Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=2[CH:17]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[C:31]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][CH:29]=[CH:28][C:27]=2[F:36])[C:22]([Cl:37])=[CH:21][N:20]=1>>[Cl:37][C:22]1[C:23]([NH:25][C:26]2[C:31]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][CH:29]=[CH:28][C:27]=2[F:36])=[N:24][C:19]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=3[CH:17]=2)=[N:20][CH:21]=1
Reactant: CS(=O)(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)CCC(C)(C)c2ccc(N)cc21
Product: CCN1C(=O)CCC(C)(C)c2ccc(Nc3ncc(Cl)c(Nc4c(F)cccc4S(C)(=O)=O)n3)cc21

Procedure:
Title compound was prepared from 8-Amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and (2,5-Dichloro-pyrimidin-4-yl)-(2-fluoro-6-methanesulfonyl-phenyl)-amine in an analogous manner to Example 1221d. Product isolated as a white solid (32 mg, 22%). MP=217-218, LCMS: 534.09 (M+H), 1H-NMR (CDCl3, 400 MHz) 6 (8.18 (s, 1H), 7.97 (s, 1H), 7.89 (d, J=7.6 Hz, 1H), 7.55-7.46 (m, 4H), 7.21 (d, J=8.6 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 3.75-3.73 (m, 2H), 2.99 (s, 3H), 2.29-2.26 (m, 2H), 2.10-1.99 (m, 2H), 1.33 (s, 6H), 1.21 (t, J=7.1 Hz, 3H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:16]([NH:18][CH2:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:17].[OH-].[Na+].Br[CH2:34][C:35]([OH:37])=[O:36].Cl>CCO.O>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:16]([NH:18][CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH2:34][C:35]([OH:37])=[O:36])[CH2:22][CH2:21]1)=[O:17]
Reactant: O=C(O)CBr
Reactant: COc1ccc(C(=O)NCC2CCNCC2)cc1OCCc1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(C(=O)NCC2CCN(CC(=O)O)CC2)cc1OCCc1ccc(Cl)cc1Cl

Procedure:
To 1 g 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-piperidin-4-ylmethyl-benzamide hydrochloride and 400 mg NaOH in 50 ml EtOH/H2O 1:1 0.35 g bromo acetic acid were added at RT. After stirring over night the reaction mixture was acidified with half concentrated HCl. After evaporation of the solvent the residue was coevaporated with toluene. The waxy brown solid was subjected to the subsequent reaction without further purification.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:25])=[C:11]([N:15]4[CH2:20][CH2:19][O:18][CH:17]([CH2:21][N:22]([CH3:24])[CH3:23])[CH2:16]4)[C:12]=3[F:14])[C:7](=[O:26])[C:6]([C:27]([O:29]CC)=[O:28])=[CH:5]2)[CH2:3][CH2:2]1.[ClH:32]>O.C(O)C>[ClH:32].[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:25])=[C:11]([N:15]4[CH2:20][CH2:19][O:18][CH:17]([CH2:21][N:22]([CH3:24])[CH3:23])[CH2:16]4)[C:12]=3[F:14])[C:7](=[O:26])[C:6]([C:27]([OH:29])=[O:28])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CCOC(CN(C)C)C3)c(F)cc2c1=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: CN(C)CC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CCO1
Yield: 80 %

Procedure:
A solution of 2.21 g of ethyl 1-cyclopropyl-6,8-difluoro-7-[2-(dimethylaminomethyl)morpholino]-1,4-dihydro-4-oxoquinoline-3-carboxylate and 5 ml of concentrated hydrochloric acid in 10 ml of water and 10 ml of ethanol is refluxed, for 2.5 hours. The resultant mixture is concentrated under reduced pressure and to the obtained crystals is added ethanol. The crystals are filtered off with suction, washed with ethanol and then dried to give 1.82 g of 1-cyclopropyl-6,8-difluoro-7-[2-(dimethylaminomethyl)morpholino]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.hydrochloride in 80% yield, melting at 267°-268° C.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=4[C:15](=[O:23])[N:14]4[CH2:24][CH2:25][C@H:13]4[C:12]=23)[N:4]=1.[CH2:26]([NH2:29])[CH2:27][CH3:28]>CN(C)C=O>[F:22][C:20]1[CH:19]=[CH:18][C:17]2[N:11]3[CH:10]=[N:9][C:8]([C:5]4[N:4]=[C:3]([CH2:2][NH:29][CH2:26][CH2:27][CH3:28])[O:7][N:6]=4)=[C:12]3[C@@H:13]3[CH2:25][CH2:24][N:14]3[C:15](=[O:23])[C:16]=2[CH:21]=1
Reactant: O=C1c2cc(F)ccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCN12
Reactant: CCCN
Solvent: CN(C)C=O
Product: CCCNCc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2cc(F)ccc2-3)no1
Yield: 73.2 %

