Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C(N(CC)CC)C.[C:19](OC(=O)C)(=[O:21])[CH3:20].C([O-])(O)=O.[Na+]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][C:19](=[O:21])[CH3:20])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc2cccnc12
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc2cccnc12
Yield: 101.3 %

Procedure:
To a stirred solution of 8-aminoquinoline (33.37 g, 0.231 mol), DMAP (4-dimethylaminopyridine) (1.40 g, 0.011 mol) and triethylamine (Et3N) (37 mL, 0.265 mol) in CH2Cl2 (methylene chloride) (275 mL) was added acetic anhydride (Ac2O) (26.5 mL, 0.281 mol). After 20 hours the reaction mixture was poured into a saturated aqueous solution of NaHCO3 (sodium bicarbonate). The phases were separated and the aqueous phase was extracted with ether (3×150 mL). The combined organic phases were dried (Na2SO4) (sodium sulfate), filtered and concentrated in vacuo to provide 43.56 g (100%) of N-(quinolin-8-yl)-acetamide as a beige solid. This material was used without further purification in subsequent steps. 1H NMR (CDCl3) δ 2.35 (s, 3H), 7.42-7.56 (m, 3H), 8.15 (dd, 1H, J=1.5, 8.4 Hz), 8.76 (dd, 1H, J=1.8, 7.2 Hz), 8.79 (dd, 1H, J=1.5, 4.2 Hz), 9.78 (br s, 1H); 13C NMR (CDCl3) δ 25.5, 116.8, 121.8, 122.0, 127.8, 128.3, 134.9, 136.8, 138.6, 148.5, 169.2. ES-MS m/z 187 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[CH2:12]([O:14][C:15](=[O:19])[CH2:16][CH2:17][NH2:18])[CH3:13].C(N(CC)CC)C>C(O)C>[CH2:12]([O:14][C:15](=[O:19])[CH2:16][CH2:17][NH:18][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)[CH3:13]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CCOC(=O)CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)CCNc1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 109.2 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (68.6 g, 0.434 mole), β-alanine ethyl ester hydrochloride (100 g, 0.651 mole), triethylamine (103.7 g, 1.03 mole) and 95% ethanol (675 ml) was refluxed for 5 hr and then stirred at room temperature overnight. The solvent was evaporated at reduced pressure and the residue was triturated in ethyl acetate (700 ml). The solid was filtered and washed with ethyl acetate. The filtrate was washed three times with water, dried over anhydrous sodium sulfate, filtered and evaporated at reduced pressure to give 113.4 g of an oil. The oil was eluted through a silica gel column (400 g) with ethyl acetate. The eluent was evaporated at reduced pressure to give 106.2 g of an oil (100% yield). A small portion of the oil was crystallized from petroleum ether to give 0.7 g of yellow solid of the title compound, mp. 32.5°-33.5° C.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)[CH:2]([CH3:4])[CH3:3].[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30](Cl)(=[O:32])=[O:31])#[N:23].C(N(CC)C(C)C)(C)C>ClCCl>[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)(=[O:32])=[O:31])#[N:23]
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Reactant: CC(C)CNCc1ccc(-c2cccc(S(C)(=O)=O)c2)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)CN(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)S(=O)(=O)c1ccccc1C#N

Procedure:
In analogy to example 13, step 2, isobutyl-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-amine (example 15, step 2) was reacted with 2-cyanobenzenesulfonyl chloride and N,N-diisopropyl ethyl amine in dichloromethane to give 2-cyano-N-isobutyl-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-benzenesulfonamide as a colorless solid. MS: 505.8 ([M+NH4]+)
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([O:10][C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13]([OH:15])=O)[CH:7]=[CH:6][C:5]=12.[C:20]([O:24][C:25](=[O:38])[C@H:26]([O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][NH2:36])=[C:31]([F:37])[CH:30]=1)[CH3:27])([CH3:23])([CH3:22])[CH3:21].O1C2C=CC(OC3N=CC=CC=3C(O)=O)=CC=2OC1.COC(=O)COC1C=CC(CN)=C(F)C=1>>[C:20]([O:24][C:25](=[O:38])[C@H:26]([O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][NH:36][C:13]([C:12]2[C:11]([O:10][C:8]3[CH:7]=[CH:6][C:5]4=[N:1][O:2][N:3]=[C:4]4[CH:9]=3)=[N:19][CH:18]=[CH:17][CH:16]=2)=[O:15])=[C:31]([F:37])[CH:30]=1)[CH3:27])([CH3:21])([CH3:22])[CH3:23]
Reactant: O=C(O)c1cccnc1Oc1ccc2nonc2c1
Reactant: C[C@@H](Oc1ccc(CN)c(F)c1)C(=O)OC(C)(C)C
Agent: COC(=O)COc1ccc(CN)c(F)c1
Agent: O=C(O)c1cccnc1Oc1ccc2c(c1)OCO2
Product: C[C@@H](Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3nonc3c2)c(F)c1)C(=O)OC(C)(C)C

