OCC)c1cccn2c(-c3c(C)nc4c(C(CC)CC)cc(C)nn34)c(C)nc12
Agent: Cl
Solvent: CC(C)=O
Product: CCC(CC)c1cc(C)nn2c(-c3c(C)nc4c(C=O)cccn34)c(C)nc12
Yield: 71.5 %

Procedure:
A solution of 3-(8-diethoxymethyl-2-methyl-imidazo[1,2-a]pyridin-3-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (2.33 g, 5.20 mmol) in acetone (25 mL) is treated with 5 M HCl (1.0 mL, 5 mmol) and the resulting solution is refluxed for 4 h. The organic solvent is removed in vacuo; the residue is diluted with H2O (100 mL), the pH is adjusted to 8-9 using sat. NaHCO3; the mixture is extracted with EtOAc (2×100 mL); dried with Na2SO4; filtered and concentrated, and purification of the crude material by silica gel chromatography gives the title compound (1.39 g, 3.72 mmol, 71%). 1H NMR (CDCl3): δ. 0.92 (t, J=7.5 Hz, 3H), 0.93 (t, J=7.5 Hz, 3H), 1.81-1.95 (m, 4H), 2.43 (s, 3H), 2.44 (s, 3H), 2.51 (s, 3H), 3.30-3.42 (m, 1H), 6.76 (s, 1H), 6.91 (t, J=7.0 Hz, 1H), 7.74 (dd, J=7.0, 1.3 Hz, 1H), 7.78 (dd, J=7.0, 1.3 Hz, 1H), 10.84 (s, 1H) ppm. ES-MS (m/z): calcd for C22H25N5O (M+H)+: 376.5. found: 376.2.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[CH:15]=[C:16]([Cl:32])[C:17]([CH3:31])=[C:18]([C:28]([NH2:30])=[O:29])[C:19]=1[C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:32][C:16]1[C:17]([CH3:31])=[C:18]([C:28]([NH2:30])=[O:29])[C:19]([C:20]2[CH:21]=[C:22]([F:27])[CH:23]=[C:24]([F:26])[CH:25]=2)=[C:14]([CH:12]([NH:11][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:13])[CH:15]=1
Reactant: Cc1c(Cl)cc(C(C)N)c(-c2cc(F)cc(F)c2)c1C(N)=O
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Cl)cc(C(C)Nc2ncnc3[nH]cnc23)c(-c2cc(F)cc(F)c2)c1C(N)=O
Temperature: 90 °C

Procedure:
A mixture of 6-bromo-9H-purine (41 mg, 0.21 mmol), 6-(1-aminoethyl)-4-chloro-3′,5′-difluoro-3-methylbiphenyl-2-carboxamide (61 mg, 0.19 mmol), and N,N-diisopropylethylamine (0.065 mL, 0.38 mmol) in isopropyl alcohol (0.7 mL) was heated at 90° C. under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C21H18ClF2N6O (M+H)+: m/z=443.1. found: 443.1.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][C:13]([C:16]1[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][C:17]=1[NH2:18])([CH3:15])[CH3:14]>>[CH3:15][C:13]([C:16]1[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][C:17]=1[NH:18][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=1[OH:11])([CH3:12])[CH3:14]
Reactant: Cc1ccc(O)c(C(=O)O)c1
Reactant: CC(C)(C)c1ccc(C(C)(C)C)c(N)c1
Product: Cc1ccc(O)c(C(=O)Nc2cc(C(C)(C)C)ccc2C(C)(C)C)c1
Yield: 61.1 %

