Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16].CN(C)[CH:22]=[O:23]>C(OCC)(=O)C>[CH3:14][N:15]([CH3:17])[CH:16]=[CH:3][C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[O:23][CH3:22])=[O:5]
Reactant: COC(OC)N(C)C
Reactant: COCC(=O)c1ccccc1
Reactant: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccccc1C(=O)C=CN(C)C
Reaction time: 3 h

Procedure:
A stirred mixture of 2-methoxyacetophenone (5.5 ml) and dimethylformamide dimethylacetal (6.7 ml) in dry dimethylformamide (40 ml) was heated under reflux for 18 hours. A further quantity of dimethylformamide dimethylacetal (1 ml) was added and reflux continued for 3 hours. The cooled reaction mixture was diluted with ethyl acetate, washed with water and brine, dried (magnesium sulphate) and evaporated under reduced pressure yielding 3-dimethylamino-1-(2-methoxyphenyl)-2-propene-1-one as an orange oil. Further product remained in the aqueous extract which was evaporated under reduced pressure to yield a residue which was dissolved in ethyl acetate. The filtered solution was washed with water and brine, dried (magnesium sulphate) and evaporated under reduced pressure to yield a further quantity of orange oil. Total yield was 5.74 g.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[C:5]([N:11]2C=[CH:14][CH:13]=[N:12]2)=[CH:4][CH:3]=1.[N:16]1NN=CC=1>>[CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[C:5]([N:11]2[N:12]=[CH:13][CH:14]=[N:16]2)=[CH:4][CH:3]=1
Reactant: c1cn[nH]n1
Reactant: Cc1ccc(-n2cccn2)c(C(=O)O)n1
Product: Cc1ccc(-n2nccn2)c(C(=O)O)n1

Procedure:
The title compound was prepared following the same general protocol as described for 6-methyl-3-(1H-pyrazol-1-yl)picolinic acid in Example A164, using 2H-1,2,3-triazole. ESI-MS (m/z): 205 [M+1]+.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:14](=[O:16])[CH3:15])[N:4]2[C:8]3[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:7]=3[S:6][C:5]=12.[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([CH:25]=O)=[CH:23][CH:24]=1>>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([CH:25]=[CH:15][C:14]([C:3]2[N:4]3[C:5]([S:6][C:7]4[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]=43)=[N:1][CH:2]=2)=[O:16])=[CH:23][CH:24]=1
Reactant: CC(=O)c1cnc2sc3c(n12)CCCCC3
Reactant: COc1ccc(C=O)cc1
Product: COc1ccc(C=CC(=O)c2cnc3sc4c(n23)CCCCC4)cc1

Procedure:
1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-ethanone (Formula N-4), 0.44 g, and anisaldehyde (0.5 mL) were condensed according to non-critical variations in PREPARATION 15 to produce 3-(4-Methoxyphenyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-2-propene-1-one, 0.65 g, (Formula N-5, X=4-methoxy), m.p. 180-187°.
Reaction SMILES: C(O[C:4](=[O:16])[C:5](=[C:9]1[C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10]1)[O:6][CH2:7][CH3:8])C.[OH-:17].[K+].Cl>>[CH2:7]([O:6][C:5]1[C:9]([C:13]([OH:17])=[O:14])=[N:10][C:11]([OH:15])=[N:12][C:4]=1[OH:16])[CH3:8]
Reactant: [OH-]
Reactant: CCOC(=O)C(OCC)=C1NC(=O)NC1=O
Agent: Cl
Agent: [K+]
Product: CCOc1c(O)nc(O)nc1C(=O)O
Temperature: 0 °C

