Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:24]3[C:23](=[O:25])[N:22]([CH2:26][CH3:27])[CH2:21][C:20]([CH3:29])([CH3:28])[O:19][C:18]=3[N:17]=[C:16](S(C)(=O)=O)[N:15]=2)=[CH:10][C:9]=1[F:34])([CH3:4])([CH3:3])[CH3:2].[CH3:36][C@H:37]1[CH2:42][O:41][CH2:40][CH2:39][NH:38]1>O1CCOCC1>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:24]3[C:23](=[O:25])[N:22]([CH2:26][CH3:27])[CH2:21][C:20]([CH3:29])([CH3:28])[O:19][C:18]=3[N:17]=[C:16]([N:38]3[CH2:39][CH2:40][O:41][CH2:42][C@@H:37]3[CH3:36])[N:15]=2)=[CH:10][C:9]=1[F:34])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN1CC(C)(C)Oc2nc(S(C)(=O)=O)nc(-c3ccc(NC(=O)OC(C)(C)C)c(F)c3)c2C1=O
Reactant: C[C@H]1COCCN1
Solvent: C1COCCO1
Product: CCN1CC(C)(C)Oc2nc(N3CCOC[C@@H]3C)nc(-c3ccc(NC(=O)OC(C)(C)C)c(F)c3)c2C1=O
Temperature: 100 °C
Yield: 35.5 %

Procedure:
2.5 g of [4-(6-ethyl-2-methanesulfonyl-8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-9-oxa-1,3,6-triazabenzocyclohepten-4-yl)-2-fluorophenyl]carbamic acid tert-butyl ester (19.66 mmol) in 20 ml of dioxane are placed in 4 microwave tubes, respectively. One quarter of (S)-3-methylmorpholine (98.32 mmol) is added to each tube, respectively. The tubes are heated for 2 hours at 100° C. in a Biotage microwave machine. The reaction media are filtered and rinsed with MeOH. The solid is washed with water, with acetonitrile and then with pentane. 3.7 g of {4-[6-ethyl-8,8-dimethyl-2-((S)-3-methylmorpholin-4-yl)-5-oxo-5,6,7,8-tetrahydro-9-oxa-1,3,6-triazabenzocyclohepten-4-yl]-2-fluorophenyl}carbamic acid tert-butyl ester are obtained. The DMSO/MeOH phase is evaporated to dryness. The residue is taken up in water and filtered, rinsed with acetonitrile and then with pentane. This product is chromatographed on silica gel with a gradient of MeOH in DCM ranging from 0 to 5%. 1.7 g of {4-[6-ethyl-8,8-dimethyl-2-((S)-3-methylmorpholin-4-yl)-5-oxo-5,6,7,8-tetrahydro-9-oxa-1,3,6-triazabenzocyclohepten-4-yl]-2-fluorophenyl}carbamic acid tert-butyl ester are obtained.
Reaction SMILES: ClN[NH:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:7]([O:9][CH3:10])=[O:8].[C:16]([N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(OCC)(=O)C>C(O)C>[CH3:15][O:14][C:13]1[C:4]2[NH:3][C:26]3[CH2:27][CH2:28][N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:24][C:25]=3[C:5]=2[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(OC)c(NNCl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1ccc(OC)c2[nH]c3c(c12)CN(C(=O)OC(C)(C)C)CC3
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of Methyl 3-(2-chlorohydrazino)-4-methoxybenzoate (from step 1) (0.0042 mol) and N-Boc-4-piperidone (0.0063 mol) in ethanol (20 ml) was stirred for 18 h at room temperature. Reaction was concentrated under vacuum and product was isolated with silica gel column chromatography using 20% ethyl acetate in petroleum ether.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:10]=[C:11]([CH:14]([CH3:16])[CH3:15])[CH:12]=[O:13].C1(P(C2C=CC=CC=2)[C@@H]([C@H](P(C2C=CC=CC=2)C2C=CC=CC=2)C)C)C=CC=CC=1.C(N(CC)CC)C>C1(C)C=CC=CC=1.[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Rh].[Rh].[Rh].[Rh]>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:10][CH:11]([CH:14]([CH3:16])[CH3:15])[CH:12]=[O:13]
Reactant: COCCCOc1cc(C=C(C=O)C(C)C)ccc1OC
Agent: [Rh]
Agent: C[C@H]([C@@H](C)P(c1ccccc1)c1ccccc1)P(c1ccccc1)c1ccccc1
Agent: [C-]#[O+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COCCCOc1cc(CC(C=O)C(C)C)ccc1OC