Procedure:
The compound of Formula (5.0.30) was prepared in a manner analogous to that described in Preparation 20, substituting 2-(benzo[2,1,3]oxadiazol-5-yloxy)-nicotinic acid and (R)-2-(4-aminomethyl-3-fluoro-phenoxy)-propionic acid tert-butyl ester for the corresponding 2-(benzo-[1,3]-dioxol-5-yloxy)-nicotinic acid and (4-aminomethyl-3-fluoro-phenoxy)-acetic acid methyl ester materials, respectively.
Reaction SMILES: C(N1CCN([NH:14][C:15](=[O:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)CC1)(OC(C)(C)C)=O.[CH2:24]([C:26]1[N:31]=[C:30]([N:32]2[CH2:37][CH2:36]N(C(OC(C)(C)C)=O)[CH2:34][CH2:33]2)[C:29]2[CH:45]=[C:46]([CH2:48][CH3:49])[S:47][C:28]=2[N:27]=1)[CH3:25]>>[CH2:24]([C:26]1[N:31]=[C:30]([N:32]2[CH2:37][CH2:36][N:14]([C:15](=[O:23])[CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:34][CH2:33]2)[C:29]2[CH:45]=[C:46]([CH2:48][CH3:49])[S:47][C:28]=2[N:27]=1)[CH3:25]
Reactant: CCc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)c2cc(CC)sc2n1
Reactant: CC(C)(C)OC(=O)N1CCN(NC(=O)Cc2ccccc2)CC1
Product: CCc1nc(N2CCN(C(=O)Cc3ccccc3)CC2)c2cc(CC)sc2n1
Yield: 27 %

Procedure:
Phenylacetamidopiperazine hydrochloride (Example 141) was reacted 2-ethyl-4-chloro-6-ethylthienopyrimidine (Example 156) according to Example 87. Yield=27%, ES-MS: (M+H)+ 395.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH2:9][CH:10]=O>CO.N>[N:1]1[CH:9]=[CH:10][N:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=12
Reactant: O=CCCl
Reactant: Nc1ccccn1
Agent: N
Solvent: CO
Product: c1ccn2ccnc2c1
Yield: 88.9 %

Procedure:
A mixture of 9.4 g (0.1 mole) of 2-aminopyridine and 19.2 g (0.11 mole) of 45% aqueous chloroacetaldehyde was stirred, during which spontaneous heating occurred. When the exothermic reaction subsided, the mixture was dissolved in methanol containing 15 ml of concentrated aqueous ammonia and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to an oil. Distillation at 80-83° and 0.2 mm Hg pressure yielded 10.5 g of imidazo[1,2-a]pyridine as an oil. A solution of 9.5 g (80.5 mmole) of imidazo[1,2-a]pyridine in 60 ml of dimethylformamide was heated to 90°. Phosphorus oxychloride (9.27 ml, ca. 100 mmole) was added dropwise over a twenty minute period, and the mixture was stirred at 90° for two hours and at room temperature for an additional twenty hours. The mixture was diluted with 60 ml of water and made basic with 30% aqueous sodium hydroxide. The resultant solid was collected by filtration, washed with water, and air dried to yield 1.8 g of 3-imidazo[1,2-a]pyridinecarboxaldehyde as the analytically pure p hydrate. [Calcd. for C8H6N2O.H2O: C, 58.53; H, 3.68; N, 17.06. Found: C, 58.77; H, 3.68; N, 17.48.]To a solution of 1.6 g (10 mmole) of 3-imidazo[1,2-a]-pyridinecarboxaldehyde in 15 ml of methanol was added 204 mg (5.4 mmole) of sodium borohydride. After one hour the mixture was acidified with concentrated hydrochloric acid and then concentrated in vacuo. Recrystallization of the residue from ethanol yielded 707 mg of 3-hydroxymethylimidazo[1,2-a]pyridine as the hydrochloride salt. A 500 mg (2.7 mmole) portion of the hydroxymethyl compound was dissolved in 3.0 ml of concentrated hydrochloric acid and heated at 80° for one hour. The mixture was concentrated in vacuo and the residue was recrystallized from isopropyl alcohol to yield 465 mg of 3-chloromethylimidazo[1,2-a]pyridine as the hydrochloride salt. A mixture of 390 mg (1.92 mmole) of the chloromethyl compound and 288 mg (1.92 mmole) of 2-mercaptobenzimidazole in 7 ml of isopropyl alcohol was stirred for one hour. The precipitate that formed was collected and partitioned between 5% aqueous sodium hydroxide and dichloromethane. The organic layer was washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. Trituration of the residue with diethyl ether yielded the title compound as an analytically pure solid. Structure assignment was supported by the nmr spectrum and by elemental analysis.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH:20]1([CH:23]=O)[CH2:22][CH2:21]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:23][CH:20]2[CH2:22][CH2:21]2)[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C
Reactant: O=CC1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cc(Br)cc(N(CC2CC2)C2CCOCC2)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.7 %