Procedure:
(2,5-dioxo-imidazolidin-4-ylidene)-ethoxy-acetic acid ethyl ester (16.02 g, 1 eq.) was dissolved in aq. 1 N KOH (281 ml, 4 eq.) and refluxed for 3.5 hrs. The mixture was cooled to 0° C. and carefully acidified with conc. HCl. After overnight cooling (4° C.), it led to the formation of white precipitate. The mixture was filtered and the precipitate was dried in vacuo. The product obtained was a white solid (7.76 g, 55%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=O)[CH2:10]2)=[CH:5][CH:4]=1.[CH2:14]([NH2:17])[CH2:15][CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:32]C(Cl)C>>[ClH:32].[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH:17][CH2:14][CH2:15][CH3:16])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)CC(=O)CC2
Reactant: CC(Cl)Cl
Reactant: CCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCCNC1CCc2ccc(OC)cc2C1
Product: Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 7-methoxy-3,4-dihydro-1H-naphthalen-2-one (6.0 g, 39.7 mmol) in dichloroethane (130 mL) under an inert atmosphere was added propylamine (3.4 mL, 41.7 mmol, 1.05 eq) followed by sodium triacetoxyborohydride (21 g, 99.3 mmol, 2.5 eq) in a single portion. The reaction was allowed to stir at room temperature for 24 h. The mixture was concentrated in vacuo and partitioned between EtOAc (200 mL) and 5% aq. NaOH (100 mL). The aqueous layer was extracted twice more with EtOAc (2×70 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO4, filtered, and concentrated. The residue was taken up in ether (125 mL) and treated with 1N HCl in ether. The salt was filtered and dried to afford (7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amine hydrochloride as a tan solid (5.0 g).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:12]=[CH:11][C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=1>C(O)(=O)C>[Br:1][C:10]1[C:6]2[CH:5]=[C:4]([Cl:3])[CH:12]=[CH:11][C:7]=2[S:8][CH:9]=1
Reactant: BrBr
Reactant: Clc1ccc2sccc2c1
Solvent: CC(=O)O
Product: Clc1ccc2scc(Br)c2c1
Temperature: 50 °C
Yield: 76.5 %

Procedure:
A solution of bromine (0.31 g, 1.95 mmol) in 1.0 ml glacial acetic acid was added to a stirred solution of 5-chlorobenzo[b]thiophene (0.300 g, 1.77 mmol)in glacial acetic acid (1.0 ml) under nitrogen atmosphere. The reaction was heated to 50° C. for 4 hours, the volatiles removed under reduced pressure, the residue diluted in methylene chloride, washed with aq. sodium bicarbonate and with brine and dried over sodium sulfate. Evaporation gave 0.335 g (76%) of a tan solid. mp 85°-86° C., FDMS m/e=249 (M+2).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].Cl.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28](Cl)=[O:29]>C1COCC1.CO>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=3)=[O:29])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: O=C(Cl)c1ccccn1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: O=C1CCC(N2C(=O)c3cccc(NC(=O)c4ccccn4)c3C2=O)C(=O)N1
Yield: 39.6 %