Procedure:
A solution of 2-(3-(methoxypropoxy)-4-methoxybenzylidene) -3-methylbutanal (7.0 mmol, 74% E and 26% Z), tetrarhodium dodecacabonyl (0.14 mmol), (2R,3R)-(+)-2,3-Bis-(Diphenylphosphino)butane (R, R-Chiraphos, 0.63 mmol) and 300 ul triethylamine in toluene (75 ml) was transferred into an autoclave. The mixture was hydrogenated at 70-80° C. and 20 bar H2. After 42 hr additional tetrarhodium dodecacarbonyl (0.14 mmol) was added to complete the reaction in 62 hr. The mixture was concentrated to 3.5 g black oil and purified by flash chromatography (heptane/ethyl acetate=2/1). Yield=1.6 g yellow oil (74%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][N:3]=1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O-])=O)=[CH:16][CH:15]=1.[Na+].C(O)CO>CN1CCCC1=O.CCOC(C)=O>[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:12])[NH:4][N:3]=2)=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)[O-])cc1
Reactant: O=c1[nH]nc(Cl)c2ccccc12
Agent: [Na+]
Solvent: OCCO
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1ccc(Sc2n[nH]c(=O)c3ccccc23)cc1
Yield: 75.1 %

Procedure:
A mixture of 4-chlorophthalazin-1(2H)-one (0.233 g, 1.29 mmol) and sodium 4-methylbenzenesulfinate (0.460 g, 2.58 mmol) in ethane-1,2-diol (0.29 mL, 5.19 mmol) and methyl-2-pyrrolidinone (2.6 mL) was microwaved at 230° C. for 30 minutes, diluted with EtOAc, washed with water and brine, dried (Na2SO4), filtered, and chromatographed (15% EtOAc/DCM) to give 0.260 g of impure title compound as a white solid: MS (APCI+) M/Z 269 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([O:10][CH2:11]C)=[O:9])=[CH:3][CH:2]=1.[H-].[Na+].[CH:15](OCC)=[O:16].Cl>C1(C)C=CC=CC=1.CCOC(C)=O.CCOCC>[OH:16][CH:15]=[C:7]([C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: CCOC(=O)Cc1ccncc1
Reactant: CCOC=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COC(=O)C(=CO)c1ccncc1
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
9 g of ethyl 2-(4-pyridinyl)acetate and 1.35 g of 95% NaH are mixed in 90 ml of toluene. The mixture is heated at 100° C. for 30 minutes and is then cooled, and 8.8 ml of ethyl formate are added. The mixture is left stirring at AT for 1 hour and at 100° C. for 45 minutes. The reaction medium is cooled and then 25.5 ml of 2N HCl are added. Filtration is carried out and then the precipitate formed is taken up in AcOEt and then in ether to produce 5.65 g of the expected compound.
Reaction SMILES: C([C:4]1[N:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[C:7]([O:14][CH3:15])=[C:6]([N:16](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[CH:5]=1)(=O)C.COCCN(S(F)(F)F)CCOC.[C:44](O)([C:46]([F:49])(F)[F:47])=O>ClCCCl>[NH2:16][C:6]1[CH:5]=[C:4]([C:46]([F:49])([F:47])[CH3:44])[N:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[C:7]=1[O:14][CH3:15]
Reactant: COC(=O)c1nc(C(C)=O)cc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1OC
Reactant: O=C(O)C(F)(F)F
Agent: COCCN(CCOC)S(F)(F)F
Solvent: ClCCCl
Product: COC(=O)c1nc(C(C)(F)F)cc(N)c1OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To a solution of methyl 6-acetyl-4-[bis(tert-butoxycarbonyl)amino]-3-methoxypyridine-2-carboxylate (0.7 g, 1.649 mmol) in DCE (3.30 ml) was added Deoxo-Fluor® (1.520 ml, 8.25 mmol) and the reaction mixture was stirred at 80° C. overnight. The mixture was allowed to cool down to room temperature and TFA (2 mL) was added. The reaction mixture was stirred at room temperature (LC monitoring). After 12 h, the reaction was completed and extracted with EtOAc (2×). The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by flash column chromatography (ISCO, SiO2 24 g, hexane/EtOAc 100:0 to 0:100 gradient) to afford methyl 4-amino-6-(1,1-difluoroethyl)-3-methoxypicolinate (336 mg, 1.365 mmol, 83% yield) as an orange oil. ESIMS m/z 245 ([M−H]−); 1H NMR (400 MHz, CDCl3) δ 7.06 (s, 1H), 4.59 (s, 2H), 3.97 (s, 3H), 3.88 (s, 3H), 1.98 (t, J=18.7 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −89.99.
Reaction SMILES: CN([CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][C:7]=1[N+:17]([O-])=O)C>C(O)C.[Ni]>[F:16][C:13]([F:14])([F:15])[O:12][C:9]1[CH:8]=[C:7]2[C:6]([CH:5]=[CH:4][NH:17]2)=[CH:11][CH:10]=1
Reactant: CN(C)C=Cc1ccc(OC(F)(F)F)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: FC(F)(F)Oc1ccc2cc[nH]c2c1
Reaction time: 18 h