Procedure:
1.8 g (5 mmol) of (S)-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one were stirred at room temperature for 2 hours with 2 g (34 mmol) of propylamine and 20 ml of N,N-dimethylformamide. By evaporation of the solvent and chromatography of the residue on silica gel while eluting with ethyl acetate/methanol 9/1 there were obtained 1.4 g (73%) of (S)-7-fluoro-1-(5-propylaminomethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted into the hydrochloride (amorphous).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:37])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=4)[CH:20]([C:29](O)=[O:30])[NH:19][CH:18]3[CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:62][C:63]1[CH:70]=[CH:69][C:66]([C:67]#[N:68])=[CH:65][C:64]=1[O:71][CH3:72]>>[C:67]([C:66]1[CH:69]=[CH:70][C:63]([NH:62][C:29]([CH:20]2[NH:19][CH:18]([CH2:32][C:33]([CH3:35])([CH3:36])[CH3:34])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:37])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[O:30])=[C:64]([O:71][CH3:72])[CH:65]=1)#[N:68]
Reactant: COc1cc(C#N)ccc1N
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C#N)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 63 (1.0 g, 1.8 mmol), was reacted with diisopropylethylamine (2.1 g, 16.5 mmol), diphenylphosphinic chloride (1.74 g, 7.3 mmol), then reacted with 4-amino-3-methoxy-benzonitrile prepared in Example 57 (0.54 g, 3.7 mmol) to give rac-(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-2-methoxy-phenyl)-amide as a white solid (Yield, 0.17 g, 16%).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CSC.[N+:12]([C:15]1[CH:16]=[C:17](/[C:21](/[CH2:25][CH3:26])=[CH:22]/[CH2:23]O)[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13]>ClCCl>[Cl:1][CH2:23]/[CH:22]=[C:21](/[C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=1)\[CH2:25][CH3:26]
Reactant: CC/C(=C\CO)c1cccc([N+](=O)[O-])c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CSC
Solvent: ClCCl
Product: CC/C(=C\CCl)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N-chlorosuccinimide (52.3 g, 0.39 mol) in dichloromethane (1.2 l) at 0° C. was added dropwise over 20 minutes dimethylsulfide (27.9 ml, 0.38 mol). To the mixture was added dropwise over 20 minutes at 0° C. a solution of (E)-3-(3-nitrophenyl)-2-penten-1-ol (Preparation 14, 80 g, 0.39 mol) in dichloromethane (300 ml). The mixture was warmed to room temperature over 1 h, stirred at room temperature for 16 h, then partitioned between water (2 l) and dichloromethane (1 l). The layers were separated and the organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica column chromatography (2 kg), eluting with 10:1 hexane/diethyl ether. Appropriate fractions were combined and concentrated in vacuo to give the title compound as a very pale yellow oil (54 g, 62%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[C:5]([N+:14]([O-])=O)=[CH:4][N:3]=1.[Sn](Cl)Cl.Cl>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[C:5]([NH2:14])=[CH:4][N:3]=1
Reactant: CCC(CC)Nc1nc(Cl)ncc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: CCC(CC)Nc1nc(Cl)ncc1N
Temperature: 80 °C
Yield: 56.8 %

