Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)Cl.[CH3:4][O:5][C:6]([CH2:8][C@@H:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:10][C:11](O)=[O:12])=[O:7].ClC(OCC)=O.C([N:26](CC)CC)C>>[C:11]([CH2:10][C@@H:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:8][C:6]([O:5][CH3:4])=[O:7])(=[O:12])[NH2:26]
Reactant: CCN(CC)CC
Reactant: COC(=O)C[C@H](CC(=O)O)CC(C)C
Agent: CCOC(=O)Cl
Solvent: ClCCl
Product: COC(=O)C[C@@H](CC(N)=O)CC(C)C
Temperature: 2.5 °C
Reaction time: 1.5 h

Procedure:
A round-bottomed flask is equipped with magnetic stirrer and charged with methylene dichloride (100 ml), (S)-3-((Methoxycarbonyl)methyl)-5-methylhexanoic acid (20 g) and with triethylamine (0.77 g) and cooled to 0-5° C. followed by addition of ethyl chloroformate (9 g). The mixture was stirred for 1-2 h at a temperature of 20° C. to 25° C., followed by quenching with 25% aqueous ammonia (100 ml). The resulted slurry is filtered and washed with water and dried to obtain a solid of (R)-methyl 3-(carbamoylmethyl)-5-methylhexanoate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[S:9]([F:12])(=[O:11])=[O:10].N(OS(=O)(=O)O)=O.[C:20]([CH2:22][CH2:23][N:24]([CH2:31][CH2:32][C:33]#[N:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)#[N:21].S(=O)(=O)(O)[NH2:36]>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.C(O)(=O)CC.CO>[Cl:1][C:2]1[C:3]([S:9]([F:12])(=[O:10])=[O:11])=[CH:4][C:5]([N:8]=[N:36][C:28]2[CH:29]=[CH:30][C:25]([N:24]([CH2:23][CH2:22][C:20]#[N:21])[CH2:31][CH2:32][C:33]#[N:34])=[CH:26][CH:27]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(Cl)c(S(=O)(=O)F)c1
Reactant: NS(=O)(=O)O
Reactant: N#CCCN(CCC#N)c1ccccc1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: O=NOS(=O)(=O)O
Solvent: CO
Solvent: CCC(=O)O
Product: N#CCCN(CCC#N)c1ccc(N=Nc2ccc(Cl)c(S(=O)(=O)F)c2)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
2-Chloro-5-amino benzene sulphonylfluoride (2.1 parts) was stirred in acetic/propionic acid 86/14 vol/vol (25 parts) and cooled to 0°-5° C. Nitrosyl sulphuric acid solution (3.8 parts) was added and stirred at 0°-5° C. for 3 hours. The diazo solution was then added to a mixture of N,N-bis(2-cyanoethyl)aniline (2.1 parts), methanol (75 parts) and sulphamic acid (1 part) stirring in ice/water (75 parts) at 0°-5° C. Stirred under these conditions for 1 hour then allowed to stand at room temperature overnight before filtering off the dye. The solid was dried overnight to yield the product 4-(4-chloro-5-fluorosulphonylphenylazo)-N,N-bis(2-cyanoethyl)aniline (3.6 parts). The dye, when applied to polyester material from an aqueous dispersion, gave yellow shades. λmax 414 nm.
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][C:4]1[N:8]([CH2:9][CH3:10])[CH:7]=[N:6][CH:5]=1.[C:11]1([P:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(#N)C>[ClH:2].[Cl-:1].[CH2:9]([N:8]1[C:4]([CH2:3][P+:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:5][N:6]=[CH:7]1)[CH3:10]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCn1cncc1CCl
Agent: Cl
Solvent: CC#N
Product: CCn1cncc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Cl-]
Yield: 71.5 %

Procedure:
5-Chloromethyl-1-ethyl-1H-imidazole hydrochloride (6.00 g), triphenylphosphine (25.73 g) and acetonitrile (80 mL) were heated under reflux overnight. After cooling, the precipitated crystals were collected by filtration and washed with hexane to give [(1-ethyl-1H-imidazol-5-yl)methyl](triphenyl)phosphonium chloride hydrochloride as colorless crystals (10.50 g, yield 72%). melting point: 287-289° C.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([O:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[CH:7]=1.C(=O)([O-])O.[K+].[CH2:23]([OH:25])[CH3:24]>>[CH2:23]([O:25][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([O:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[CH:7]=1)[CH3:24]
Reactant: Cc1cc(Oc2cc(F)ccc2[N+](=O)[O-])n[nH]1
Reactant: CCO
Agent: O=C([O-])O
Agent: [K+]
Product: CCOc1ccc([N+](=O)[O-])c(Oc2cc(C)[nH]n2)c1
Yield: 59.8 %