Procedure:
To a stirred suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2.0 mmol) in THF (30 ml) was added pyridine-2-carbonyl chloride hydrochloride (0.71 g, 4.0 mmol). The mixture was heated to reflux for 18 hours. The solvent was evaporated in vacuo and the resulting solid was slurried in a biphasic mixture of diethyl ether (20 ml)/20% NH4OH (20 ml) and filtered to give an off-white solid. The solid was re-slurried in methanol (20 ml) and filtered to give 0.30 g (40%) of product: mp 336-338° C.; 1H NMR (DMSO-d6) δ 11.83 (s, 1H), 11.20 (s, 1H), 8.92 (d, J=8.4 Hz, 1H), 8.81 (d, J=3.6 Hz, 1H), 8.22 (d, J=7.7 Hz, 1H), 8.15 (t, J=7.4 Hz, 1H), 7.92 (t, J=7.7 Hz, 1H), 7.77-7.72 (m, 1H), 7.65 (d, J=7.2 Hz, 1H), 5.22 (dd, J=5.2 and 12.5 Hz, 1H), 3.00-2.86 (m, 1H), 2.69-2.52 (m, 2H), 2.15-2.11 (m, 1H); 13C NMR (DMSO-d6) δ 172.67, 169.67, 168.20, 166.61, 162.69, 148.83, 148.19, 138.45, 136.50, 136.16, 131.39, 127.72, 124.23, 122.46, 118.29, 116.32, 48.96, 30.91, 21.98; Anal. Calcd. For C19H14N4O5: C, 60.32; H, 3.73; N, 14.81. Found: C, 60.05; H, 3.57; N, 14.45.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH2:15][C:16]1[N:21]=[C:20]([N:22]([CH3:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:19]=[C:18]([C:30](=[NH:33])[NH:31]O)[N:17]=1.NC1N=C(N(C)C2C=CC=C(C)C=2)N=C(C(NO)=N)N=1>N1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:10][N:33]=[C:30]([C:18]3[N:19]=[C:20]([N:22]([CH3:29])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:21]=[C:16]([NH2:15])[N:17]=3)[N:31]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CN(c1ccccc1)c1nc(N)nc(C(=N)NO)n1
Agent: Cc1cccc(N(C)c2nc(N)nc(C(=N)NO)n2)c1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(Cl)nc3)n2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Chloropyridine-3-carboxylic acid (Ig, 6.35 mmol) and thionyl chloride (10 mL, 138 mmol) were heated to reflux for 2 hours. The mixture was concentrated under vacuum and the residue was azeotroped with diethyl ether and evaporated. A portion of this acid chloride (0.75 g, 4.26 mmol) was then added to a solution of 4-amino-N-hydroxy-6-[methyl(phenyl)amino]-1,3,5-triazine-2-carboximidamide (prepared in an analogous manner to Intermediate 1, 0.920 g, 3.55 mmol) in pyridine (12 mL) and the mixture was stirred at room temperature overnight before being heated to 70 C for 3 h. The mixture was cooled to room temperature and concentrated under vacuum. Water was added and the mixture was stirred for 30 min. The solids were filtered and washed with further water. The solid was then azeotroped with toluene and dried under vacuum to afford the title compound, which was used without purification in the next step. Method B HPLC-MS: MH+ requires m/z=381 Found: m/z=381, Rt=1.99 min (35%).
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([C:16](=[O:19])[NH:17][N:18]=2)[C:5]([CH3:15])=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][N:29]=1.O>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[C:3]2[N:4]([C:16](=[O:19])[N:17]([CH2:27][C:28]3[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][N:29]=3)[N:18]=2)[C:5]([CH3:15])=[CH:6][C:7]=1[C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=1
Reactant: N#Cc1ccc(CCl)nc1
Reactant: Cc1cc(-c2ccc(Cl)cc2)c(Br)c2n[nH]c(=O)n12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccc(Cl)cc2)c(Br)c2nn(Cc3ccc(C#N)cn3)c(=O)n12
Temperature: 70 °C
Reaction time: 1 h
Yield: 110 %

Procedure:
To a stirring solution of 8-bromo-7-(4-chlorophenyl)-5-methyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (40 mg, 0.11 mmol) in DMF (0.25 mL) at room temperature under argon was added K2CO3 (50 mg, 0.36 mmol), followed by 6-(chloromethyl)nicotinonitrile (20 mg, 0.13 mmol). The reaction mixture was stirred at 70° C. for 1 h. The reaction mixture was cooled to room temperature, water (2 mL) and EtOAc (5 mL) were added. The layers were separated. The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure to obtain 55 mg of the title compound as a yellow solid. HPLC/MS: retention time=3.55 min, [M+H]+=454.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.Br[CH:14]1[CH2:19][CH2:18][CH2:17][CH:16]=[CH:15]1>C1COCC1.CCCCCC>[CH:19]1([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:18][CH2:17][CH2:16][CH:15]=[CH:14]1
Reactant: BrC1C=CCCC1
Reactant: Cc1ccccn1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C1=CC(Cc2ccccn2)CCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 46.9 %

