Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([CH:30]=[C:31]([O:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[CH:32]=1)[CH2:8][N:9]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[S:10]([C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[C:14]=1[OH:21])(=[O:12])=[O:11])=[N+]=[N-].C1(C)C=CC=CC=1>CCOC(C)=O.CO.[OH-].[OH-].[Pd+2]>[NH2:1][CH2:4][C:5]1[CH:6]=[C:7]([CH:30]=[C:31]([O:33][C:34]2[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=2)[CH:32]=1)[CH2:8][N:9]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)[S:10]([C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[C:14]=1[OH:21])(=[O:12])=[O:11]
Reactant: [N-]=[N+]=NCc1cc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc(Oc2ccc(F)cc2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CO
Product: NCc1cc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc(Oc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.9 %

Procedure:
A mixture of N-(3-(azidomethyl)-5-(4-fluorophenoxy)benzyl)-3,5-dichloro-N-(4-fluorobenzyl)-2-hydroxybenzenesulfonamide (1.0 g, 1.652 mmol) and 100 mg of 20% of Pd(OH)2 on carbon in EtOAc (15 mL) and MeOH (15 mL) was stirred at rt under 1 atm of H2 gas for 3 h. To the mixture was added toluene. The resulting mixture was stirred for a while, and the solid was filtered, washed with methanol. The filtrate was concentrated in vacuo to obtain the desired product (0.88 g, 1.519 mmol, 92% yield) as a white solid. 1H NMR (CD3OD): δ 7.49 (d, J=2.8 Hz, 1H), 7.35 (d, J=2.8 Hz, 1H), 7.21-7.09 (m, 4H), 6.99-6.90 (m, 5H), 6.85 (s, 1H), 6.64 (s, 1H), 4.48 (s, 2H), 4.40 (s, 2H), 3.93 (s, 2H); MS (ESI): (M+H)+=579.0.
Reaction SMILES: CS(O[C:6]1[N:7]=[C:8]([S:20][CH3:21])[N:9]=[N:10][C:11]=1[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].[CH3:28][CH:29]1[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]1.C(OCC)(=O)C.CCCCCC>O1CCOCC1.O>[Cl:19][C:14]1[CH:13]=[C:12]([C:11]2[N:10]=[N:9][C:8]([S:20][CH3:21])=[N:7][C:6]=2[N:31]2[CH2:32][CH2:33][CH2:34][CH:29]([CH3:28])[CH2:30]2)[CH:17]=[C:16]([Cl:18])[CH:15]=1
Reactant: CC1CCCNC1
Reactant: CSc1nnc(-c2cc(Cl)cc(Cl)c2)c(OS(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CSc1nnc(-c2cc(Cl)cc(Cl)c2)c(N2CCCC(C)C2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.9 %

Procedure:
A crude solution of 6-(3,5-dichlorophenyl)-3-(methylsulfanyl)-1,2,4-triazin-5-yl methanesulfonate (5.43 mmol) in dioxane (3 mL), was treated with K2CO3 (1.0 g, 7.2 mmol) and 3-methyl piperidine (1.68 g, 16.9 mmol), and the resulting mixture was stirred at room temperature overnight. After completion of the reaction (TLC, ethyl acetate/hexane, 1:1), the mixture was poured into water (25 mL) and extracted with DCM or ethyl acetate (3×25 ml). The combined organic extracts were then dried over Na2SO4, concentrated in vacuo and purified by flash chromatography, eluting with 15% ethyl acetate in hexane to afford 6-(3,5-dichlorophenyl)-5-(3-methylpiperidin-1-yl)-3-(methylsulfanyl)-1,2,4-triazine (0.8 g, 40%).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=[C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([F:29])[CH:27]=3)[NH:22][C:21]2=[O:30])[CH:14]=1.CO.[Li+].[OH-].Cl>O>[F:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:30])[C:20]2=[CH:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[C:12]([NH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:32])=[O:2])=[O:31]
Reactant: COC(=O)CCCCCCCNC(=O)c1cccc(C=C2C(=O)Nc3ccc(F)cc32)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCCCCCNC(=O)c1cccc(C=C2C(=O)Nc3ccc(F)cc32)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.9 %

Procedure:
8-(3-((5-fluoro-2-oxoindolin-3-ylidene)methyl)benzamido)octanoic acid methyl ester (438 mg, 1 mmol) and 300 ml of CH3OH were stirred at room temperature while 25 ml of 4 N solution of LiOH in H2O was added. The mixture was stirred for 24 hours at room temperature. The mixture is neutralized with concentrated hydrochloric acid to pH 7 and evaporated under vacuum to remove methanol. The residue was adjusted to pH 3 with concentrated hydrochloric acid. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (305 mg, 72% yield) as a brown solid. LC-MS (m/z) 425 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.OS(O)(=O)=O.[CH3:17][CH2:18]O>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:17][CH3:18])=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: CCO
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(Br)cc1C

