Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([CH:15]1[CH2:17][CH:16]1[C:18]1[C:19]([F:38])=[CH:20][C:21]2[C:31](=[O:32])[C:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:29][N:23]3[C@@H:24]([CH3:28])[CH2:25][O:26][C:27]=1[C:22]=23)=[O:14])(C)(C)C>>[C:13]([CH:15]1[CH2:17][CH:16]1[C:18]1[C:19]([F:38])=[CH:20][C:21]2[C:31](=[O:32])[C:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:29][N:23]3[C@@H:24]([CH3:28])[CH2:25][O:26][C:27]=1[C:22]=23)([OH:14])=[O:12]
Reactant: CCOC(=O)c1cn2c3c(c(C4CC4C(=O)OC(C)(C)C)c(F)cc3c1=O)OC[C@@H]2C
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cn2c3c(c(C4CC4C(=O)O)c(F)cc3c1=O)OC[C@@H]2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
5 ml of trifluoroacetic acid was added to 570 mg of ethyl (S)-10-(2-tert-butoxycarbonylcyclopropyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. Diethyl ether was added to the residue obtained. The resulting crystals were collected by filtration to obtain 460 mg (yield: 92.9%) of ethyl (S)-10-(2-carboxycyclopropyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate.
Reaction SMILES: [CH:1]1([CH2:4][C:5]([NH:13]S(C(C)(C)C)=O)([CH3:12])[C:6]2[O:7][C:8]([CH3:11])=[N:9][N:10]=2)[CH2:3][CH2:2]1.Cl.O1CCOCC1>CO>[CH:1]1([CH2:4][C:5]([C:6]2[O:7][C:8]([CH3:11])=[N:9][N:10]=2)([NH2:13])[CH3:12])[CH2:3][CH2:2]1
Reactant: Cc1nnc(C(C)(CC2CC2)NS(=O)C(C)(C)C)o1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1nnc(C(C)(N)CC2CC2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.1 %

Procedure:
To a solution of N-[2-cyclopropyl-1-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl]-2-methyl-propane-2-sulfinamide (example 173a, 520 mg, 1.46 mmol) in MeOH (8 ml) was added a 4M solution of hydrochloric acid in dioxane (729 μl, 2.92 mmol). The reaction mixture was stirred at room temperature for 1 hour. Reaction was quenched by addition of potassium carbonate and stirred for 15 minutes. The insolubles were removed by filtration and the filtrate was evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a dichloromethane-methanol gradient to yield the title compound (130 mg, 50%). MS (ESI, m/z): 182.2 (M+H+).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[C:12]([CH3:17])=[N:13][O:14][C:15]=1[CH3:16])=[O:10])[NH:2]2.[NH2:18][C:19]1[S:20][C:21]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)=[C:22]([C:24](O)=[O:25])[N:23]=1>>[NH2:18][C:19]1[S:20][C:21]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)=[C:22]([C:24]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[C:12]([CH3:17])=[N:13][O:14][C:15]=3[CH3:16])=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:25])[N:23]=1
Reactant: Nc1nc(C(=O)O)c(-c2cccc(F)c2)s1
Reactant: Cc1noc(C)c1C(=O)NC[C@@H]1C[C@@H]2C[C@@H]2N1
Product: Cc1noc(C)c1C(=O)NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1

Procedure:
prepared by reaction of 3,5-dimethyl-isoxazole-4-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 2-amino-5-(3-fluoro-phenyl)-thiazole-4-carboxylic acid. LC-MS (basic): tR=1.23 min; [M+H]+=456.1.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]([CH2:12][OH:13])[CH:9]=[CH:10][CH:11]=1.N1C=CC=CC=1.[Cl:20][C:21]([Cl:31])=[CH:22][C@@H:23]1[C@H:25]([C:26](Cl)=[O:27])[C:24]1([CH3:30])[CH3:29]>C1(C)C=CC=CC=1>[Cl:20][C:21]([Cl:31])=[CH:22][C@@H:23]1[C@H:25]([C:26]([O:13][CH2:12][C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[CH:7]=2)=[O:27])[C:24]1([CH3:29])[CH3:30]
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)Cl
Reactant: OCc1cccc(-c2ccco2)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)OCc1cccc(-c2ccco2)c1
Yield: 94.3 %