Procedure:
Following a modified version of the procedure given in J. M. Ontoria et al., Bioorg. Med. Chem. Lett. 16 (2006), 4026, a solution of 2-methyl-pyridine (0.50 g, 5.37 mmol) in 10 ml of anhydrous THF was cooled to −78° C. under an atmosphere of argon. n-Butyllithium (2.36 ml of a 2.5 M solution in hexane, 5.91 mmol) was added dropwise and the solution was stirred at −78° C. for 1 h. 3-bromo-cyclohexene (0.68 ml, 5.91 mmol) was added then dropwise and the temperature was allowed to rise to ambient temperature over 3 h. After stirring overnight, the mixture was quenched by addition of 20 ml of water and extracted twice with EA. The combined organic phases were washed with a saturated solution of sodium chloride, dried over sodium sulfate, filtered and evaporated to dryness to give 0.436 g of 2-(cyclohex-2-en-1-ylmethyl)-pyridine as an orange oil. This product was dissolved in 8.4 ml of ethanol, 5% palladium on charcoal (50% in water; 0.087 g) was added, and the mixture was hydrogenated under a hydrogen pressure of 3.2 bar for 4 h at room temperature. The catalyst was then filtered off and the filtrate was evaporated to dryness under reduced pressure to give 0.415 g of the title compound as an oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[N:8][CH:9]=[CH:10][C:2]1=2.[CH3:11][O:12][C:13]1[CH:17]=[C:16]([C:18](Cl)=[O:19])[O:15][N:14]=1.C(N(CC)CC)C.O>ClCCl>[O:1]1[CH2:6][CH2:5][N:4]([C:18]([C:16]2[O:15][N:14]=[C:13]([O:12][CH3:11])[CH:17]=2)=[O:19])[C:3]2[CH:7]=[N:8][CH:9]=[CH:10][C:2]1=2
Reactant: COc1cc(C(=O)Cl)on1
Reactant: c1cc2c(cn1)NCCO2
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCOc3ccncc32)on1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 10 ml flask, 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine (100 mg, 0.73 mmol) and 3-methoxy-isoxazol-5-carbonyl chloride (131 mg, 0.80 mmol) were dissolved in dichloromethane. Triethylamine (0.51 ml, 3.65 mmol) was added thereto and then stirred at room temperature for 2 hours. After completion of the reaction by adding water dropwise, the reaction mixture was extracted with dichloromethane, and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on amine silica eluting with a solvent of dichloromethane:methanol=30:1. The fractions containing the product were collected and evaporated to obtain the target compound 43, i.e., (2,3-dihydro-pyrido[4,3-b][1,4]oxazin-4-yl)-(3-methoxy-isoxazol-5-yl)-methanone, as pale-brown solid (149 mg, 78%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=[O:32])[NH:17][C:18]1[S:19][CH:20]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=2)[N:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[Sn]Cl>CCO.CCOC(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:32])[NH:17][C:18]1[S:19][CH:20]=[C:21]([C:23]2[CH:24]=[CH:25][C:26]([NH2:29])=[CH:27][CH:28]=2)[N:22]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1nc(-c2ccc([N+](=O)[O-])cc2)cs1)C1CCCN1C(=O)OCc1ccccc1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2csc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)n2)cc1
Temperature: 25 °C

Procedure:
400 mg (0.88 mmol) of 2-[4-(4-Nitro-phenyl)-thiazol-2-ylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester was dissolved in 30 mL of 1:1 mixture of EtOH/EtOAc. To this solution was added SnCl2 (0.7 g, 3.1 mmol). Reaction mixture was heated under reflux for 5 hours. After 5 hours reaction mixture was cooled to room temperature and evaporated. It was redissolved in EtOAc (150 mL) and washed using sat. K2CO3. Organic phase was isolated, washed using brine and water and evaporated to dryness to give Compound 5050. MS: 422.1 (M+H+).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=O)[CH:14]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:13]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:10]2[CH2:11][CH2:12][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH2:9]2)[CH:14]=1
Reactant: O=Cc1cccc(-c2ccccc2)c1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: c1ccc(-c2cccc(CN3CCN(c4ccccc4)CC3)c2)cc1

Procedure:
48.6 mg of the target compound (0.15 mmol, 18.3%) was obtained using 1-phenylpiperazine (266 mg, 1.64 mmol), biphenyl-3-carbaldehyde (150 mg, 0.82 mmol) and NaBH(OAc)3 (529 mg, 2.46 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]([CH3:20])[C:10]([NH:12][C:13]([NH:15]C(C)(C)C)=[O:14])=[NH:11]>Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]([CH3:20])[C:10]([NH:12][C:13]([NH2:15])=[O:14])=[NH:11]
Reactant: CN(C(=N)NC(=O)NC(C)(C)C)c1c(Cl)cccc1Cl
Agent: Cl
Product: CN(C(=N)NC(N)=O)c1c(Cl)cccc1Cl