Procedure:
To a stirred solution of methyl 5-bromo-2-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate (1 g, 3.04 mmol) and cyclopropanecarbaldehyde (1.06 g, 15.24 mmol) in methanol (15 mL), acetic acid (0.456 g, 7.6 mmol) was added The reaction mixture was stirred at room temperature for 8 h. Sodium cyanoborohydride (0.488 g, 7.62 mmol) was then added at 0° C. and reaction mixture stirred overnight at room temperature. The solvent was then removed under reduced pressure and the crude product purified by column chromatography to afford methyl 5-bromo-3-((cyclopropylmethyl)(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzoate (0.275 g, 23.70%).
Reaction SMILES: CN1C(=O)CCC(C)(C)[C:4]2C=C([N+]([O-])=O)C=C[C:3]1=2.[CH3:19][C:20]1([CH3:35])[CH2:26][CH2:25][C:24](=[O:27])[NH:23][C:22]2[CH:28]=[C:29]([N+:32]([O-:34])=[O:33])[CH:30]=[CH:31][C:21]1=2>>[CH2:3]([N:23]1[C:24](=[O:27])[CH2:25][CH2:26][C:20]([CH3:35])([CH3:19])[C:21]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][C:22]1=2)[CH3:4]
Reactant: CC1(C)CCC(=O)Nc2cc([N+](=O)[O-])ccc21
Reactant: CN1C(=O)CCC(C)(C)c2cc([N+](=O)[O-])ccc21
Product: CCN1C(=O)CCC(C)(C)c2ccc([N+](=O)[O-])cc21

Procedure:
1-Ethyl-5,5-dimethyl-8-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one was prepared in a manner analogous to the preparation of 1,5,5-Trimethyl-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one using 5,5-Dimethyl-8-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one as starting material to yield a yellow solid (65%). mp 83° C.; LCMS: m/z=263.05 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.11 (m, 1H), 8.06 (m, 1H), 7.60 (d, 1H, J=8.6 Hz), 3.91 (m, 2H), 2.32 (m, 2H), 1.42 (s, 6H), 1.38 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]3[N:29]([CH3:30])[C:28](=[O:31])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)[CH:13]=2)[C:3]=1[CH:4]=[O:5].C=C(C)C.[O-:36]Cl=O.[Na+]>C(O)(C)(C)C.O.C(OCC)(=O)C>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]3[N:29]([CH3:30])[C:28](=[O:31])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)[CH:13]=2)[C:3]=1[C:4]([OH:36])=[O:5]
Reactant: [O-][Cl+][O-]
Reactant: Cc1cccc(COc2cccc(OCc3nc4ccccc4c(=O)n3C)c2)c1C=O
Agent: C=C(C)C
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: Cc1cccc(COc2cccc(OCc3nc4ccccc4c(=O)n3C)c2)c1C(=O)O
Reaction time: 1 h

