Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]2[C:11]=1[C:10](=[O:12])[CH:9]([CH:13]=[O:14])[CH2:8][CH2:7]2.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[OH:12][C:10]1[C:11]2[C:6](=[C:5]([O:15][CH3:16])[CH:4]=[CH:3][C:2]=2[F:1])[CH:7]=[CH:8][C:9]=1[CH:13]=[O:14]
Reactant: COc1ccc(F)c2c1CCC(C=O)C2=O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: COc1ccc(F)c2c(O)c(C=O)ccc12

Procedure:
8-Fluoro-2-formyl-5-methoxy-1-tetralone (20 g) was dissolved in dioxan. 2,3-Dichloro-5,6-dicyanobenzoquinone (21 g) was added and the mixture was heated under reflux for 2 hours. The mixture was allowed to cool and was filtered to remove solids. The solvent was removed under reduced pressure and the residue taken up in ethyl acetate. The product solution was washed with saturated NaHCO3 (aq) (×3), dried (MgSO4), filtered and evaporated to give a dark solid. This material was recrystallised from ethyl acetate/hexane to give 1-hydroxy-5-methoxy-8-fluoro-2-naphthaldehyde, m.p. 156°-158° C.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:18][CH:19]([S-:22])[CH2:20][CH3:21].[Na+]>CC(S)CC>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]([S:22][CH:19]([CH2:20][CH3:21])[CH3:18])=[NH:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCC(C)[S-]
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Agent: CCC(C)S
Agent: [Na+]
Product: CCC(C)SC(=N)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and sodium 2-butanethiolate in 2-butanethiol there is obtained 2-butyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-thiocarboximidate which is purified by flash chromatography on silica gel using n-hexane/ethyl acetate (1:1) as the eluent, 1H-NMR(CDCl3): 1.05 (t, CH2CH3), 1.42 (d, CH--CH3), 1.46-1.93 (m, CH2CH3), 2.81-3.37 (m, 1H), 4.41 (s, 4H), 5.1 (broad s, NH), 7.37-7.70 (8H).
Reaction SMILES: [C:1]([C:4]1[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[C:6]2[C:11]([C:12]=1[C:13]#[N:14])=[CH:10][CH:9]=[CH:8][CH:7]=2)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:28].[Na+]>CO.C(#N)C>[NH2:28][CH:1]([C:4]1[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[C:6]2[C:11]([C:12]=1[C:13]#[N:14])=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:2]
Reactant: CC(=O)c1c(C#N)c2ccccc2n1-c1cccc(F)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: CC(N)c1c(C#N)c2ccccc2n1-c1cccc(F)c1
Temperature: 65 °C
Yield: 102.6 %

Procedure:
A mixture of 2-acetyl-1-(3-fluorophenyl)-1H-indole-3-carbonitrile (43 mg, 0.15 mmol) and ammonium acetate (0.119 g, 1.54 mmol) in methanol (1.5 mL) and acetonitrile (1.5 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, sodium cyanoborohydride (29 mg, 0.46 mmol) was added to the resultant mixture. The reaction was heated at 65° C. overnight. The reaction was then cooled to room temperature, quenched with saturated NaHCO3 solution, and extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the desired product (43 mg), which was used directly in the next step. LCMS calculated for C17H15FN3(M+H)+: m/z=280.1. Found: 280.1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:11][CH:12]=C)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].I([O-])(=O)(=O)=[O:15].[Na+]>C(O)(C)C.O.[Os](=O)(=O)(=O)=O>[CH3:1][O:2][C:3]([C:5]1([CH2:11][CH:12]=[O:15])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: C=CCC1(C(=O)OC)CCCCC1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: COC(=O)C1(CC=O)CCCCC1
Reaction time: 24 h
Yield: 31 %