Procedure:
Combine N,N-dimethyl-2-(2-nitro-4-trifluoromethoxyphenyl)vinylamine (4.64 g, 16.8 mmol) and Raney® nickel (900 mg) in ethanol (100 ml). Hydrogenate at 60 psi (410 kPa) and ambient temperature. After 18 hours, filter through celite, concentrate the filtrate to residue, and chromatograph on silica gel eluting with hexanes/ethyl acetate (30/70) to give, after evaporation, the title compound as an off-white powder: mp 59° C. MS (ACPI): m/e 200.0 (M−1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[C@:9]([CH3:27])([C:23]([F:26])([F:25])[F:24])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[Br:29][C:30]1[CH:31]=C[C:33]([C:36]([OH:38])=O)=[N:34][CH:35]=1.CC[N:41]=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[C@:9]([CH3:27])([C:23]([F:26])([F:25])[F:24])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:36]([C:33]3[N:34]=[CH:35][C:30]([Br:29])=[CH:31][N:41]=3)=[O:38])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)ccc2F)CO[C@@]1(C)C(F)(F)F
Reactant: O=C(O)c1ccc(Br)cn1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(NC(=O)c3ncc(Br)cn3)ccc2F)CO[C@@]1(C)C(F)(F)F
Reaction time: 16 h

Procedure:
To a solution of [(2R,5R)-5-(5-amino-2-fluoro-phenyl)-2,5-dimethyl-2-trifluoromethyl-5,6-di-hydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (76 mg, 0.187 mmol) in DMF (2 ml) was added 5-bromopyridine-2-carboxylic acid (47 mg, 0.225 mmol), EDC.HCl (48 mg, 0.244 mmol), HOAt (29 mg, 0.206 mmol) and DIPEA (0.08 ml, 0.469 mmol) and the reaction mixture was kept at 25° C. for 16 h. The mixture was concentrated, the residue dissolved in EtOAc and washed with saturated NaHCO3 solution and brine, dried over MgSO4, filtered and purified by chromatography on silica gel (hexane-EtOAc 20:1 to 1:1) to provide the title compound as a light yellow foam: HPLC RtH5=1.297 min); ESIMS: 590, 592 [(M+H)+]; 1H NMR (360 MHz, CDCl3): δ 10.98 (br s, 1H), 9.71 (br s, 1H), 8.94 (s, 2H), 7.89 (m, 1H), 7.49 (dd, 1H), 7.12 (dd, 1H), 4.38 (d, 1H), 4.04 (d, 1H), 1.66 (s, 3H), 1.56 (s, 3H), 1.52 (s, 9H).
Reaction SMILES: [CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([N:20]=[CH:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.C1COCC1.[BH4-].[Na+]>CO>[CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:15][CH2:16][N:17]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][CH:23]=3)[CH2:18][CH2:19]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1
Reactant: C[C@]1(CN2CCN(N=Cc3ccc(C(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@]1(CN2CCN(NCc3ccc(C(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.6 %