Procedure:
Using 5-methylsalicylic acid and 2,5-bis[(1,1-dimethyl)ethyl]aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([N:14]3[CH:23]([CH3:24])[CH2:22][C:21]4[C:16](=[CH:17][C:18](B5OC(C)(C)C(C)(C)O5)=[CH:19][CH:20]=4)[CH2:15]3)[N:11]=[C:10]([NH2:34])[N:9]=2)[CH2:4][CH2:3]1.Br[C:36]1[N:37]=[C:38]([O:41][CH2:42][CH3:43])[S:39][CH:40]=1>>[CH2:42]([O:41][C:38]1[S:39][CH:40]=[C:36]([C:18]2[CH:17]=[C:16]3[C:21]([CH2:22][CH:23]([CH3:24])[N:14]([C:12]4[CH:13]=[C:8]([N:5]5[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]5)[N:9]=[C:10]([NH2:34])[N:11]=4)[CH2:15]3)=[CH:20][CH:19]=2)[N:37]=1)[CH3:43]
Reactant: CC1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CCOc1nc(Br)cs1
Product: CCOc1nc(-c2ccc3c(c2)CN(c2cc(N4CCN(C)CC4)nc(N)n2)C(C)C3)cs1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 116 starting from 4-(4-methylpiperazin-1-yl)-6-[3-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine and 4-bromo-2-ethoxy-1,3-thiazole (Indofine, Cat. No. 08-932). LCMS (M+H)+: m/z=466.2.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7](O)(=O)/[CH:8]=[CH:9]/[CH2:10][CH2:11][CH:12]=[CH2:13].C(N(CC)CC)C.COP([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])(OC)=O.[H-].[Na+].[Cl-].[NH4+]>C1(C)C=CC=CC=1.O.C(COC)OC>[CH:11]12[CH2:12][C:13](=[CH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:7]1[CH:8]=[CH:9][CH2:10]2
Reactant: COP(=O)(CC(=O)OC(C)(C)C)OC
Reactant: C=CCC/C=C/C(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)C=C1CC2CC=CC12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Oxalyl chloride (10 mL) was added dropwise to a solution of (2E)-hepta-2,6-dienoic acid (3.27 g, 25.9 mmol) in toluene (60 mL) under ice cooling. The mixture was stirred for 20 minutes, then removed from the ice water bath, and gradually heated to room temperature. After stirring for 50 minutes, the reaction solution was stirred for 1 hour under heating to reflux. The solution was allowed to cool, and the solvent was then distilled off under reduced pressure. To the residue, toluene was further added, and the solvent was then distilled off again under reduced pressure. The residue was dissolved in toluene (20 mL), and this solution was added dropwise over 1 hour to a solution of triethylamine (9.19 g, 91 mmol) in toluene (20 mL) heated in advance to 90° C. After the completion of the dropwise addition, the mixture was further heated with stirring for 2 hours. The reaction solution was cooled, then diluted with saturated saline and water, and filtered through Celite. The filtrate was separated into organic and aqueous layers. The organic layer was then washed with 1 N hydrochloric acid, then dried over magnesium sulfate, and filtered. The filtrate was added to a reaction solution prepared in advance from a solution of tert-butyl dimethoxyphosphorylacetate (5.98 g, 25.9 mmol) in dimethoxyethane (20 mL) and sodium hydride (>65% oil, 986.7 mg, 25.9 mmol), and the mixture was stirred for 1.5 hours. To the reaction solution, a saturated aqueous solution of ammonium chloride, saturated saline, and water were added in this order, and the reaction solution was subjected to extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then filtered. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the compound of interest as a pale yellow oil substance (1.73 g, 32%, E/Z mixture).
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][C:18]4[N:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=4)[CH:13]=3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1CCC(C(O)=O)CC1.Cl.N[C@@H](C)C(NC1C=NC(OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=CC=1)=O.Cl.N[C@H](C)C(NC1C=NC(OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=CC=1)=O.C(OC([NH:101][CH:102]([CH:106]([CH3:108])[CH3:107])[C:103](O)=[O:104])=O)(C)(C)C>>[NH2:101][CH:102]([CH:106]([CH3:108])[CH3:107])[C:103]([NH:24][C:21]1[CH:22]=[N:23][C:18]([O:17][C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[O:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:16][CH2:15]3)=[CH:19][CH:20]=1)=[O:104]
Reactant: CC(C)C(NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Agent: C[C@@H](N)C(=O)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Agent: C[C@H](N)C(=O)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Agent: Cl
Product: CC(C)C(N)C(=O)Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1

Procedure:
2-Amino-3-methyl-N-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]butyramide and its derivatives were prepared as described for piperidine-4-carboxylic acid [6-(2-phenylchroman-6-yloxy)pyridine-3-yl]amine in Example 19 a) and b) but replacing N-(tert-butoxycarbonyl)isonipecotic acid with (S), (R) or (SR)-2-tert-butoxycarbonylamino-3-methylbutyric acid.