Procedure:
To a solution of 1-allyl-cyclohexanecarboxylic acid methyl ester (4.0 g, 21.5 mmol) in isopropanol (35 mL) was added a solution of sodium periodate (10.1 g, 47.3 mmol) in H2O (35 mL) followed by the addition of osmium tetroxide (16 mg, 0.065 mmol). More isopropanol (30 mL) and H2O (35 mL) was added and the resulting suspension was stirred for 24 hours. Then, the reaction mixture was poured into ice/H2O (200 mL) and extracted with EtOAc (2×200 mL) in a separatory funnel. The organic layers were combined and dried over Na2SO4, filtered and concentrated to provide a crude oil which was purified by flash column chromatography (10 to 60% EtOAc/heptane) to provide 1.24 g (31% yield over two steps) of the title compound as an oil.
Reaction SMILES: [C:1]([N:8](C)[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:28][C:29]2[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=2[O:35][CH2:36][CH3:37])[C:16]([C:18]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]=2[Cl:27])=[O:17])[CH2:11][CH2:10]1)(OC(C)(C)C)=O.Br[C:43]1[CH:44]=[N:45][C:46]([NH:49][CH3:50])=[N:47][CH:48]=1>>[ClH:27].[ClH:27].[CH2:36]([O:35][C:34]1[CH:33]=[CH:32][C:31]([C:43]2[CH:44]=[N:45][C:46]([NH:49][CH3:50])=[N:47][CH:48]=2)=[CH:30][C:29]=1[CH2:28][N:15]([CH:12]1[CH2:11][CH2:10][CH:9]([NH:8][CH3:1])[CH2:14][CH2:13]1)[C:16]([C:18]1[S:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[C:19]=1[Cl:27])=[O:17])[CH3:37]
Reactant: CCOc1ccc(B(O)O)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: CNc1ncc(Br)cn1
Product: CCOc1ccc(-c2cnc(NC)nc2)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(NC)CC1
Product: Cl

Procedure:
The title compound was prepared from boronic acid (12) (25 mg, 42 μmol) and 5-bromo-2-methylaminopyrimidine (6.5 mg, 41 μmol) in accordance with Method L2.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10].[CH:13]([C:15]([CH2:17][CH3:18])=[O:16])=[CH2:14]>CCCCCC.O1CCCC1>[CH3:6][O:7][C:8](=[O:12])[C:9]([CH3:11])([CH3:10])[CH:14]=[CH:13][C:15](=[O:16])[CH2:17][CH3:18]
Reactant: COC(=O)C(C)C
Reactant: C=CC(=O)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC(=O)C=CC(C)(C)C(=O)OC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of n-butyllithium in hexane (224 ml; 2.2 M) was added to tetrahydrofuran (THF, 300 ml) at -60° followed by diiospropylamine (52 g) and this mixture was then warmed to room temperature stirred for 5 min and then cooled to -72° C. Methylisobutyrate (50 g) was then slowly added and the mixture was stirred for 11/2 hr at -70° C. Freshly distilled ethyl vinyl ketone (42 g) in THF (60 ml) was added to the above mixture over 10 min and the mixture was then stirred for a further 1/2 hr at -60° C. and subsequently at room temperature for 2 hr.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:20][S:21][CH2:22][CH2:23][CH2:24][CH2:25]O.C(C=P(CCCC)(CCCC)CCCC)#N.CCCCCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[CH2:25][CH2:24][CH2:23][CH2:22][S:21][CH3:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Reactant: CSCCCCO
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CSCCCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Yield: 64.7 %

Procedure:
The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (0.94 g, 3.1 mmol) obtained in Example 5 was dissolved in toluene (15 ml). After addition of 4-(methylthio)-1-butanol (0.25 ml, 2.1 mmol) and cyanomethylenetri-n-butylphosphorane (1.0 g, 4.1 mmol), the resulting mixture was heated under reflux for 14 hours under an argon atmosphere. The reaction mixture was allowed to cool down. Then, 4-(methylthio)-1-butanol (0.25 ml, 2.1 mmol) was added, followed by heating under reflux for 6 hours under an argon atmosphere. The reaction mixture was allowed to cool down and then, concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=10:1) to yield a colorless oil. The resulting colorless oil was solidified with hexane, whereby the title compound (0.55 g, 44%) was obtained as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@@H:4]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1.[Sn](Cl)Cl>CO.ClCCl>[CH3:1][O:2][C:3](=[O:25])[C@@H:4]([NH:17][C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1
Reactant: COC(=O)[C@H](CSCc1ccc([N+](=O)[O-])cc1)NC(=O)OC(C)(C)C
Agent: Cl[Sn]Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@H](CSCc1ccc(N)cc1)NC(=O)OC(C)(C)C
Temperature: 50 °C