Procedure:
To a solution of (2-chloro-5-nitro-pyrimidin-4-yl)-(1-ethyl-propyl)-amine (1 g, 4.1 mmol) in anhydrous EtOH (50 mL) is added Tin(II) chloride (2.3 g, 12.3 mmol) and concentrated HCl (1 mL) at ambient temperature. The reaction is heated to 80° C. for 1 h and quenched with 1N NaOH at 0° C. The mixture is extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated in vacuo to give 0.5 g of (2-chloro-5-amino-pyrimidin-4-yl)-(1-ethyl-propyl)-amine. The crude is used as is.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([CH:8]2[O:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])[CH:7]=1.[CH:17]1([N:23]=[C:24]=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(N(CC)CC)C.ClCCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([CH:8]2[O:12][C:11](=[O:13])[N:10]([C:24](=[O:25])[NH:23][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:9]2=[O:14])[CH:7]=1
Reactant: COc1ccc(Cl)cc1C1OC(=O)NC1=O
Reactant: O=C=NC1CCCCC1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1C1OC(=O)N(C(=O)NC2CCCCC2)C1=O
Temperature: 25 °C
Reaction time: 19 h

Procedure:
5-(5-Chloro-2-methoxyphenyl)oxazolidine-2,4-dione (1.21 g., 5 mmoles) was suspended in 50 ml. of 1,2-dichloroethane. Triethylamine (1 drop) and then cyclohexylisocyanate (626 mg., 5 mmoles) were added. The reaction mixture was stirred for 19 hours at room temperature, washed in sequence with two portions of 1 N sodium hydroxide, two portions of 1 N hydrochloric acid and once with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to solids. Recrystallization from toluene gave purified 5-(5-chloro-2-methoxyphenyl)-3-cyclohexylcarbamoyloxazolidine-2,4-dione [435 mg., m.p. 150°-153° C., ir (KBr) 1818, 1761, 1527, 1493, 1364 cm-1 ].
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[C:10]([Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15])([CH3:13])([CH3:12])[CH3:11]>>[Br:9][C:5]1[CH:6]=[C:7]([F:8])[C:2]([C:18]#[C:17][Si:14]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:16])[CH3:15])=[N:3][CH:4]=1
Reactant: C#C[Si](C)(C)C(C)(C)C
Reactant: Fc1cc(Br)cnc1Br
Product: CC(C)(C)[Si](C)(C)C#Cc1ncc(Br)cc1F

Procedure:
The product was prepared analogously to Example 48.1c from 23.4 g (92.0 mmol) of 2,5-dibromo-3-fluoropyridine and 17.5 mL (92.0 mmol) of tert-butylethynyldimethylsilane (with triethylamine as base and PdCl2(PPh3)2 as catalyst). Yield: 23.3 g (81% of theoretical); C13H17BrFNSi (M=314.269); calc.: molpeak (M+H)+:314/316 (Br); found: molpeak (M+H)+:314/316 (Br).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([NH:11][C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH2:22])[CH:18]=3)[N:13]=1)[CH2:8][CH2:7]2.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31](O)=[O:32])[CH2:26][CH2:25]1>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([NH:11][C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:22][C:31](=[O:32])[CH2:30][N:27]4[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]4)[CH:18]=3)[N:13]=1)[CH2:8][CH2:7]2
Reactant: Nc1ccc2nc(NC3CCc4cccc(F)c43)ccc2c1
Reactant: CN1CCN(CC(=O)O)CC1
Product: CN1CCN(CC(=O)Nc2ccc3nc(NC4CCc5cccc(F)c54)ccc3c2)CC1

Procedure:
The title compound was prepared in accordance with the general method 14 described in example 119 from rac-N2-(7-fluoro-indan-1-yl)-quinoline-2,6-diamine and (4-methyl-piperazin-1-yl)-acetic acid; MS: m/e=434.4 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH2:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([C:30]([O:32]C)=O)[C:26]([O:28]C)=[O:27])=[CH:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].C(=O)([O-])[O-].[Na+].[Na+].Cl.[NH2:41][OH:42].Cl>O1CCCC1.CO>[OH:42][NH:41][C:30](=[O:32])[CH:25]([CH2:24][C:21]1[CH:20]=[CH:19][C:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][N:2]([CH3:1])[C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[O:4])[CH:13]=2)=[CH:23][CH:22]=1)[C:26]([OH:28])=[O:27]
Reactant: COC(=O)C(Cc1ccc(-c2cccc(CN(C)C(=O)c3ccccc3)c2)cc1)C(=O)OC
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CN(Cc1cccc(-c2ccc(CC(C(=O)O)C(=O)NO)cc2)c1)C(=O)c1ccccc1
Temperature: 60 °C
Yield: 69.4 %