Procedure:
Reaction of 3-(5-fluoro-2-nitrophenyloxy)-5-methylpyrazole with ethanol was carried out in the presence of potassium hydrogencarbonate in the same manner as in Example 40, to give a yellow viscous substance of 3-(5-ethoxy-2-nitrophenyloxy)-5-methylpyrazole (yield: 59.8%). 1H-NMR (CDCl3, TMS, ppm): δ 1.39 (t, J=7.0 Hz, 3H), 2.28 (s, 3H), 4.04 (q, J=7.0 Hz, 2H), 5.72 (s, 1H), 6.68 (dd, J=2.6 and 9.1 Hz, 1H), 6.73 (d, J=2.6 Hz, 1H), 8.04 (d, J=9.1 Hz, 1H), 9.62 (br s, 1H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[OH:11].[C:12](Cl)(Cl)=[S:13]>O.C(OCC)C>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]2[N:2]=[C:12]([SH:13])[O:11][C:4]=2[CH:5]=1
Reactant: COc1ccc(N)c(O)c1
Reactant: S=C(Cl)Cl
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: COc1ccc2nc(S)oc2c1

Procedure:
2-amino-5-methoxyphenol hydrochloride (6 g) in 80 ml of water was stirred at room temperature while thiophosgene (3.92 g) was added dropwise as a solution in 30 ml of diethyl ether at a rate such that the resultant exotherm was controlled.
Reaction SMILES: [Na:1][Na].[SH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=[O:12]>CO>[SH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=[O:12].[OH-:12].[Na+:1]
Reactant: [Na][Na]
Agent: O=C(O)Cc1ccccc1S
Solvent: CO
Product: [Na+]
Product: [OH-]

Procedure:
To a mixture of the disodium salt of o-mercaptophenylacetic acid (formed by treatment of o-mercaptophenylacetic acid (1.68 g) with sodium hydroxide (0.8 g) in methanol (10 ml) followed by evaporation of half of the resultant solution to dryness and re-dissolution in 10 ml of DMF) and copper-bronze was added a solution of 2,5-dichloropyridine in DMF (5 ml). The reaction mixture was heated to 110°-120° C. for 90 minutes, added to water, acidified, and then extracted (×3) with ether. The combined ether layers were extracted with 2N sodium hydroxide (×1) and the resultant orange aqueous phase was acidified with dilute hydrochloric acid. The resulting suspension was filtered, and the solid was thoroughly washed with water and dried to give [2'-(5"-chloropyridin-2"-ylthio)phenyl]-acetic acid (0.88 g) as a fawn-coloured solid, m.p. 141°-4° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[H-].[Na+].[CH:30]1([OH:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>O1CCOCC1.CN(C=O)C>[CH:30]1([O:36][C:2]2[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=2)[C:5]([NH:7][C:8]2[S:9][C:10]3[C:16]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=3[N:12]=2)=[O:6])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: OC1CCCCC1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(OC4CCCCC4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with sodium hydride and cyclohexanol in dioxane and DMF. ES-MS m/e (%): 469 (M+H+, 100).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[SH:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]2[N:18]([C@@H:21]3[O:27][C@H:26]([CH2:28][OH:29])[C@@H:24]([OH:25])[C@H:22]3[OH:23])[N:19]=[CH:20][C:13]=12.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([S:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]2[N:18]([C@@H:21]3[O:27][C@H:26]([CH2:28][OH:29])[C@@H:24]([OH:25])[C@H:22]3[OH:23])[N:19]=[CH:20][C:13]=12)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCC=Cc1ccccc1
Reactant: OC[C@H]1O[C@@H](n2ncc3c(S)ncnc32)[C@H](O)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OC[C@H]1O[C@@H](n2ncc3c(SCC=Cc4ccccc4)ncnc32)[C@H](O)[C@@H]1O
Temperature: 40 °C