Procedure:
This reaction was conducted in the manner of Example 3, Step 2 using 1.5 g (0.009 mol) of 3-(2-furanyl)phenylmethanol, 0.7 g (0.009 mol) of pyridine, 50 mL of toluene, and 2.0 g (0.009 mol) of cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarbonyl chloride. The crude oily product was subjected to distillation under reduced pressure to give 3.1 g of [3-(2-furanyl)phenyl]methyl cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate, b.p. 160° C./0.1 mm.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:16])[C:8]3[N:9]2[C:12](=[O:15])[NH:13][N:14]=3)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1>CN(C)C=O>[N:20]1([C:2]2[CH:11]=[C:10]3[C:5]([NH:6][C:7](=[O:16])[C:8]4[N:9]3[C:12](=[O:15])[NH:13][N:14]=4)=[CH:4][C:3]=2[N+:17]([O-:19])=[O:18])[CH:24]=[CH:23][N:22]=[CH:21]1
Reactant: c1c[nH]cn1
Reactant: O=c1[nH]c2cc([N+](=O)[O-])c(F)cc2n2c(=O)[nH]nc12
Solvent: CN(C)C=O
Product: O=c1[nH]c2cc([N+](=O)[O-])c(-n3ccnc3)cc2n2c(=O)[nH]nc12
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To a solution of 0.5 g (~1.89 mmol) 8-fluoro-7-nitro[1,2,4]triazolo[4.3-a]quinoxaline-1,4(2H,5H)-dione in 10 ml dry N,N-dimethylformamide was added 0.4 g (~5.9 mmol) imidazole. The reaction mixture was stirred at 120° C. for 2h. Evaporation in vacuo gave the title compound as an oil, which was solidified by stirring with water. Yield: 0.34 g (58%). M.p.>300° C. decomp.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[N:8](CCO)[C:9](=[O:33])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH3:24])[CH:11]3[C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=3[CH3:32])[C:5]2=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C>CO>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:33])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH3:24])[CH:11]3[C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=3[CH3:32])[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)cc1C1N(C)C(=O)CC(c2cccc(Cl)c2)C12C(=O)N(CCO)c1cc(Cl)ccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1ccc(F)cc1C1N(C)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 70.9 %

Procedure:
To a solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-2,3-dihydro-1′-methyl-2,6′-dioxospiro[indole-3,3′-piperidine]-1-ethanol (0.09 g, 0.175 mmol) prepared in example 56b in methanol (10 mL) was added N,N′-diisopropylethylamine (2 mL, 11.1 mmol) and the crude was refluxed for 1 h. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and water. The organic layer was separated, and concentrated. The residue was purified by chromatography (EtOAc:CH2Cl2=1:2) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-1′-methylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.06 g, 70.6%).
Reaction SMILES: [CH3:1][C:2]1[C:22]([O:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:21][C:5]2[CH2:6][C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[CH:9]([CH2:11][C:12]([O:14]CC)=[O:13])[CH2:10][C:4]=2[CH:3]=1.N1C=CC=CC=1NCCCOC1C=CC2C[C@H](CC(OCC)=O)C3C=CC=CC=3CC=2C=1>>[CH3:1][C:2]1[C:22]([O:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:21][C:5]2[CH2:6][C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[CH:9]([CH2:11][C:12]([OH:14])=[O:13])[CH2:10][C:4]=2[CH:3]=1
Reactant: CCOC(=O)CC1Cc2cc(C)c(OCCCNc3ccccn3)cc2Cc2ccccc21
Agent: CCOC(=O)C[C@H]1Cc2ccc(OCCCNc3ccccn3)cc2Cc2ccccc21
Product: Cc1cc2c(cc1OCCCNc1ccccn1)Cc1ccccc1C(CC(=O)O)C2