Procedure:
To a suspension of 2-methyl-6-[3-(3-methyl-4-oxo-3,4-dihydro-quinazolin-2-ylmethoxy)phenoxymethyl]-benzaldehyde (120 mg, 0.28 mmol, example 102) in t-butanol (1.5 mL) is added iso-butene (0.5 mL) followed by NaClO2 (220 mg, tech grade 1.6 mmol) in water (1.5 mL) and NaH2PO4.H2O (220 mg, 1.6 mmol) in water (1.5 mL). This mixture is stirred for 1 h (during which time the solids dissolve) then diluted with ethyl acetate, washed with water and brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (10% methanol in dichloromethane). This product was suspended in chloroform and filtered through celite. The filtrate is concentrated under reduced pressure to give the title compound as an amorphous solid. 1H NMR (300 MHz, CDCl3): δ 8.41 (d, 1H), 7.84 (m, 2H), 7.62 (m, 1H), 7.33 (m, 2H), 7.20 (m, 1H), 7.14 (t, 1H), 6.81 (m, 1H), 6.70 (m, 2H), 5.29 (s, 2H), 5.25 (s, 2H), 3.80 (s, 2H), 2.52 (s, 3H). MS (ESI) 430 (M+H)+.
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)=[O:2].[CH3:9][OH:10]>F[B-](F)(F)F.C[N+](C)(C)C.[Ni]>[CH:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[O:10][CH3:9])=[O:2]
Reactant: CO
Reactant: O=CN1CCCCC1
Agent: [Ni]
Agent: *CC*
Agent: C[N+](C)(C)C
Product: COC1CCCCN1C=O
Yield: 84.3 %

Procedure:
An electrode assembly consisting of an anode of glassy carbon, a nickel cathode and two bipolar connected electrodes of glassy carbon inserted between the two outer electrodes was fitted in the cell of the device as described in Example 1. All four electrodes were framed as described in Example 1. Polyethylene nets (mesh width 3×5 mm and thickness of filaments 0.5 mm) between the plates had the function of spacers. In this cell, a mixture of 4,800 g of 1-formylpiperidine, 13,600 g of methanol and 68 g of tetramethylammonium tetrafluoroborate was electrolyzed at 27.5 A, 45 volts and 25° C. for 27 hours and 33 minutes (corresponding to 2,273 Ahr). After distillative work up, 5,120 g of 1-formyl-2-methoxypiperidine were isolated, corresponding to a current efficiency of 80.3%.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[F:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[C@H:14]1[CH2:20][N:19]2[C:21]([CH:24]=[O:25])=[CH:22][N:23]=[C:18]2[C@H:17]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:16][CH2:15]1>O1CCCC1>[CH:1]1([CH:24]([OH:25])[C:21]2[N:19]3[CH2:20][C@H:14]([C:8]4[CH:9]=[CH:10][CH:11]=[C:12]([F:13])[C:7]=4[F:6])[CH2:15][CH2:16][C@@H:17]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:18]3=[N:23][CH:22]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(C=O)cnc21
Reactant: Br[Mg]C1CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(C(O)C3CC3)cnc21
Reaction time: 0.5 h

Procedure:
Cyclopropylmagnesium bromide (0.5 M in tetrahydrofuran; 1.53 mL, 0.77 mmol) was added to a solution of tert-butyl (6S,9R)-6-(2,3-difluorophenyl)-3-formyl-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-ylcarbamate (60 mg, 0.15 mmol) in tetrahydrofuran (1 mL) at 0° C. After 30 min, the reaction was quenched with water and the mixture was extracted with dichloromethane (3×). The organic layer was washed with water, saturated brine, dried over magnesium sulfate, filtered and concentrated. MS 434.2 (M+1).
Reaction SMILES: Cl.[F:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]([C:11]2[CH:16]=[C:15]([C:17]3[CH2:21][CH:20]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[O:19][N:18]=3)[N:14]=[C:13]([CH3:28])[N:12]=2)=[O:10])=[CH:5][C:4]=1[O:31][CH3:32].[C:33]([O:36][CH2:37][C:38](Cl)=[O:39])(=[O:35])[CH3:34]>ClCCl.O>[C:33]([O:36][CH2:37][C:38]([N:25]1[CH2:24][CH2:23][CH:22]([CH:20]2[O:19][N:18]=[C:17]([C:15]3[CH:16]=[C:11]([C:9](=[O:10])[NH:8][CH2:7][C:6]4[CH:29]=[CH:30][C:3]([F:2])=[C:4]([O:31][CH3:32])[CH:5]=4)[N:12]=[C:13]([CH3:28])[N:14]=3)[CH2:21]2)[CH2:27][CH2:26]1)=[O:39])(=[O:35])[CH3:34]
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1cc(CNC(=O)c2cc(C3=NOC(C4CCNCC4)C3)nc(C)n2)ccc1F
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: COc1cc(CNC(=O)c2cc(C3=NOC(C4CCN(C(=O)COC(C)=O)CC4)C3)nc(C)n2)ccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.2 %