Procedure:
Cinnamyl bromide (3.04 g) was added to a stirred solution of 4-mercapto-1-β-D-ribofuranosylpyrazolo[3,4-d]-pyrimidine (4.0 g) and potassium carbonate (2.13 g) in N,N-dimethylformamide. The solution was heated (40° C. on an oil bath) for 2 hours. After cooling the reaction mixture was poured into water (0.6 l) and the resultant precipitate was collected and washed with water. The 4-cinnamylthio-1-β-D-ribofuranosylpyrazolo[3,4-d]pyrimidine so obtained was recrystallised from methanol, washed with water and dried (in vacuo at 55° C.), yield 3.2 g, m.p. 165°-166° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9](=O)[CH2:10][Cl:11].P(Cl)(Cl)(Cl)=O>ClCCCl>[ClH:11].[Cl:11][CH2:10][C:9]1[N:1]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]2=[CH:7][N:8]=1
Reactant: O=C(CCl)NCc1cnccn1
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: Cl
Product: ClCc1ncc2cnccn12
Yield: 167.4 %

Procedure:
In 1,2-dichloroethane (5.0 ml) was dissolved N-(2-pyrazinylmethyl)chloroacetamide (0.50 g) followed by addition of phosphorus oxychloride (5.0 ml) at room temperature. The mixture was refluxed for 40 minutes and, then, concentrated under reduced pressure. The residue was dissolved in methanol (1.0 ml) followed by addition of diethyl ether to give crude 3-chloromethylimidazo[1,5-a]pyrazine hydrochloride as powder (0.46 g). This powder (0.18 g) was added to a mixture of (2RS,3RS)-2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)-2-butanol (0.25 g), ethanol (2.5 ml) and 28% sodium methoxide-methanol (0.36 ml) at room temperature and the mixture was stirred for 7 minutes. The reaction mixture was poured into water (20 ml) and extracted with ethyl acetate (20 ml×3). The organic layers were combined, washed with saturated aqueous sodium chloride solution (10 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (2 cm×8 cm), and elution was carried out with methanol-methylene chloride (5:95). The desired fractions were combined and further subjected to silica gel chromatography (2 cm×8 cm) and elution was carried out with methylene chloride-ethylacetate (1:2). The desired fractions were combined and concentrated. To the residue were added to a mixture of diethyl ether and hexane, whereupon (2RS,3RS)-2-(2,4-difluorophenyl)-3-(imidazo[1,5-a]pyradin-3-yl)methylthio-1-(1H-1,2,4-triazol-1-yl)-2-butanol (compound 5.7:0.02 g) was separated out as a colorless powder.
Reaction SMILES: [CH3:1][C:2]([C@H:4]1[C@@H:8]2[C@H:9]3[C@@:14]([CH3:17])([CH2:15][CH2:16][C@@:7]2([CH:31]=[O:32])[CH2:6][CH2:5]1)[C@:13]1([CH3:30])[CH2:18][CH2:19][C@H:20]2[C:26]([CH3:28])([CH3:27])[C:24](=[O:25])[CH:23]=[CH:22][C@:21]2([CH3:29])[C@H:12]1[CH2:11][CH2:10]3)=[CH2:3].OO.[O-:35]Cl=O.[Na+]>CC#N.O.O>[CH3:3][C:2]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:14]([CH3:17])([CH2:15][CH2:16][C@@:7]2([C:31]([OH:35])=[O:32])[CH2:6][CH2:5]1)[C@@:13]1([CH3:30])[C@@H:12]([C@:21]2([CH3:29])[C@@H:20]([CH2:19][CH2:18]1)[C:26]([CH3:28])([CH3:27])[C:24](=[O:25])[CH2:23][CH2:22]2)[CH2:11][CH2:10]3)=[CH2:1]
Reactant: [O-][Cl+][O-]
Reactant: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@@H](CC[C@@H]4[C@@]5(C)C=CC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: OO
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CCC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
The betulone aldehyde prepared from the last step is dissolved in a mixture of NaH2PO4.H2O (877 mg) and CH3CN—H2O (17 mL) and the suspension cooled to 0-5° C. 30% aqueous H2O2 (220 μL) and a solution of NaClO2 (200 mg) in water (16 mL) are then successively added, the mixture warmed to room temperature and stirred at this temperature for 1 h. The reaction is quenched by addition of Na2S2O5 (380 mg), and extracted with ethyl acetate. The organic extract is washed with water and brine, dried (Na2SO4), filtered, and concentrated. The residue is then subjected to column chromatography to afford betulonic acid (550 mg) as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3([O:14][C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=4)[CH2:13][CH2:12]3)[CH2:10][O:9]2)=[CH:4][CH:3]=1.[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2([O:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[CH2:12][CH2:13]2)([OH:9])[CH2:10][N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)=[CH:6][CH:7]=1
Reactant: c1c[nH]cn1
Reactant: Clc1ccc(OC2(C3(c4ccc(Cl)cc4)CO3)CC2)cc1
Product: OC(Cn1ccnc1)(c1ccc(Cl)cc1)C1(Oc2ccc(Cl)cc2)CC1