Procedure:
According to the procedure of Example 6 (c), except substituting ethyl (±)-10,11-dihydro-2-methyl-3-[3-(pyridin-2-ylamino)-1-propyloxy]-5H-dibenzo[a,d]cycloheptene-10-acetate for the ethyl (R)-10,11-dihydro-3-[3-(pyridin-2-ylamino)-1-propyloxy]-5H-dibenzo[a,d]cycloheptene-10-acetate, the title compound was obtained as an off white solid. 1H NMR (400 MHz, CDCl3) δ7.75 (d, 1 H), 7.65 (t, 1 H), 7.15 (m, 3 H), 7.05 (m, 1 H), 6.83 (s, 1 H), 6.7 (d, 1 H), 6.65 (m, 1 H), 6.60 (s,1 H), 4.25 (d, J=15.1 Hz, 1 H), 4.05 (t, 2 H), 3.80 (m, 1 H), 3.75 (d, J=15.1 Hz, 1 H), 3.50 (t, 2 H), 3.25 (dd, 1 H), 2.85 (dd, 1 H), 2.68 (dd, 1 H), 2.60 (dd, 1 H), 2.15 (t, 2 H), 2.10 (s, 3 H); MS (ES) m/e 417.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[F:18][C:19]1[CH:20]=[C:21]([CH2:25][C:26](O)=[O:27])[CH:22]=[CH:23][CH:24]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:26](=[O:27])[CH2:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([F:18])[CH:20]=2)[CH2:7]1
Reactant: O=C(O)Cc1cccc(F)c1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: O=C(Cc1cccc(F)c1)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 49.9 %

Procedure:
Example 3 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 1 (0.055 g) and (3-fluorophenyl)acetic acid (0.031 g) to give the title compound (0.041 g).
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.Cl[C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][N:26]=1>>[C:29]([C:28]1[CH:31]=[CH:32][C:25]([N:21]2[CH2:22][CH2:23][CH:18]([N:4]([CH:1]3[CH2:3][CH2:2]3)[C:5](=[O:17])[C:6]3[CH:7]=[CH:8][C:9]([C:12]4[O:16][CH:15]=[N:14][CH:13]=4)=[CH:10][CH:11]=3)[CH2:19][CH2:20]2)=[N:26][CH:27]=1)#[N:30]
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Reactant: N#Cc1ccc(Cl)nc1
Product: N#Cc1ccc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)nc1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide and 6-chloro-nicotinonitrile following a procedure analogous to that described in Example 19. LC (method 9): tR=2.02 min; Mass spectrum (ESI+): m/z=414 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:17]O)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16].P(Br)(Br)[Br:20].C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:17][Br:20])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16]
Reactant: OCc1ccc(Oc2ccc(F)cc2F)c(Br)c1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Fc1ccc(Oc2ccc(CBr)cc2Br)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.8 %

Procedure:
To a solution of Example 287b (3.70 g, 11.74 mmol) in dichloromethane (20 mL) was added phosphorus tribromide (1.11 mL, 11.7 mmol) dropwise. The reaction mixture was stirred at ambient temperature for 3 hours, and poured into ice water. The pH was adjusted to basic by the careful addition of saturated aqueous sodium bicarbonate and the mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride, dried with anhydrous sodium sulfate, filtered, and concentrated to provide the title compound (4.15 g, 93%).
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C(OC([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]1[NH:21][CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][C:34]([C:37]#[C:38][C:39]4[NH:43][C:42]([C@@H:44]5[CH2:48][CH2:47][CH2:46][N:45]5C(OC(C)(C)C)=O)=[N:41][CH:40]=4)=[CH:33][CH:32]=3)=[CH:27][CH:26]=2)[N:24]=1)=O)(C)(C)C>ClCCCl>[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[NH:45]1[CH2:46][CH2:47][CH2:48][C@H:44]1[C:42]1[NH:43][C:39]([C:38]#[C:37][C:34]2[CH:35]=[CH:36][C:31]([C:28]3[CH:29]=[CH:30][C:25]([C:23]4[N:24]=[C:20]([C@@H:16]5[CH2:17][CH2:18][CH2:19][NH:15]5)[NH:21][CH:22]=4)=[CH:26][CH:27]=3)=[CH:32][CH:33]=2)=[CH:40][N:41]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(C#Cc4cnc([C@@H]5CCCN5C(=O)OC(C)(C)C)[nH]4)cc3)cc2)c[nH]1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: C(#Cc1cnc([C@@H]2CCCN2)[nH]1)c1ccc(-c2ccc(-c3c[nH]c([C@@H]4CCCN4)n3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 195 %