Procedure:
A mixture of (2R)-methyl-2-tert-butoxycarbonylamino-3-(4-nitro-benzylsulfanyl)-propionate (3.75 g, 10.1 mmol) and tin (II) chloride (5.76 g, 30.0 mmol) in methanol (50 mL) was stirred at 50° C. Upon completion (TLC: 5% methanol in dichloromethane), the mixture was cooled to room temperature, quenched with saturated potassium fluoride solution (75 mL) and extracted with diethyl ether (3×75 mL). The combined extract was washed sequentially with water and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Flash chromatography purification (SiO2; 1-2% methanol in dichloromethane as eluent) yielded the titled compound as an off-white solid. 1H NMR (CDCl3, 300 MHz) δ 7.08 (2H, d, J=8 Hz, ArH), 6.25 (2H, d, J=8 Hz, ArH), 4.53 (1H, m, CHN), 3.75 (3H, s, OCH3), 3.63 (2H, s, PhCH2S), 2.84 (2H, m, CH2CHN), 1.46 (9H, s, CMe3); ESI-LCMS e/z calculated for C16H24N2O4S 340.146, found 341 (M+H)+, 363 (M+Na)+.
Reaction SMILES: CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH3:23][C:24]([CH3:53])([CH3:52])[C@H:25]([NH:37][C:38]([C@H:40]([CH2:49][CH:50]=[CH2:51])[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:39])[C:26]([NH:28][C@@H:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:30])=[O:27].[CH3:54][C:55]1[CH:56]=[C:57](Br)[CH:58]=[CH:59][C:60]=1[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:53][C:24]([CH3:52])([CH3:23])[C@H:25]([NH:37][C:38]([C@H:40]([CH2:49]/[CH:50]=[CH:51]/[C:57]1[CH:58]=[CH:59][C:60]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[C:55]([CH3:54])[CH:56]=1)[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:39])[C:26]([NH:28][C@@H:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:30])=[O:27]
Reactant: C=CC[C@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@H](C)c1ccccc1)C(C)(C)C
Reactant: Cc1cc(Br)ccc1-c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(/C=C/C[C@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@H](C)c2ccccc2)C(C)(C)C)ccc1-c1ccccc1
Yield: 69 %

Procedure:
A mixture of palladium acetate (52 mg, 0.23 mmol) and tri-(2-methylphenyl)phosphine (141 mg, 0.46 mmol) in anhydrous acetonitrile (10 mL) was sonicated at room temperature for 1 min until a creamy-coloured suspension formed. This suspension was added via Pasteur pipette to a stirred solution of tert-butyl (3R)-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)hex-5-enoate (Preparation 2)(861 mg, 2.0 mmol), 3-methyl-4-phenylbromobenzene (M. Gomberg, J. C. Pernert, J. Amer. Chem. Soc., 1926, 48, 1372-84, and see also Preparation 19B)(1.32 gm, 5.34 mmol), and triethylamine (1.28 mL, 9.29 mmol) in anhydrous acetonitrile (15 mL) under nitrogen. The mixture was purged with nitrogen, then heated at reflux for 24 h. The mixture was poured into ethyl acetate (200 mL) and washed with saturated aqueous sodium chloride (2×100 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution with dichloromethane:ethyl acetate) to give mainly tert-butyl (3R,5E)-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)-6-[3-methyl-(4-phenyl)phenyl]hex-5-enoate as a colourless foam (1.91 gm, 69%). 1H NMR suggests that two alkene isomers, the (5Z) and (4E) were also present. The mixture of alkenes was taken onto the next step (see b, below).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:25][N:26](C)[C:27](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][N:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:41]>C(OCC)(=O)C.CC(O)C>[ClH:41].[F:1][C:2]1[C:3]([CH2:25][NH:26][CH3:27])=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][N:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: COc1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)nc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cn(S(=O)(=O)c2ccc(OC)cn2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88 %