Procedure:
To a mixture of (S)-N-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]-N-(4-trifluoromethylbenzylidene)amine prepared in Example 504 (100 mg, 0.23 mmol) and THF (4 ml), sodium borohydride (13 mg, 0.34 mmol) was added with cooling on ice-bath followed by stirring at room temperature for 30 minutes. To the reaction mixture, methanol (1 ml) was added, and the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=2/1) to afford (S)-N-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]-N-(4-trifluoromethylbenzyl)amine (32 mg, yield 31%) as a light yellow powder.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)(O)[CH3:15])[CH:12]=[CH:13][C:8]=2[S:7][C:6]2[N:23]=[CH:24][CH:25]=[N:26][C:5]1=2.ClS(OC)(=O)=O.O.C(OCC)(=O)C>ClCCl>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:14]([C:11]2[CH:12]=[CH:13][C:8]3[S:7][C:6]4[N:23]=[CH:24][CH:25]=[N:26][C:5]=4[N:4]([CH2:3][O:2][CH3:1])[C:9]=3[CH:10]=2)=[CH2:15])[CH:18]=1
Reactant: COCN1c2cc(C(C)(O)c3cccnc3)ccc2Sc2nccnc21
Agent: COS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: C=C(c1cccnc1)c1ccc2c(c1)N(COC)c1nccnc1S2
Yield: 79.8 %

Procedure:
To a solution of 303 mg of 1-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)1-(pyridin-3-yl)ethanol in dichloromethane was added in a nitrogen atmosphere 0.32 ml of methyl chlorosulfonate and the resulting mixture was heated under reflux for 2 hours. Then the reaction mixture was brought back to room temperature and distributed into water and ethyl acetate. The extract was dried over anhydrous magnesium sulfate and filtered. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) to thereby give 230 mg of the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:11])=[C:8]([OH:10])[CH:9]=1)[CH3:2].[CH2:12](Br)[CH3:13].[ClH:15]>C(O)C>[ClH:15].[CH2:1]([N:3]([CH2:12][CH3:13])[C:4]1[CH:5]=[CH:6][C:7]([CH3:11])=[C:8]([OH:10])[CH:9]=1)[CH3:2]
Reactant: CCBr
Reactant: CCNc1ccc(C)c(O)c1
Agent: Cl
Solvent: CCO
Product: CCN(CC)c1ccc(C)c(O)c1

Procedure:
5 gm of 5-(ethylamino)-2-methylphenol were dissolved in 50 ml of ethanol, then alkylated analogously to the procedure described in Example 4 with 5,2 gm ethyl bromide, and worked up. The hydrochloride had a melting point of 192° C.
Reaction SMILES: N12CCCN=C1CCC[CH2:3][CH2:2]2.C(I)C.[C:15]([NH:18][CH2:19][C@@H:20]([NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[C:21]([OH:23])=[O:22])(=[O:17])[CH3:16].C(NC(NC(OCC1C=CC=CC=1)=O)(C)C(OCC)=O)(=O)C>C(#N)C>[C:15]([NH:18][CH2:19][C@@H:20]([NH:24][C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])[C:21]([O:23][CH2:2][CH3:3])=[O:22])(=[O:17])[CH3:16]
Reactant: CC(=O)NC[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: C1CCC2=NCCCN2CC1
Agent: CCOC(=O)C(C)(NC(C)=O)NC(=O)OCc1ccccc1
Solvent: CC#N
Solvent: CCI
Product: CCOC(=O)[C@@H](CNC(C)=O)NC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (0.45 ml., 3.0 mmole) and ethyl iodide (0.3 ml., 3.75 mmole) are added to a solution of (R)-3-(acetylamino)-2-[[(benzyloxy)carbonyl]amino]propanoic acid (0.7 g., 2.5 mmole) in acetonitrile (15 ml.). The reaction is allowed to stir overnight then concentrated in vacuo. The residue is dissolved in methylene chloride, washed with 2N hydrochloric acid (2×50 ml.), sodium bicarbonate (2×50 ml.), and brine, and then dried over sodium sulfate. The solvent is removed in vacuo and the resulting oil is chromatographed on silica gel eluting with ethyl acetate to yield 0.6 g. of (R)-3-(acetylamino-2-[[(benzyloxy)carbonyl]amino]propanoic acid, ethyl ester as a clear oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]([O:11]CC)=[O:10])=[CH:3][CH:2]=1.[OH-].[K+].Cl>O.CCO>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCc1ccncc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCc1ccncc1
Yield: 72.1 %