Procedure:
To a cold solution of N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide hydrochloride (1.8 g, 3.87 mmol, Preparation #K.1) in dichloromethane (20 mL) were added TEA (3.3 mL, 23.2 mmol) and acetoxyacetyl chloride (0.5 mL, 4.65 mmol). The reaction mixture was slowly warmed to RT and stirred for about 10 min. The reaction mixture was diluted with water (10 mL) and the product was extracted with DCM (2×20 mL). The combined organic layers were washed with water (1×25 mL) followed by brine (1×50 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford 2-(4-(3-(6-(4-fluoro-3-methoxybenzylcarbamoyl)-2-methylpyrimidin-4-yl)-4,5-dihydroisoxazol-5-yl)piperidin-1-yl)-2-oxoethyl acetate as a brown solid 1.8 g (90%).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:29][C:30](=[N:36]O)[C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:19][CH:20]=3)[CH2:12][CH:11]([C:26]3[O:28][N:36]=[C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:29]=3)[CH2:10]2)=[O:8])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: CCOC(=O)C(N)=NO
Product: CCOC(=O)c1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
80 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 29 mg (0.22 mmol, 1.1 eq.) of ethyl 2-amino(hydroxyimino)ethanoate were reacted according to the General Method 1. Yield: 24 mg (22% of theory)
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([OH:25])C>C(O)(=O)C>[C:1]1([C:7]2[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][C:21]([OH:25])=[O:22])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCO
Reactant: OCCCCOc1cc(-c2ccccc2)nc2ccccc12
Solvent: CC(=O)O
Product: O=C(O)CCCOc1cc(-c2ccccc2)nc2ccccc12
Reaction time: 1 h