Procedure:
To a solution of tert-butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-methoxypyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (1.38 g) in ethyl acetate (6 mL) and 2-propanol (3 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (9 mL), and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol-water to give the title compound as a white solid (yield 1.06 g, 88%).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:22])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:21])=[CH:17]/[C:18]([OH:20])=O.C(N(S(F)(F)F)CC)C.[C:32]([O:51][CH2:52][C@H:53]([CH2:74][O:75][P:76]([O:79][CH2:80][CH2:81][NH2:82])([OH:78])=[O:77])[O:54][C:55](=[O:73])[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62]/[CH:63]=[CH:64]\[CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])(=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]/[CH:40]=[CH:41]\[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]>C(OCC)C>[C:32]([O:51][CH2:52][C@@H:53]([O:54][C:55](=[O:73])[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62]/[CH:63]=[CH:64]\[CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])[CH2:74][O:75][P:76]([O:79][CH2:80][CH2:81][NH:82][C:18](=[O:20])/[CH:17]=[C:16](\[CH3:21])/[CH:15]=[CH:14]/[CH:13]=[C:12](\[CH3:22])/[CH:11]=[CH:10]/[C:3]1[C:4]([CH3:8])([CH3:9])[CH2:5][CH2:6][CH2:7][C:2]=1[CH3:1])([OH:78])=[O:77])(=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]/[CH:40]=[CH:41]\[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC[C@H](COP(=O)(O)OCCN)OC(=O)CCCCCCC/C=C\CCCCCCCC
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)O)C(C)(C)CCC1
Agent: CCN(CC)S(F)(F)F
Solvent: CCOCC
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OC[C@H](COP(=O)(O)OCCNC(=O)/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C)OC(=O)CCCCCCC/C=C\CCCCCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.9 %

Procedure:
To a solution of retinoic acid (250 mg, 0.83 mmol) in diethyl ether stirring (20 mL) at −78° C., a solution of (diethylamino)sulfur trifluoride (130 μl, 0.90 mmol) in cold ether (20 mL) was added through a syringe. The reaction mixture was taken out of the cold bath and the stirring was continued at room temperature for an additional 2 hr. At the end, the solvent was removed by rotary evaporation. The residue was redissolved chloroform (50 mL) in the presence of solid Na2CO3 (50 mg). To this solution was added 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (600 mg, 0.81 mmol) and the reaction mixture was stirred at room temperature for an additional 24 hrs. The solvent was removed by rotary evaporation. The residue was purified by silica gel chromatography with a dichloromethane/methanol gradient to yield Z)-(2R)-3-(((2-((2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraenamido)ethoxy)(hydroxy)phosphoryl)oxy)propane-1,2-diyl dioleate (240 mg, 28%). 1H NMR (400 MHz, CDCl3) δ 0.87 (t, 6H, CH3), 1.01 (s, 6H, CH3) 1.20-1.40 (m, 40H, CH2), 1.40-1.60 (m, 8H, CH2), 1.70 (s, 3H, CH3—C═C), 1.80-2.10 (m, 8H), 2.32 (m, 4H, CH2C(═O)), 3.50 (m, 2H), 3.92-4.18 (m, 5H), 4.35 (m, 2H), 5.20 (m, 1H, NHC(═O)), 5.31 (m, 4H, CH═CH), 5.80-6.90 (m, 6H, CH═CH).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:22][C:21](=[O:23])[C:20]4[C:15](=[C:16]([CH3:27])[CH:17]=[C:18]5[CH:26]=[N:25][NH:24][C:19]5=4)[N:14]=3)=[CH:11][C:10]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:34]([NH2:37])([CH3:36])[CH3:35]>C(#N)C.O>[CH:34]([NH:37][C:21]([C:20]1[C:15]([NH:14][C:13]([C:12]2[N:8]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[N:9]=[C:10]([O:28][CH2:29][C:30]([F:31])([F:32])[F:33])[CH:11]=2)=[O:22])=[C:16]([CH3:27])[CH:17]=[C:18]2[C:19]=1[NH:24][N:25]=[CH:26]2)=[O:23])([CH3:36])[CH3:35]
Reactant: Cc1cc2cn[nH]c2c2c(=O)oc(-c3cc(OCC(F)(F)F)nn3-c3ncccc3Cl)nc12
Reactant: CC(C)N
Solvent: O
Solvent: CC#N
Product: Cc1cc2cn[nH]c2c(C(=O)NC(C)C)c1NC(=O)c1cc(OCC(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 500 mg of the above 7-[2-(3-chloro-pyridin-2-yl)-5-(2,2,2-trifluoro-ethoxy)-2H-pyrazol-3-yl]-5-methyl-1H-8-oxa-1,2,6-triaza-cyclopenta[a]naphthalen-9-one in 10 mL of acetonitrile/water (4:1, v/v) is added 885 μL (10.4 mmol) of isopropylamine. The reaction mixture is stirred for 16 hours at ambient temperature and then concentrated in vacuo. The residue is taken-up with brine and ethyl acetate. The phases are separated and the aqueous layer is washed with ethyl acetate. The combined organic layers are washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography (SiO2, hexane/ethyl acetate 4:6) affords 60 mg (10% over two steps) of the product as a white solid; LC/MS:536/538 (M+H)+, m.p.: 247-250° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][C@H:15]([NH:19][CH3:20])[CH2:14]2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([NH2:28])[N:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[NH2:28][C:24]1[N:23]=[C:22]([N:19]([CH3:20])[C@H:15]2[CH2:16][CH2:17][CH2:18][N:13]([C:11](=[O:12])[CH2:10][NH:9][C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH2:14]2)[CH:27]=[CH:26][N:25]=1
Reactant: Nc1nccc(Cl)n1
Reactant: CN[C@H]1CCCN(C(=O)CNc2cc(Cl)cc(Cl)c2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(c1ccnc(N)n1)[C@H]1CCCN(C(=O)CNc2cc(Cl)cc(Cl)c2)C1