Procedure:
3.2 g=10 mmol of 2-(4-chlorophenyl)-2-[1-(4-chlorophenoxy)cyclopropan-1-yl]-oxirane (compound from Example 14) were reacted with 2.04 g=30 mmol of imidazol, as specified in Example 2a), in the absence of a solvent, and 2.9 g (75% of theory) of melting point: 172°-173° C. were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([F:12])([F:11])[F:10])=[N:4][NH:5][C:6]=1[CH2:7][CH3:8].C([O-])([O-])=O.[K+].[K+].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][N:29]([C:32](=[O:34])[CH3:33])[CH2:28][CH2:27]2)=[CH:22][C:21]=1[O:35][CH3:36].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][N:29]([C:32](=[O:34])[CH2:33][N:5]3[C:6]([CH2:7][CH3:8])=[C:2]([Cl:1])[C:3]([C:9]([F:10])([F:12])[F:11])=[N:4]3)[CH2:28][CH2:27]2)=[CH:22][C:21]=1[O:35][CH3:36]
Reactant: CCc1[nH]nc(C(F)(F)F)c1Cl
Reactant: COc1cc(N2CCN(C(C)=O)CC2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(c2ccc(Cl)c(OC)c2)CC1

Procedure:
Protocol T was followed using 4-Chloro-5-ethyl-3-trifluoromethyl-1-H-pyrazol, K2CO3, 1-[4-(4-Chloro-3-methoxyphenyl)-piperazine-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=2/3, Rf=0.53) afforded the title compound as white solid. 1H NMR (400 MHz, CDCl3); 7.18-7.22 (d, 2H), 6.38-6.48 (m, 2H), 4.98 (s, 2H), 3.86 (s, 3H), 3.66-3.76 (m, 4H), 3.1-3.2 (m, 4H), 2.66-2.74 (q, 2H), 1.18-1.28 (m, 3H). MS (ES) M+H) expected=464.82, found 465.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[Br:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[NH:20][C:19](=[O:26])[C:18]2=[CH:27]OC.CCOC(C)=O.O>CN(C)C=O>[Br:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[NH:20][C:19](=[O:26])[C:18]2=[CH:27][NH:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:8][CH:9]=1
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Reactant: Nc1ccc(-c2ccncc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NC(=O)c2ccc(Br)cc2C1=CNc1ccc(-c2ccncc2)cc1
Yield: 77.1 %

Procedure:
4-Pyridin-4-yl-phenylamine (130 mg, 0.76 mmol) and 6-bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione (200 mg, 0.71 mmol) is heated in N,N-dimethylformamide (10 mL) at 100° C. for 2 h. EtOAc (100 mL) and H2O (20 mL) is then added. The EtOAc layer is washed with H2O (3×20 mL) and brine (15 mL) and dried over MgSO4. After removal of EtOAc, the precipitate is collected and washed with MeOH and Et2O and dried to provide the title compound (230 mg, 77%). 1H NMR (300 MHz, DMSO) δ 12.59 (1H, d, J=12.9 Hz), 11.50 (1H, s), 9.0 (1H, d, J=12.6 Hz), 8.53-8.64 (3H, m), 7.43-7.95 (8H, m). MS (ESI) m/z 420.0, 422.0 (M+H)+1; Anal. Cacl. for C21H14BrN3O2: C, 60.02; H, 3.36; N, 10.00. Found: C, 59.4; H, 3.26; N, 9.34.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]1.CCN(C(C)C)C(C)C.[F:16][C:17]1[CH:18]=[C:19]([C@H:23]2[CH2:27][CH2:26][CH2:25][N:24]2[C:28]2[CH:29]=[CH:30][C:31]3[N:32]([C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([C:43]5[CH:48]=[CH:47][N:46]=[C:45](S(C)(=O)=O)[N:44]=5)[N:38]=4)=[CH:35][N:36]=3)[N:33]=2)[CH:20]=[CH:21][CH:22]=1>CS(C)=O.C(Cl)Cl>[F:16][C:17]1[CH:18]=[C:19]([C@H:23]2[CH2:27][CH2:26][CH2:25][N:24]2[C:28]2[CH:29]=[CH:30][C:31]3[N:32]([C:34]([C:37]4[N:38]=[C:39]([C:43]5[CH:48]=[CH:47][N:46]=[C:45]([N:1]6[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]6)[N:44]=5)[CH:40]=[CH:41][CH:42]=4)=[CH:35][N:36]=3)[N:33]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: CS(=O)(=O)c1nccc(-c2cccc(-c3cnc4ccc(N5CCC[C@@H]5c5cccc(F)c5)nn34)n2)n1
Reactant: O[C@@H]1CCNC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O[C@@H]1CCN(c2nccc(-c3cccc(-c4cnc5ccc(N6CCC[C@@H]6c6cccc(F)c6)nn45)n3)n2)C1
Temperature: 120 °C