Procedure:
A mixture of 130 mg (0.3 mmol) of dimethyl 2-(3′{[methyl-(1-phenylmethanoyl)amino]methyl}biphenyl-4-ylmethyl)malonate (prepared in Example 15(b)), 2 ml of methanol, 2 ml of tetrahydrofuran, 480 mg of sodium carbonate (4.5 mmol) and 200 mg (1.5 mmol) of hydroxylamine hydrochloride is heated at 60° C. for 18 hours. The reaction medium is neutralized to pH 6-7 with hydrochloric acid solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on a column of silica, eluted with a mixture of heptane and ethyl acetate (75/25). 90 mg (72%) of the desired product, with a melting point of 60° C., are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4]([CH3:11])[CH2:5][CH2:6][CH2:7][C:8](=[O:10])[CH3:9].CC(OC)(C)C.[OH-].[Na+].CC(CC(C)=O)C>P(=O)(O)(O)O>[CH3:1][O:2][C:3](=[O:12])[C@@H:4]([CH3:11])[CH2:5][CH2:6][CH2:7][C:8](=[O:10])[CH3:9]
Reactant: COC(=O)C(C)CCCC(C)=O
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: CC(=O)CC(C)C
Product: COC(=O)[C@@H](C)CCCC(C)=O
Temperature: 10 °C
Reaction time: 48 h
Yield: 40.3 %

Procedure:
10.6 g (content 94.3%, 5.75 mmol) of a racemate of 2-methyl-6-oxoheptanoic acid methyl ester and 20.0 g of MTBE were suspended in 50.0 g of 0.1 M phosphoric acid buffered solution (pH 7.0). The suspension was cooled to 10° C., then, 2.0 g (moisture percentage 56%, enzymatic activity 4028 KU/Kg, reduced by dry product) of immobilized Aspergillus flavus ATCC11492 strain-derived esterase (prepared by a method described in JP-A No. 2003-70471) was added, and the mixture was stirred at 10° C. for 48 hours while maintaining pH at 7.5 to 8.0 by appropriately adding 4% NaOH aqueous solution. Thereafter, the reaction solution was filtrated using Radiolite (filtration aid, trade name: manufactured by Showa Chemical Industry Co., Ltd.), to remove the esterase. The resultant filtrate was extracted twice with 25 g and 12.5 g of MIBK, then, the resultant organic layers were combined and washed with 15% saline, to obtain a MIBK solution of optically active (S)-2-methyl-6-oxoheptanoic acid methyl ester (optical purity 98.8% ee, yield 40.3%). The optical purity was analyzed by HPLC [Chiralpak AS-H, 4.6 mm×25 cm (manufactured by Daicel Chemical Industries, Ltd.)] like in Example 1.
Reaction SMILES: [N+]([NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1)([O-])=O.[CH3:19][N:20]([CH2:22][C:23]1[S:24][CH:25]=[C:26]([CH2:28][S:29][CH2:30][CH2:31]N)[N:27]=1)[CH3:21]>>[CH3:21][N:20]([CH2:22][C:23]1[S:24][CH:25]=[C:26]([CH2:28][S:29][CH2:30][CH2:31][NH:4][C:5]2[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[CH:7][N:6]=2)[N:27]=1)[CH3:19]
Reactant: CN(C)Cc1nc(CSCCN)cs1
Reactant: O=c1[nH]c(N[N+](=O)[O-])ncc1Cc1ccncc1
Product: CN(C)Cc1nc(CSCCNc2ncc(Cc3ccncc3)c(=O)[nH]2)cs1

Procedure:
Following the procedure of Example 1, 2-nitroamino-5-(4-pyridyl)methyl-4-pyrimidone was reacted with 2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylamine to yield 2-[2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl]amino-5-(4-pyridyl)methyl-4-pyrimidone as a trihydrochloride salt melting at 200°-202° C. after recrystallization from a methanol/ethanol solvent mixture.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([CH2:17][C:18]([OH:20])=O)[CH:14]=[CH:13][C:11]=2[N:12]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.[NH2:56][C:57]1[CH:58]=[CH:59][C:60]([CH:66]([CH3:73])[CH2:67][C:68]([O:70][CH2:71][CH3:72])=[O:69])=[C:61]2[C:65]=1[CH2:64][CH2:63][CH2:62]2>CN(C)C=O>[C:1]1([CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([CH2:17][C:18]([NH:56][C:57]3[CH:58]=[CH:59][C:60]([CH:66]([CH3:73])[CH2:67][C:68]([O:70][CH2:71][CH3:72])=[O:69])=[C:61]4[C:65]=3[CH2:64][CH2:63][CH2:62]4)=[O:20])[CH:14]=[CH:13][C:11]=2[N:12]=1
Reactant: Cc1ccccc1Nc1nc2ccc(CC(=O)O)cc2o1
Reactant: CCOC(=O)CC(C)c1ccc(N)c2c1CCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC(C)c1ccc(NC(=O)Cc2ccc3nc(Nc4ccccc4C)oc3c2)c2c1CCC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 104.6 %