Procedure:
A stirred solution of 2-(3,5-dichlorophenylamino)-1-((S)-3-(methylamino)piperidin-1-yl)ethanone (0.3 mg, 1.0 mmol), 4-chloropyrimidin-2-amine (60 mg, 0.5 mmol), DIEA (0.17 mL, 1.9 mmol) in DMF (2 mL) was heated to 100° C. for 2 days. The reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried over Na2SO4 and evaporated in vacuo to give the crude compound which was purified (silica gel, gradient MeOH in CH2Cl2) to give the (20 mg, 5.2%). 1H NMR (400 MHz, CD3OD): δ 7.77-7.73 (m, 1H), 6.64-6.56 (m, 3H), 6.10-6.00 (m, 1H), 4.58-4.45 (m, 2H), 4.10-3.84 (m, 3H), 2.96 (s, 3H), 2.58-2.81 (m, 1H), 2.03-1.90 (m, 4H), 1.60-1.48 (m, 1H). LC-MS: m/z [M+1]=409 & [M+23]=431.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([N:11]2[CH2:16][CH2:15][C@:14]([CH2:23][C:24]([OH:27])([CH3:26])[CH3:25])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:13][C:12]2=[O:28])[CH3:10])=[CH:5][CH:4]=1)#[CH:2].Br[C:30]1[CH:35]=[CH:34][N:33]=[C:32]([O:36][CH3:37])[CH:31]=1.C(NCC)C>[Cu]I.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.CN(C=O)C>[OH:27][C:24]([CH3:25])([CH3:26])[CH2:23][C@@:14]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[O:13][C:12](=[O:28])[N:11]([C@H:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[C:2][C:30]3[CH:35]=[CH:34][N:33]=[C:32]([O:36][CH3:37])[CH:31]=3)=[CH:8][CH:7]=2)[CH3:10])[CH2:16][CH2:15]1
Reactant: C#Cc1ccc([C@H](C)N2CC[C@](CC(C)(C)O)(c3ccccc3)OC2=O)cc1
Reactant: COc1cc(Br)ccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Solvent: CN(C)C=O
Product: COc1cc(C#Cc2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)ccn1
Temperature: 120 °C
Yield: 10.7 %