Procedure:
To a solution of ethyl 3-pyridin-4-ylpropanoate (Method 7; 103.1 g, 576 mmol) in water (400 ml) and EtOH (20 ml) at room temperature was added potassium hydroxide (60 g, 1600 mmol). After 18 hours hydrochloric acid (100 ml) was added to give a white solid 62.8 g (73%). NMR (300 MHz) 8.38 (d, 2H), 7.21 (d, 2H), 2.70 (t, 2H), 2.52 (t, 2H); m/z 152.2.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1.[CH2:29]([O:31][C:32](=[O:35])[CH2:33]Br)[CH3:30].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)(Cl)Cl>[CH2:29]([O:31][C:32](=[O:35])[CH2:33][O:1][CH2:2][C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:13]=[CH:14][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:16][CH:17]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1)[CH3:30]
Reactant: Cc1c(CO)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)COCc1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c2c1C
Temperature: 80 °C
Yield: 27.6 %

Procedure:
A mixture of 6-hydroxymethyl-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile (Example 3B) (36 mg, 0.097 mmol), bromo-acetic acid ethyl ester (24 mg, 0.146 mmol) and K2CO3 (67 mg, 0.48 mmol) in DMF (0.6 ml) was heated at 80° C. for 45 min, then diluted with CHCl3 (50 ml), washed with H2O (2×20 ml), dried with Na2SO4. Concentrated in vacuo and purified by prep. TLC to give the title compound (12.2 mg, 28%) (50% EtOAc—hexanes). It has a retention time of 6.62 min (standard LCl method, 8 min run). MS Found: (M+H)+=457.1
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([OH:14])=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(O[CH:18]1C=CC2C(=CC=CC=2)[N:19]1C(OCC)=O)C.C(N(CC)CC)C.[Cl-].C[NH3+]>C(#N)C>[NH2:1][C:2]1[N:11]=[C:10]([C:12](=[O:14])[NH:19][CH3:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CCOC(=O)N1c2ccccc2C=CC1OCC
Reactant: Nc1nc(C(=O)O)c2ccccc2n1
Agent: C[NH3+]
Agent: [Cl-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CNC(=O)c1nc(N)nc2ccccc12
Reaction time: 16 h

Procedure:
1.2 100 mg of 2-amino-4-carboxyquinazoline and 261.6 mg of ethyl 2-ethoxy-1,2-dihydroquinoline-1-carboxylate are suspended in 5 ml of acetonitrile, and 146.6 μl of triethylamine are added. 53.6 mg of methylammonium chloride are added, and the mixture is stirred at 80° (bath temperature) for 16 hours. The mixture is cooled, the solvent is removed, and the product is purified by means of RP flash chromatography (Isco Compamion®);
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:26][S:27]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)(=[O:29])=[O:28]>>[CH3:26][S:27]([C:30]1[CH:35]=[C:34]([C:2]2[CH:25]=[CH:24][C:5]3[C:6]4[N:7]=[C:8]([C:14]5[N:15]([CH2:19][C:20]([F:22])([F:23])[F:21])[N:16]=[CH:17][N:18]=5)[S:9][C:10]=4[CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)[CH:33]=[CH:32][CH:31]=1)(=[O:29])=[O:28]
Reactant: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Product: CS(=O)(=O)c1cccc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)c1