Procedure:
In step 14-3, (R)-pyrrolidin-3-ol (136 mg, 1.56 mmol) and DIEA (453 uL, 2.6 mmol) were added to a solution of (R)-6-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3-(6-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2-yl)imidazo[1,2-b]pyridazine (14-3) (268 mg, 0.52 mmol) in DMSO (3 mL). The mixture was heated to 120° C. for 1 hour. The mixture was diluted with CH2Cl2, washed with H2O and brine, dried over Na2SO4, filtered and concentrated. The mixture was purified by column chromatography (silica gel, CH2Cl2/CH3OH, 5% gradient) to give (R)-1-(4-(6-(6-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)pyrimidin-2-yl)pyrrolidin-3-ol (14-4). LC/MS: 523.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([NH:16][NH2:17])=O)=[N:4][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][N:7]=1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](N)=[NH:24].C([O-])C.[Na+]>CN(C=O)C>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:5]2[N:4]=[C:3]([C:14]3[NH:24][C:23]([C:19]4[S:18][CH:22]=[CH:21][CH:20]=4)=[N:17][N:16]=3)[C:2]([NH2:1])=[N:7][CH:6]=2)[CH:9]=1
Reactant: N=C(N)c1cccs1
Reactant: NNC(=O)c1nc(-c2cccnc2)cnc1N
Agent: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncc(-c2cccnc2)nc1-c1nnc(-c2cccs2)[nH]1
Temperature: 160 °C
Yield: 42.1 %

Procedure:
3-amino-6-(3-pyridyl)pyrazine-2-carbohydrazide (40 mg, 0.173 mmoles), thiophene-2-carboxamidine (21.92 mg, 0.173 mmoles) and sodium ethanolate (11.82 mg, 0.173 mmoles) were added to a microwave vial. DMF (1 mL) was then added and the vial sealed and heated in the microwave at 160° C. for 40 minutes. The reaction mixture was filtered and purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound (23.4 mg, 31% Yield). 1H NMR (400.0 MHz, DMSO-d6) δ 14.96 (s, 1H), 9.55 (s, 1H), 8.99 (s, 1H), 8.84 (d, J=6.1 Hz, 1H), 8.69 (dd, J=1.2, 4.9 Hz, 1H), 7.95 (s, 2H), 7.81 (d, J=3.0 Hz, 1H), 7.73-7.68 (m, 2H) and 7.22 (dd, J=3.8, 4.8 Hz, 1H) ppm; MS (ES+) 323.10
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8](=[O:13])[CH2:7][CH2:6][C:5]2([CH3:15])[CH3:14].N1C=CN=C1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].O>CN(C)C=O>[C:24]([Si:21]([CH3:23])([CH3:22])[O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8](=[O:13])[CH2:7][CH2:6][C:5]2([CH3:15])[CH3:14])([CH3:27])([CH3:26])[CH3:25]
Reactant: Cc1cc2c(cc1O)C(C)(C)CCC2=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2c(cc1O[Si](C)(C)C(C)(C)C)C(C)(C)CCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
A solution of 6-hydroxy-4,4,7-trimethyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 171, 2.04 g, 10 mmol) in anhydrous N,N-dimethyl formamide (10 mL) under argon was treated with imidazole (1 g, 14.7 mmol) followed by tert-butyldimethylsilyl chloride (1.5 g, 10 mmol). After stirring the reaction mixture at ambient temperature overnight, it was poured into water and extracted with diethyl ether (×2). The combined organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to a residue that was purified by flash column chromatography on silica gel (230-400 mesh) usng 8-14% ethyl acetate in hexane as the eluent to afford the title compound (2.5 g, 79%).
Reaction SMILES: Br[CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:9][O:10][C:11]1[CH:26]=[CH:25][C:14]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:16])=[CH:13][CH:12]=1>[Zn].C1C=CC=CC=1>[CH3:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([C:15]([C:14]2[CH:25]=[CH:26][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)([OH:16])[CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:22][CH:21]=1
Reactant: CCOC(=O)C(C)Br
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2)cc1
Agent: [Zn]
Solvent: c1ccccc1
Product: CCOC(=O)C(C)C(O)(c1ccc(OC)cc1)c1ccc(OC)cc1
Yield: 50.5 %