Procedure:
TFA (0.25 mL, 3.2 mmol) was added to a stirring solution of (S)-tert-butyl 2-(5-((4′-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-4-yl)biphenyl-4-yl)ethynyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (17.8 mg) in DCE (1 mL) and stirred at rt for 1 h. The crude reaction was concentrated to yield a TFA salt of 2-((S)-pyrrolidin-2-yl)-5-((4′-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-4-yl)biphenyl-4-yl)ethynyl)-1H-imidazole (24 mg).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([O:27]C(=O)C)=[C:8]2[C:16]([Cl:17])=[CH:15][N:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+].CO>>[Cl:17][C:16]1[C:8]2[C:9](=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[O:5])[C:7]=2[OH:27])[N:14]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH:15]=1
Reactant: CCOC(=O)c1nc(C#N)c2c(c(Cl)cn2Cc2ccc(OC)cc2)c1OC(C)=O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Cn2cc(Cl)c3c(O)c(C(=O)NCC(=O)O)nc(C#N)c32)cc1

Procedure:
Prepared in analogy to that of Example 1(e) from 4-acetoxy-3-chloro-7-cyano-1-(4-methoxy-benzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 415 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[C:6]([Br:17])[CH:5]=1)(=[O:3])[CH3:2].[Br-:18].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(O)C>[Br:17][C:6]1[CH:5]=[C:4]([C:1](=[O:3])[CH2:2][Br:18])[CH:9]=[CH:8][C:7]=1[NH:10][C:11](=[O:16])[C:12]([F:13])([F:14])[F:15]
Reactant: CC(=O)c1ccc(NC(=O)C(F)(F)F)c(Br)c1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCO
Product: O=C(CBr)c1ccc(NC(=O)C(F)(F)F)c(Br)c1
Yield: 46.1 %

Procedure:
N-(4-acetyl-2-bromophenyl)-2,2,2-trifluoroacetamide (12.1 g; 39.0 mmol) and tetrabutylammonium tribromide (18.8 g; 39.0 mmol) were dissolved separately in ethanol. After combination, and refluxing for 4 hrs, there was precipitate formation. The solvent was removed. NaHCO3 solution was added to neutralize any residue acid. The solid was filtered, and washed with CH2Cl2, to afford 7.0 g (yield 46%) of product as pale green solid. 1H NMR (400 MHz, CDCl3) δ 8.64 (s, 1H, N—H), 8.51 (d, 3JHH=8.6 Hz, 1H, Ar—H), 8.25 (d, 4JHH=2.0 Hz, 1H, Ar—H), 7.98 (dd, 3JHH=8.6 Hz, 4JHH=2.0 Hz, 1H, Ar—H), 4.38 (s, 2H, —CH2—Br).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([C:8]([OH:10])=[O:9])[CH2:3]1.C(OP(ON1C(=O)C2C=CC=CC=2N=N1)(OCC)=O)C.C(N(CC)C(C)C)(C)C.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>ClCCl>[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([C:8]([OH:10])=[O:9])[CH2:3]1.[N:40]1([C:8]([C@@H:4]2[CH2:5][CH2:6][CH2:7][C:2](=[O:1])[CH2:3]2)=[O:10])[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1
Reactant: C1COCCN1
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Agent: O=C1CCC[C@@H](C(=O)O)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCC[C@@H](C(=O)N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 107.2 %