Procedure:
A solution of 4-[(2-phenyl-4-quinolyl)oxy]butanol (2.20 g) in glacial acetic acid (10 cc) is added slowly to a solution, cooled to 5° C., of chromic anhydride (2.25 g) in 90% strength acetic acid (5 cc). The temperature is allowed to rise to approximately 20° C., and the mixture is then stirred for one hour at this temperature. Ethanol (50 cc) is then added, the solvents are evaporated off under reduced pressure, the residue is taken up with water (100 cc) and the insoluble material is drained and washed several times with water. This insoluble material is taken up with normal sodium hydroxide solution (15 cc) and heated under reflux for two hours. The insoluble material is removed by filtration and the filtrate acidified by adding glacial acetic acid. The precipitate obtained is drained. 4-[(2-Phenyl-4-quinolyl)oxy]butanoic acid (0.740 g), m.p. 264° C., is obtained.
Reaction SMILES: N#N.Cl[CH2:4][C:5]1[S:9][C:8]([C:10]2([CH3:15])[O:14][CH2:13][CH2:12][O:11]2)=[N:7][CH:6]=1.[N+:16]([C:19]1[CH:20]=[N:21][NH:22][CH:23]=1)([O-:18])=[O:17].C([O-])([O-])=O.[K+].[K+].[Br-]>CC(C)=O>[CH3:15][C:10]1([C:8]2[S:9][C:5]([CH2:4][N:21]3[CH:20]=[C:19]([N+:16]([O-:18])=[O:17])[CH:23]=[N:22]3)=[CH:6][N:7]=2)[O:14][CH2:13][CH2:12][O:11]1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: CC1(c2ncc(CCl)s2)OCCO1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC(C)=O
Product: CC1(c2ncc(Cn3cc([N+](=O)[O-])cn3)s2)OCCO1
Temperature: 25 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-chloromethyl-2-(2-methyl-[1,3]dioxolan-2-yl)-thiazole (495 mg, 2.25 mmol) in acetone (1.0 mL) was added to a solution of 4-nitro-1H-pyrazole (268 mg, 2.37 mmol) in acetone (1.0 mL). K2CO3 (1.57 g, 11.27 mmol) followed by TBA bromide (145 mg, 0.45 mmol) were added and the reaction mixture was stirred at rt until completion. The solvent was removed under reduced pressure and water (10 mL) followed by EA (10 mL) were added. The aq. layer was extracted with EA (10 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (10:1 to 2:1 hept-EA) gave the title compound as a yellow oil. TLC: rf (1:2 hept-EA)=0.24. LC-MS-conditions 01: tR=0.82 min, [M+H]+=296.93.
Reaction SMILES: CS(O[C@H:6]1[CH2:10][CH2:9][C@@H:8]([NH:11][C:12]2[C:13]3[N:14]([CH:21]=[CH:22][CH:23]=3)[N:15]=[CH:16][C:17]=2[C:18](=[O:20])[NH2:19])[C:7]1([CH3:25])[CH3:24])(=O)=O>CN(C)C=O>[CH3:24][C:7]1([CH3:25])[CH:6]=[CH:10][CH2:9][CH:8]1[NH:11][C:12]1[C:13]2[N:14]([CH:21]=[CH:22][CH:23]=2)[N:15]=[CH:16][C:17]=1[C:18]([NH2:19])=[O:20]
Reactant: CC1(C)[C@@H](OS(C)(=O)=O)CC[C@H]1Nc1c(C(N)=O)cnn2cccc12
Solvent: CN(C)C=O
Product: CC1(C)C=CCC1Nc1c(C(N)=O)cnn2cccc12
Temperature: 130 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
A mixture of crude cis-3-(3-carbamoylpyrrolo[1,2-b]pyridazin-4-ylamino)-2,2-dimethylcyclopentyl methanesulfonate (from Step 1), 1,8-diazabiclo[5,4,0]undec-7-ene (0.235 mL, 1.561 mmol) and N,N-dimethylformamide (2 mL) was stirred at 130° C. for 2 h, cooled to room temperature and quenched with saturated sodium bicarbonate (3 mL). Following addition of ethyl acetate (80 mL), the mixture was washed with water, brine, dried (MgSO4), filtered and concentrated. Silica gel chromatography, eluting with 20 to 100% ethyl acetate in hexanes, gave the title compound (40 mg, 47% yield for 2 steps). 1H NMR (400 MHz, methanol-d4) δ ppm 10.70 (1 H, d, J=8.58 Hz), 7.87-8.20 (1 H, m), 7.57 (1 H, dd, J=2.64, 1.54 Hz), 6.99 (1 H, dd, J=4.73, 1.43 Hz), 6.67 (1 H, dd, J=4.62, 2.86 Hz), 5.60-5.87 (2 H, m), 4.47-4.64 (1 H, m), 2.78-3.15 (1 H, m), 2.23-2.51 (1 H, m), 1.01-1.24 (6 H, m); MS (ES+) m/z:=271.2 (M+H).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][C:11]1[CH:15]=[CH:14][S:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[S:13]1[C:12]2[C:2]3[CH:3]=[N:4][CH:5]=[CH:6][C:7]=3[O:8][CH2:9][CH2:10][C:11]=2[CH:15]=[CH:14]1
Reactant: Ic1cnccc1OCCc1ccsc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: c1cc2c(cn1)-c1sccc1CCO2
Yield: 84.6 %

Procedure:
3-Iodo-4-(2-(thiophen-3-yl)ethoxy)pyridine (1.66 g, 5.00 mmol), palladium acetate (112 mg, 0.500 mmol), triphenylphosphine (262 mg, 1.00 mmol) and potassium carbonate (1.38 g, 10.0 mmol) in N,N-dimethylformamide (80 mL, 1000 mmol) were heated at 115° C. for 2 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was washed with water and brine, and dried over MgSO4. The crude product was purified on a silica gel column eluting with 50% ethyl acetate in hexane to give 4,5-dihydropyrido[4,3-b]thieno[2,3-d]oxepine (yield 0.86 g, 85%). 1H NMR (400 MHz, CDCl3) δ 8.93 (s, 1H), 8.25 (d, J=5.5, 1H), 7.23 (d, J=5.2, 1H), 6.89 (dd, J=3.6, 5.3, 2H), 4.43-4.33 (m, 2H), 3.29-3.20 (m, 2H). MS (ESI+) 204.0