Procedure:
A mixture of 8.25 g of ethyl 2-bromopropionate, 11.81 g of 4,4'-dimethoxybenzophenone, 7.16 g of zinc and 70 ml of benzene was heated on an oil bath for 4 hours under reflux. The mixture was then allowed to stand to cool, after which the reaction solution was filtered. The filtrate was washed with 10% w/v aqueous sulfuric acid, with water and with a saturated aqueous solution of sodium chloride, in that order. After the mixture had been dried, the solvent was distilled off under reduced pressure. The residue was subjected to flash column chromatography through silica gel (about 400 mesh, 300 g). 7.92 g of the title compound were obtained as white crystals, melting at 67°-69° C. (after recrystallisation from a mixture of methylene chloride and hexane), from those fractions eluted with a 100:2 ny volume mixture of hexane and ethyl acetate.
Reaction SMILES: C([O:3][C:4](=[O:29])[C@H:5]([CH3:28])[CH2:6][C@H:7]([N:21]1[C:25](=[O:26])[CH2:24][CH2:23][C:22]1=[O:27])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)C.[OH-].[Na+].C1C[O:35]CC1.C(O)C>O>[C:12]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:13]=[CH:14][C:9]([CH2:8][C@@H:7]([NH:21][C:25](=[O:26])[CH2:24][CH2:23][C:22]([OH:27])=[O:35])[CH2:6][C@@H:5]([CH3:28])[C:4]([OH:3])=[O:29])=[CH:10][CH:11]=1
Reactant: C1CCOC1
Reactant: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)N1C(=O)CCC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)CCC(=O)O)C(=O)O
Reaction time: 16 h

Procedure:
(2R,4S)-5-Biphenyl-4-yl-4-(2,5-dioxopyrrolidin-1-yl)-2-methylpentanoic acid ethyl ester (590 mg) is added to a mixture of 1 M NaOH (2.75 ml), THF (9 ml) and ethanol (9 ml). The mixture is stirred for 16 h. The mixture is diluted with water (20 ml) and extracted with isopropyl acetate. The water phase is acidified with 1 M HCl (5 ml) and extracted with isopropyl acetate. The combined organic phases are dried (MgSO4) and concentrated in vacuo to give (2R,4S)-5-Biphenyl-4-yl-4-(3-carboxypropionylamino)-2-methyl-pentanoic acid (3-a, R1=4-oxo-pentanoic acid, R2=H, R3=H). 1H NMR (DMSO): 1.05 (2H), 1.35 (1H), 1.79 (1H), 2.29 (2H), 2.39 (3H), 2.70 (2H), 3.97 (1H), 7.25 (2H), 7.34 (1H), 7.44 (2H), 7.56 (2H), 7.63 (2H), 7.74 (1H), 12.01 (2H).
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:5])[CH3:4].[N+:15]([C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([N+]([O-])=O)[C:19]=1[C:20]#[N:21])([O-:17])=[O:16]>>[C:20]([C:19]1[C:18]([N+:15]([O-:17])=[O:16])=[CH:25][CH:24]=[CH:23][C:22]=1[O:1][CH2:2][C:3]([NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:5])[CH3:4])#[N:21]
Reactant: CC(C)(CO)NC(=O)c1ccccc1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: CC(C)(COc1cccc([N+](=O)[O-])c1C#N)NC(=O)c1ccccc1
Yield: 91 %

Procedure:
Prepared as in Example 197c from N-(1-hydroxy-2-methylpropan-2-yl)benzamide (Boyd, R. N.; Hansen, R. H. J. Am. Chem. Soc. 1953, 75, 5896) and 2,6-dinitrobenzonitrile in 91% yield as a pale yellow solid. MS 340 (MH+).