Procedure:
(1R)-3-Oxo-cyclohexanecarboxylic acid was prepared according to the procedure described by R. D. Allan et al. in Aust. J. Chem., 1981, 34, 2231. A solution of (1R)-3-oxo-cyclohexanecarboxylic acid (1 eq, 2.52 g, 18.1 mmol), 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT, H. Li et al. Organic Letters, 1999, 1, 91) (1.05 eq, 19.0 mmol, 5.68 g) and N,N-diisopropylethylamine (15 eq, 27.1 mmol, 4.7 mL) in anhydrous dichloromethane (70 mL) was allowed to stir at room temperature for 75 minutes. Morpholine (1.2 eq, 21.72 mmol, 1.9 mL) was added and the solution was stirred at ambient temperature for 16 h. The mixture was concentrated under vacuum to an oil which was purified by flash chromatography eluting with a 2.5% methanol-dichloromethane gradient on silica gel to give (3R)-3-(morpholine-4-carbonyl)-cyclohexanone (2.05 g, 54%).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH3:23])=[C:9]([NH:11][C:12]([C:14]2[N:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)=[O:13])[CH:10]=1)[NH2:4].[Cl:24][CH2:25][C:26](OC(=O)CCl)=O>CN1CCCC1=O.O>[Cl:24][CH2:25][C:26]1[O:1][N:2]=[C:3]([C:5]2[CH:6]=[CH:7][C:8]([CH3:23])=[C:9]([NH:11][C:12]([C:14]3[N:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]4=[N:16][CH:15]=3)=[O:13])[CH:10]=2)[N:4]=1
Reactant: O=C(CCl)OC(=O)CCl
Reactant: Cc1ccc(C(N)=NO)cc1NC(=O)c1cnc2ccccn12
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc(-c2noc(CCl)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 110 °C

Procedure:
A mixture of N-(5-(N′-hydroxycarbamimidoyl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide 9 (500 mg, 1.62 mmol) and 2-chloroacetic anhydride (553 mg, 3.23 mmol) in anhydrous 1-methyl-2-pyrrolidinone (10 mL) was heated in the microwave at 110° C. for 12 minutes. The crude was diluted with water and extracted with ethyl acetate. The organic was washed with water/brine mixture and dried over anhydrous sodium sulfate. The crude product was purified by silica chromatography. MS m/z 368.08 (M+1)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.Cl[CH2:9][C:10]1[N:11]=[C:12]([NH2:15])[S:13][CH:14]=1>CN(C=O)C.C(OCC)(=O)C>[O:4]1[CH2:5][CH2:6][N:1]([CH2:9][C:10]2[N:11]=[C:12]([NH2:15])[S:13][CH:14]=2)[CH2:2][CH2:3]1
Reactant: Nc1nc(CCl)cs1
Reactant: C1COCCN1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1nc(CN2CCOCC2)cs1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
Morpholine (350 μL, 4.0.0 mmol) is added to a solution of 4-chloromethyl-thiazol-2-ylamine hydrochloride (368 mg, 2.00 mmol) in DMF (7 mL). The reaction is stirred at 90° C. for 16 h. The reaction is diluted with ethyl acetate and washed with water. The aqueous layer is concentrated in vacuo and extracted with ethyl acetate. The combined organic layers are dried over MgSO4 and evaporated to give brown crystals which are used without further purification. 1H-NMR (400 MHz, d6-DMSO) δ=2.41-2.42 (m, 4H, CH2CH2), 3.30 (s, 2H, CH2), 3.55-3.60 (m, 4H, CH2CH2), 6.33 (s, 1H, Har), 6.85 (bs, 2H, NH2).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+].[CH2:18]([CH2:25][NH:26][CH2:27][C@H:28]1[CH2:37][CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33](S(C(F)(F)F)(=O)=O)[CH:34]=2)[C@H:29]1[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C.O>[CH2:18]([CH2:25][NH:26][CH2:27][C@H:28]1[CH2:37][CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:34]=2)[C@H:29]1[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=S(=O)(c1ccc2c(c1)CC[C@H](CNCCc1ccccc1)[C@@H]2c1ccccc1)C(F)(F)F
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: c1ccc(CCNC[C@H]2CCc3cc(-c4ccccc4)ccc3[C@H]2c2ccccc2)cc1
Temperature: 90 °C
Yield: 46.6 %