Procedure:
A mixture as 33.7 g (0.106 mole) of 1-(2,6-dichlorophenyl-N-methylamidino)-3-(t-butyl)urea and 200 ml of conc. hydrochloric acid is refluxed for 1/2 hour. The reaction mixture is cooled, filtered and washed with 10 ml of 1:1 HCl/H2O and dried. The product is then recrystallized from ethanol-ether to obtain 1-(2,6-dichlorophenyl-N-methylamidino)urea.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:27][CH2:26][C@H:25]([CH2:28][OH:29])[CH2:24]1>>[Br:1][C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@H:25]([CH2:28][OH:29])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: OC[C@H]1CCNC1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 33.1 using 5-bromo-6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Stage 169.2) and (S)-1-pyrrolidin-3-yl-methanol to afford an off-white crystalline solid. HPLC (Condition 4) tR=5.82 min, UPLC-MS (Condition 3) tR=1.14 min, m/z=476.2/478.3 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[CH3:20][N:21]1[CH:25]=[C:24]([C:26]([OH:30])([C:28]#[CH:29])[CH3:27])[N:23]=[CH:22]1>>[F:19][C:3]1[C:2]([C:29]#[C:28][C:26]([OH:30])([C:24]2[N:23]=[CH:22][N:21]([CH3:20])[CH:25]=2)[CH3:27])=[CH:18][C:6]2[C:7]3[N:8]([CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Reactant: C#CC(C)(O)c1cn(C)cn1
Product: Cn1cnc(C(C)(O)C#Cc2cc3c(cc2F)OCCn2cc(C(N)=O)nc2-3)c1
Yield: 11 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-(1-methyl-1H-imidazol-4-yl)but-3-yn-2-ol to give the titled compound as a colorless solid (15 mg, 11%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[C@@H:5]1[CH2:10][CH2:9][CH2:8][NH:7][CH2:6]1)[CH3:2].[CH2:12]([N:14]([CH2:17]C)CC)[CH3:13].ClC(OCC)=[O:21]>ClCCl>[CH2:12]([NH:14][C:17]([N:7]1[CH2:8][CH2:9][CH2:10][C@@H:5]([C:4]([O:3][CH2:1][CH3:2])=[O:11])[CH2:6]1)=[O:21])[CH3:13]
Reactant: CCOC(=O)Cl
Reactant: CCN(CC)CC
Reactant: CCOC(=O)[C@@H]1CCCNC1
Solvent: ClCCl
Product: CCNC(=O)N1CCC[C@@H](C(=O)OCC)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
(R)-Ethylnipecotate (J. Org. Chem., 56, 1991, 1166-1170) (3.0 g, 0.019 mole) in dry dichloromethane (50 ml) was cooled to 0° C. under argon. Triethylamine (3.19 ml, 0.023 mole) was added, followed dropwise by ethyl chloroformate (1.83 ml, 0.019 mole) in dry dichloromethane (6 ml) and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with dichloromethane, washed with water, dried (magnesium sulfate) and evaporated in vacuo to afford the title compound 3.45 g (79%) as a colourless oil; 1H NMR (CDCl3) 1.28 (6H, t, J 7 Hz), 1.38-1.82 (3H, m), 2.00-2.15 (1H, m), 2.38-2.55 (1H, m), 2.77-3.13 (2H, m), 3.91-4.04 (1H, m), 4.07-4.35 (5H, m).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[O:20][CH2:19][CH2:18][N:17]([CH2:21][CH2:22][CH3:23])[CH2:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[CH2:21]([N:17]1[CH2:18][CH2:19][O:20][CH:15]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[CH2:16]1)[CH2:22][CH3:23]
Reactant: CCCN1CCOC(c2ccc(OCc3ccccc3)cc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCCN1CCOC(c2ccc(O)cc2)C1
Temperature: 80 °C
Yield: 70.9 %