Procedure:
A mixture of 2-(2-o-tolylamino-benzoxazol-6-yl)acetic acid (0.398 g, Reference Example 2), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.59 g) and diisopropylethylamine (0.24 g) in dimethylformamide was stirred at room temperature for 10 minutes and then treated with a solution of ethyl 3-[7-amino-indan-4-yl]-butanoate hydrochloride (0.4 g, Reference Example 5) in dimethylformamide. After shaking and then allowing to stand at room temperature for 16 hours the reaction mixture was evaporated under high vacuum. The residual red oil was dissolved in ethyl acetate and the solution was washed with 5% aqueous sodium bicarbonate, then with water, then dried over sodium sulfate and then evaporated to give the title compound (0.754 g) as an oil.
Reaction SMILES: Cl[C:2]1[C:3]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][N:10]=2)[N:7]=1.[OH-:23].[Na+]>O1CCOCC1.O>[C:11]1([C:8]2[N:6]3[NH:7][C:2](=[O:23])[C:3]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][C:5]3=[N:10][N:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Clc1nn2c(-c3ccccc3)nnc2cc1-c1ccccc1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=c1[nH]n2c(-c3ccccc3)nnc2cc1-c1ccccc1
Yield: 92.3 %

Procedure:
To a solution of 6-chloro-3,7-diphenyl-1,2,4-triazolo[4,3-b]pyridazine (from Example 2, Step c) (1.02 g, 3.34 mmol) in 1,4-dioxane (60 ml) and water (12 ml) was added 4 M aqueous NaOH (4.17 ml, 16.7 mmol), and the solution was heated at reflux for 7.5 h whilst stirring magnetically. The mixture was then concentrated in vacuo and the aqueous residue was partitioned between water (200 ml) and diethyl ether (100 ml). The aqueous layer was then acidified with 5 M aqueous HCl until the pH was ca. 3. The resulting precipitated solid was collected by filtration, washed with water, then hexane, and dried at 60° C. under vacuum to give 0.8885 g (92%) of the title compound as a white solid. 1H NMR (360 MHz, d6-DMSO) δ 7.47-7.63 (6H, m), 7.71 (2H, dd, J=8.0, J=1.8 Hz), 8.31 (1H, s), 8.46 (2H, m), 12.80 (1H, br s); MS (ES+) m/e 289 [MH]+.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([B:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]2)[CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O>CO.[Pd]>[CH3:16][C:14]1([CH3:17])[C:13]([CH3:18])([CH3:19])[O:12][B:11]([C:9]2[CH:10]=[C:4]([NH2:1])[C:5]([NH2:6])=[CH:7][CH:8]=2)[O:15]1
Reactant: CC1(C)OB(c2ccc(N)c([N+](=O)[O-])c2)OC1(C)C
Agent: [Pd]
Solvent: CO
Product: CC1(C)OB(c2ccc(N)c(N)c2)OC1(C)C

Procedure:
To a solution of commercially available 2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.0 g, 7.5 mmol) in MeOH (50 mL) was added 10% wet Pd—C (50% water in weight, 200 mg). The reaction mixture was flushed with H2 and hydrogenated at 3.3 bar for 2 h. Upon completion the suspension was filtered through Celite to remove the catalyst. The filtrate was concentrated under reduced pressure to give 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene-1,2-diamine, that was submitted to the next step without further purification.
Reaction SMILES: CCN=C=NCCCN(C)C.[NH2:12][C:13]1[S:14][C:15]([CH3:21])=[C:16]([CH3:20])[C:17]=1[C:18]#[N:19].[C:22]1([CH:28]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:29](O)=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:18]([C:17]1[C:16]([CH3:20])=[C:15]([CH3:21])[S:14][C:13]=1[NH:12][C:29](=[O:30])[CH:28]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)#[N:19]
Reactant: O=C(O)C(Cc1ccccc1)c1ccccc1
Reactant: Cc1sc(N)c(C#N)c1C
Agent: CCN=C=NCCCN(C)C
Product: Cc1sc(NC(=O)C(Cc2ccccc2)c2ccccc2)c(C#N)c1C
Reaction time: 19 h