Procedure:
A mixture of (S)-3-((S)-1-(4-ethynylphenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one (10 mg, 0.027 mmol), 4-bromo-2-methoxypyridine (10 mg, 2 equiv), CuI (0.5 mg, 10% mol), Pd(PPh3)2Cl2 (1.9 mg, 10% mol), diethylamine (1 mL), dry DMF (1 mL) was degassed, refilled with nitrogen gas (3×). The mixture was then heated in the microwave for 45 min at 120° C. LC-MS found the reaction was complete. The mixture was filtered, concentrated, acidified with 5% aq HCl and purified by prep HPLC to afford (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-((2-methoxypyridin-4-yl)ethynyl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (1.4 mg). LC-MS Method 1 tR=1.92 min, m/z 485 (M+1); 1H NMR (CD3OD) 7.41-7.27 (m, 7H), 6.97 (m, 4H), 5.55 (q, 1H), 3.92 (s, 3H), 3.04 (m, 1H), 2.49 (m, 2H), 2.21 (m, 1H), 2.14 (s, 2H), 1.53 (d, 3H), 1.28 (t, 1H), 1.26 (s, 3H), 0.96 (s, 3H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[NH2:6][C:7]1[CH:12]=[C:11]([NH:13][CH2:14][CH3:15])[C:10]([C:16]#[N:17])=[C:9]([Cl:18])[N+:8]=1[CH2:19][CH3:20]>>[Cl-:18].[NH2:6][C:7]1[CH:12]=[C:11]([NH:13][CH2:14][CH3:15])[C:10]([C:16]#[N:17])=[C:9]([N:1]=[N+:2]=[N-:3])[N+:8]=1[CH2:19][CH3:20]
Reactant: CCNc1cc(N)[n+](CC)c(Cl)c1C#N
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Product: CCNc1cc(N)[n+](CC)c(N=[N+]=[N-])c1C#N
Reaction time: 2 h
Yield: 74.7 %

Procedure:
0.8 gms (.012 mole) of sodium azide was added to an aqueous solution containing 2.6 gms (.01 mole) of 2-amino-6-chloro-5-cyano-1-ethyl-4-ethylamino pyridinium chloride (compound 2 - Table 1) left for 2 hours at room temperature and then cooled. 2.0 gms (70% yield) of 2-amino-6-azido-5-cyano-1-ethyl-4-ethylamino pyridinium chloride crystallised out (MPt 164° - 165°C).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([O:16][CH3:17])[C:4]=1[C:5](O)=[O:6].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:53]1([CH:59]([NH2:69])[C:60]2([N:64]3[CH2:68][CH2:67][CH2:66][CH2:65]3)[CH2:63][O:62][CH2:61]2)[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>CN(C)C=O>[CH3:17][O:16][C:8]1[CH:9]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:11]=[C:3]([C:2]([F:1])([F:18])[F:19])[C:4]=1[C:5]([NH:69][CH:59]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:60]1([N:64]2[CH2:65][CH2:66][CH2:67][CH2:68]2)[CH2:63][O:62][CH2:61]1)=[O:6]
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)O
Reactant: NC(c1ccccc1)C1(N2CCCC2)COC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)NC(c1ccccc1)C1(N2CCCC2)COC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
2,4-Bis(trifluoromethyl)-6-methoxybenzoic acid (155 mg, 0.538 mmol) was dissolved in 2 mL dimethylformamide. N,N-Diisopropyl ethyl amine (78 mg, 0.605 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (205 mg, 0.539 mmol) were added. After 5 minutes of stirring at room temperature C-phenyl-C-(3-pyrrolidin-1-yl-oxetan-3-yl)-methylamine (intermediate B) (125 mg, 0.539 mmol) in 2 mL dimethylformamide was added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated off. The residue was taken up in 2N sodium carbonate solution and ethyl acetate and was extracted three times with ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography on silica gel (heptane/ethyl acetate 1:0-1:1) yielded 2-methoxy-N-[phenyl-(3-pyrrolidin-1-yl-oxetan-3-yl)-methyl]-4,6-bis-trifluoromethyl-benzamide as an off-white solid (173 mg, 64%), MS: m/e=503.2 [(M+H)+].