Procedure:
Benzyl ether from example 28 (3.0 g, 9.64 mmol) was dissolved in methanol (150 ml) and 10% palladium on charcoal (800 mg) was added. The reaction mixture was stirred for a few minutes before ammonium formate (6.17 g, 96.4 mmol) was added portionwise. The reaction mixture was carefully heated to 80° C. until gas evolution had ceased. After cooling, the reaction mixture was filtered through arbacel, washed with methanol (50 ml) and concentrated in vacuo to give the title compound as a white crystalline solid (1.51 g, 6.83 mmol, 71%). 1H NMR (CDCl3, 400 MHz) δ: 0.91 (t, 3H), 1.58 (q, 2H), 2.10 (t, 1H), 2.22 (t, 1H), 2.40 (dd, 2H), 2.81 (d, 1H), 2.93 (d, 1H), 3.85 (t, 1H), 4.02 (dd, 1H), 4.57 (d, 1H), 6.79 (d, 2H), 7.21 (d, 2H). LRMS: m/z 222 (M-H+).
Reaction SMILES: [H-].[Na+].[CH:3]1([N:6]2[CH:10]=[N:9][N:8]=[C:7]2[C:11]2[CH:12]=[C:13]([NH:17][C:18]([C:20]3[CH:25]=[C:24]([C:26]4[CH:27]=[N:28][C:29](F)=[CH:30][CH:31]=4)[CH:23]=[CH:22][N:21]=3)=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH2:5][CH2:4]1.[CH:33]1([OH:37])[CH2:36][CH2:35][CH2:34]1>>[CH:33]1([O:37][C:29]2[N:28]=[CH:27][C:26]([C:24]3[CH:23]=[CH:22][N:21]=[C:20]([C:18]([NH:17][C:13]4[CH:14]=[CH:15][CH:16]=[C:11]([C:7]5[N:6]([CH:3]6[CH2:5][CH2:4]6)[CH:10]=[N:9][N:8]=5)[CH:12]=4)=[O:19])[CH:25]=3)=[CH:31][CH:30]=2)[CH2:36][CH2:35][CH2:34]1
Reactant: OC1CCC1
Reactant: O=C(Nc1cccc(-c2nncn2C2CC2)c1)c1cc(-c2ccc(F)nc2)ccn1
Agent: [H-]
Agent: [Na+]
Product: O=C(Nc1cccc(-c2nncn2C2CC2)c1)c1cc(-c2ccc(OC3CCC3)nc2)ccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55 %

Procedure:
Sodium hydride (60% in mineral oil, 15 mg, 0.38 mmol) was added to 0.5 mL of cyclobutanol and the reaction mixture was stirred for 10 minutes at room temperature. (N-(3-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)phenyl)-6-fluoro-3,4′-bipyridine-2′-carboxamide) (24 mg, 0.06 mmol) in cyclobutanol (0.2 mL) was added and the reaction mixture was heated to 90° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure, neutralized with 1 M HCl and purified by reverse-phase HPLC to give the product as a white powder (15 mg, 55% yield). C26H24N6O2. 453.1 (M+1). 1H NMR (DMSO) d 10.92 (s, 1H), 8.79 (d, J=5.2 Hz, 1H), 8.72 (d, J=2.4 Hz, 1H), 8.62 (s, 1H), 8.58 (s, 1H), 8.41 (d, J=1.2 Hz, 1H), 8.26 (dd, J=4.8, 2.4 Hz, 1H), 8.07 (d, J=−8.0 Hz, 1H), 8.03 (dd, J=5.2, 2.0 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.55 (t, J=8.0 Hz, 1H), 6.95 (d, J=8.8 Hz, 1H), 5.22 (p, J=7.6 Hz, 1H), 3.66 (m, 1H), 2.45 (m, 2H), 2.10 (m, 2H), 1.85 (m, 1H), 1.70 (m, 1H), 1.08 (m, 2H), 0.95 (m, 2H).
Reaction SMILES: [CH2:1]([C:12]1[N:16]=[C:15]([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)[O:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][C:30]([C@H:33]([NH2:35])[CH3:34])=[CH:29][CH:28]=1>>[F:25][C:26]([F:36])([F:37])[C:27]1[CH:28]=[CH:29][C:30]([C@H:33]([NH:35][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([C:15]3[O:14][N:13]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:16]=3)=[CH:18][CH:19]=2)[CH3:34])=[CH:31][CH:32]=1
Reactant: CCCCCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Reactant: C[C@@H](N)c1ccc(C(F)(F)F)cc1
Product: CCCCCCCCCCCc1noc(-c2ccc(CN[C@H](C)c3ccc(C(F)(F)F)cc3)cc2)n1
Yield: 71 %

Procedure:
The same procedure as employed in the preparation of Example 226 (step a) but using 4-(3-undecyl-1,2,4-oxadiazol-5-yl)benzaldehyde and (1R)-1-[4-(trifluoromethyl)phenyl]ethylamine gave the title compound as a colorless oil (71%). M+(LC/MS(ESI)): 502.4. HPLC (Condition A), Rt: 5.04 min (HPLC purity: 99.6%).