Procedure:
EDCI (61 mg; 0.32 mmol) was added to a solution of 2-Amino-3-cyano-4,5-dimethylthiophene (prepared in Example 1, Step 1; 24 mg; 0.148 mmol) and 2,3-diphenylpropionic acid (72 mg; 0.32 mmol). After stirring for 19 h, the reaction mixture was applied directly to a silica gel column (Merck Silica gel 60, 230–400 mesh, eluent: 10%–33% ethylacetate/hexanes) to provide N-(3-Cyano-4,5-dimethyl-thiophen-2-yl)-2,3-diphenyl-propionamas a white solid (17.0 mg; 39%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:7]([O:14][N:15]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][C:20](F)=[C:21]([F:26])[CH:22]=2)[N:17]([CH2:28][CH3:29])[C:16]1=[O:30])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>C(#N)C>[CH2:7]([O:14][N:15]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][C:20]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)=[C:21]([F:26])[CH:22]=2)[N:17]([CH2:28][CH3:29])[C:16]1=[O:30])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C1CNCCN1
Reactant: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(F)cc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(N3CCNCC3)cc21
Yield: 54.4 %

Procedure:
Piperazine (0.06 g, 0.72 mmol) was added to a solution of 3-benzyloxy-1-ethyl-6,7-difluoro-1H-quinazoline-2,4-dione (Example C, 0.2 g, 0.6 mmol) and triethylamine (0.17 mL, 1.2 mmol) in 30 mL of acetonitrile. The solution was warmed to reflux for 24 hours, cooled, and concentrated to a solid. The solid was dissolved in chloroform washed with 1N HCl, saturated NaHCO3, brine, and dried over magnesium sulfate. The solution was concentrated to give 0.13 g of the title compound as a solid, mp 166-167° C.
Reaction SMILES: [CH:1]1([C:4]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:7]([C:8]([OH:10])=O)=[C:6]([CH2:17][CH3:18])[CH:5]=2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH:53]1[CH2:58][CH2:57][CH:56]([C:59]2[CH:66]=[CH:65][C:62]([C:63]#[N:64])=[CH:61][CH:60]=2)[CH2:55][CH2:54]1>CN(C)C=O>[C:63]([C:62]1[CH:61]=[CH:60][C:59]([CH:56]2[CH2:57][CH2:58][N:53]([C:8]([C:7]3[C:6]([CH2:17][CH3:18])=[CH:5][C:4]([CH:1]4[CH2:2][CH2:3]4)=[C:12]([CH:11]=3)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[CH2:54][CH2:55]2)=[CH:66][CH:65]=1)#[N:64]
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Reactant: CCc1cc(C2CC2)c(C(=O)OC)cc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(C2CC2)c(C(=O)OC)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99.1 %

Procedure:
To a round-bottom flask, which was purged and maintained with a nitrogen atmosphere, was added a solution of 4-cyclopropyl-2-ethyl-5-(methoxycarbonyl)benzoic acid (compound 226.6., 500 mg, 2.01 mmol, 1.00 equiv) in N,N-dimethylformamide (20 mL). HBTU (1.53 g, 4.03 mmol, 2.00 equiv), DIEA (780 mg, 6.04 mmol, 3.00 equiv) were added to the reaction solution, and it was stirred for 5 min at 25° C. 4-(piperidin-4-yl)benzonitrile (compound 1.5, 410 mg, 2.20 mmol, 1.10 equiv) was added to the above mixture. After stirring for 15 h at 25° C., the reaction was quenched by the addition of water. The mixture was extracted with 100 mL of ethyl acetate and the combined organic layers were washed with 4×40 mL of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (4:1) as eluent to furnish 0.830 g (99%) of methyl 5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclopropyl-4-ethylbenzoate as a colorless oil.