Procedure:
Following the procedure for 114, 8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 3-methylsulfonylphenylboronic acid to give 148. MS(ESI+) 507.0. 1H NMR (400 MHz, DMSO) δ 8.44 (d, J=8.3, 1H), 8.31 (s, 1H), 8.25 (s, 1H), 8.14 (d, J=8.0, 1H), 7.93 (d, J=7.8, 1H), 7.75 (t, J=7.8, 1H), 7.67 (dd, J=8.3, 1.7, 1H), 7.55 (d, J=1.7, 1H), 5.88 (q, J=8.6, 2H), 4.45 (t, J=4.9, 2H), 3.52 (t, J=4.9, 2H), 3.32 (s, 3H)
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[CH3:15][O-:16].[Na+].O>CO>[Cl:1][C:2]1[N:11]=[C:10]([O:16][CH3:15])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: C[O-]
Reactant: COc1ccc2nc(Cl)nc(Cl)c2c1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc2nc(Cl)nc(OC)c2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 61.8 %

Procedure:
A solution of 2,4-dichloro-6-methoxyquinazoline (0.33 g) in methanol (5 mL) was added sodium methoxide (0.086 g), and the mixture was stirred at room temperature for 6 h. Water was added to the reaction mixture, and the aqueous layer was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel, chloroform/methanol=50:1) to obtain 2-chloro-4,6-dimethoxyquinazoline (0.20 g).
Reaction SMILES: O[CH2:2][C:3]1([CH2:8][O:9][CH3:10])[CH2:7][S:6][S:5][CH2:4]1.[H-].[Na+].S1([O:19][CH2:18][CH2:17][O:16]1)(=O)=O.Cl>C1COCC1>[OH:16][CH2:17][CH2:18][O:19][CH2:2][C:3]1([CH2:8][O:9][CH3:10])[CH2:7][S:6][S:5][CH2:4]1
Reactant: O=S1(=O)OCCO1
Reactant: COCC1(CO)CSSC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC1(COCCO)CSSC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
A solution of 4-Hydroxymethyl-4-methoxymethyl-1,2-dithiacyclopentane (0.1 g) in THF (20 ml) was added to a suspension of sodium hydride (0.03 g) in THF (20 ml) and the mixture was stirred at room temperature for 30 min. Ethylene sulfate (0.14 g) was added and the resulting mixture stirred at room temperature for 48 h. Hydrochloric acid (3M, 5 ml) was added, and the aqueous layer extracted with ethyl acetate (5×20 ml). The organic layers were combined and washed with water (50 ml) and dried (Na2SO4). The solvent was removed under reduced pressure and the resulting oil purified by flash chromatography (ethyl acetate-light petroleum, 1:1 as eluant) to give 4-(2-hydroxyethoxy)methyl-4-methoxymethyl-1,2-dithiacyclopentane (66.8 mg, 54%). 1H-n.m.r. (CDCl3) δ2.93 (AB quartet, 4H), 3.34 (s, 3H), 3.36 (s, 2H), 3.46 (s, 2H), 3.56 (m, 2H). 3.70 (m, 2H); 13C-n.m.r. (CDCl3) δ44.7, 56.2, 59.3, 61.6, 72.2, 72.3, 74.2; m/z 224 (M+)
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[C:13]12([CH2:23][CH2:24]O)[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[CH2:9]([O:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:24][CH2:23][C:13]23[CH2:22][CH:17]4[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]4)[CH2:14]2)[CH2:20]3)=[CH:12][CH:11]=1)[CH3:10]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: OCCC12CC3CC(CC(C3)C1)C2
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OCCC23CC4CC(CC(C4)C2)C3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 4-hydroxybenzoate (83 mg) and 1-adamantaneethanol (90 mg) were combined in tetrahydrofuran (2 mL). Polymer-supported triphenylphosphine (250 mg of 3 mmol/g) and di-tert-butyl azodicarboxylate (173 mg) were added. The reaction was stirred at room temperature overnight. The resin was removed by filtration through celite. The filtrate was concentrated under vacuum, and the residue was triturated with 95/5 hexanes/ether to afford the title compound.