Procedure:
Benzene boronic acid (301 mg), tetrakis(triphenylphosphine)palladium(0) (65 mg), lithium chloride (238 mg) and aqueous sodium carbonate solution (2 M, 2.25 cm3) were added to a stirred solution of cis-2-(N-benzylmethylamino)methyl-6-trifluoromethanesulfonyl-1-phenyl-1,2,3,4-tetrahydronaphthalene (1.1 g) in 1,2-dimethoxyethane (60 cm3) under an atmosphere of nitrogen. The stirred mixture was heated at 90° C. for 46 h before being allowed to cool to room temperature. Water (100 cm3) and ethyl acetate (100 cm3) were added and the organic layer was washed with water (3×100 cm3), dried (Na2SO4), and the solvent was removed under reduced pressure. The crude product (908 mg) was purified by column chromatography [silica, eluting with toluene-ethyl acetate (19:1)] to afford the title compound as a gum (452 mg); positive ion ESI (M+H)+ 417.9.
Reaction SMILES: [C:1]1([N:7]2[C:12]3[N:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH2:10][NH:9][C:8]2=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O.[H-].[Na+].[C:25]1(C)[CH:30]=CC(S(OC(C)C)(=O)=O)=C[CH:26]=1>O>[C:1]1([N:7]2[C:12]3[N:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH2:10][N:9]([CH:25]([CH3:30])[CH3:26])[C:8]2=[O:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)OC(C)C)cc1
Reactant: O=C1NCc2cccnc2N1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)N1Cc2cccnc2N(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 256.8 %

Procedure:
To a solution of 4.5 g of 1-phenyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine and 50 ml of dry dimethylformamide was added 1.2 g of 50% sodium hydride and the mixture was stirred for 30 minutes at room temperature, and then heated to a temperature of 90° - 100° C. To this was gradually added 1.28 g of isopropyl p-toluenesulfonate and the whole was reacted for 1 hour. After the reaction was complete, the solvent was distilled off from the mixture under reduced pressure. The residue obtained was diluted with water to produce a crude precipitate, which was collected by filtration and then dissolved in ethyl ether. Separation and purification were accomplished by applying the solution on a column of alumina, and the eluate was concentrated to give 4.1 g of 1-phenyl-3-isopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine as colorless prisms, melting at 164° - 165° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:6][B:5]([OH:7])[C:4]2[CH:8]=[C:9]([N+:12]([O-])=O)[CH:10]=[CH:11][C:3]1=2.CCN(CC)CC.[Cl:23][C:24]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27].CCOC(C)=O.Cl>C1COCC1.[Pd]>[Cl:23][C:24]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:25]=1[C:26]([NH:12][C:9]1[CH:10]=[CH:11][C:3]2[C:2]([CH3:15])([CH3:1])[O:6][B:5]([OH:7])[C:4]=2[CH:8]=1)=[O:27]
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Reactant: CC1(C)OB(O)c2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)OB(O)c2cc(NC(=O)c3ccc(F)cc3Cl)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.2 %

Procedure:
A solution of 3,3-dimethyl-6-nitro-3H-benzo[c][1.2]oxaborol-1-ol (500 mg, 2.4 mmol) in THF (60 mL) was pass through H-Cube equipped with a 10% Pd/C Catcart (30×4 mm). The flow rate was set at 1.0 mL/min and TLC indicated complete consumption of starting material after one run. To the obtained light yellow solution was added Et3N (1.1 mL, 7.7 mmol, 3.2 equiv.), followed by drop wise addition of 2-cloro-4-fluoro-benzoyl chloride (0.51 mL, 3.8 mmol, 1.6 equiv.). The mixture was allowed to stir at room temperature over 18 h before poured into a 1:1 mixture of EtOAc/HCl (1 N). The layers were separated and the aqueous phase was extracted with EtOAc (3×). Combined organics was washed with H2O, brine and concentrated under reduced pressure to give a white solid. The solid was dissolved in minimal amount of THF and treated with heptanes. The precipitate was collected by filtration and washed with heptanes to give the title compound as a white solid. LCMS (M/Z): 334 (M+H); 1H NMR (DMSO-d6) δ: 10.49 (s, 1H), 9.06 (s, 1H), 8.01 (d, J=1.7 Hz, 1H), 7.60-7.65 (m, 2H), 7.55 (dd, J=9.0, 2.5 Hz, 1H), 7.28-7.37 (m, 2H), 1.40 (s, 6H). Amount obtained: 726 mg, (91.2% yield).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.S(O[CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1)(C1C=CC(C)=CC=1)(=O)=O>>[CH3:1][C:2]1[N:3]([CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:21][CH2:20]2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Product: Cc1nccn1CC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
The title compound was prepared according to the method described for Preparation 146 using 2-methyl-1H-imidazole and tert-butyl 4-((tosyloxy)methyl)piperidine-1-carboxylate.