Procedure:
4-bromo-2-methylbenzoic acid (10 g, 46.5 mmol) was dissolved in 200 mL EtOH, 5 mL conc H2SO4 was added and the mixture was refluxed for 18 h. The reaction volume was reduced in vacuo to 50 mL, and neutralized to pH 7 with satd. aqueous NaHCO3 and extracted with EtOAc. The organic layer was dried (Na2SO4), filtered and the filtrate was concentrated to give the product (6.5 g) as an oil.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10](=[O:12])[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:13](O)[CH2:14][OH:15]>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][N:3]=[C:4]([C:10]1([O:15][CH2:14][CH2:13][O:12]1)[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(=NOC)C(C)=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCOC(=O)C(=NOC)C1(C)OCCO1
Yield: 70 %

Procedure:
A solution of ethyl 2-methoxyimino-3-oxobutyrate (syn isomer 17.3 g), ethylene glycol (12.4 g) and p-toluenesulfonic acid (0.5 g) in benzene (260 ml) was heated under reflux while removing water. The resultant solution was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in turn and dried over magnesium sulfate. After evaporating the solvent from the solution, the residue was distilled under reduced pressure to give ethyl 2-methoxyimino-3,3-ethylenedioxybutyrate (syn isomer, 15.2 g), bp 97° to 102° C./4 mmHg.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[N+:6]1([O-])[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1>>[Cl:3][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][N:11]=2)[N:6]=[CH:7][CH:8]=1
Reactant: [O-][n+]1cccc2ncccc21
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccnc2cccnc12
Temperature: 100 °C
Yield: 36 %

Procedure:
POCl3 (8.5 ml) was added to [1,5]naphthyridine 1-oxide 483 (0.85 g, 5.81 mmol) at 0° C. and the mixture was heated at 100° C. for 6 h. After cooling, the mixture was concentrated in vacuo, neutralized with NaHCO3 solution and the aqueous phase was extracted with EtOAc (40 ml). The organic phase was washed with water and brine, dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with n-hexane/EtOAc (88:12) as the eluent to give the title compound (0.35 g, 36%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH:10]([O:16][CH:17]([CH3:19])[CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:5][N:4]=1)#[N:2].[ClH:20].[H][H]>C(O)C.[C].[Pd]>[ClH:20].[NH2:2][CH2:1][C:3]1[CH:8]=[C:7]([CH2:9][CH:10]([O:16][CH:17]([CH3:18])[CH3:19])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:5][N:4]=1
Reactant: CCOC(=O)C(Cc1ccnc(C#N)c1)OC(C)C
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(Cc1ccnc(CN)c1)OC(C)C

Procedure:
1.0 g of ethyl 3-(2-cyano-4-pyridyl)-2-isopropoxypropanoate was dissolved in 70 mL ethanol, and 1.9 mL conc. hydrochloric acid and 0.9 g of 10% palladium-carbon were added thereto, and the mixture was stirred at room temperature for 2 hours in a hydrogen atmosphere. After the catalyst was filtered off and the solvent was evaporated, the reaction product was subjected to azeotropic distillation with ethyl acetate and toluene, to give 1.21 g of ethyl 3-[2-(aminomethyl)-4-pyridyl]-2-isopropoxypropanoate hydrochloride was obtained as a crude product.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[C:5]([Cl:14])=[CH:4][N:3]=1.[C:15]([Zn]C#N)#[N:16]>CN(C=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[Cl:14][C:5]1[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:7][C:2]([C:15]#[N:16])=[N:3][CH:4]=1
Reactant: N#C[Zn]C#N
Reactant: FC(F)(F)COc1cc(Cl)ncc1Cl
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CN(C)C=O
Product: N#Cc1cc(OCC(F)(F)F)c(Cl)cn1
Temperature: 100 °C
Reaction time: 18 h
Yield: 73 %

Procedure:
To a solution of 2,5-dichloro-4-(2,2,2-trifluoroethoxy)-pyridine (Example 24a, 1.48 g, 6.02 mmol) in dry DMF (30 mL) under an argon atmosphere was added dicyanozinc (707 mg, 6.02 mmol), 1,1′-bis(diphenylphosphino)ferrocene (267 mg, 481 μmol) and tris(dibenzylideneacetone) dipalladium(0) (275 mg, 301 μmol). The reaction was stirred at 100° C. for 18 h, cooled and filtered through a pad of celite. The filtrate was diluted with ethylacetate and extracted with a 1.0M aqueous solution of sodium bicarbonate. The organic phase was collected and the aqueous solution was back-extracted with ethylacetate. The organic phases were combined, dried over sodium sulfate and evaporated down to dryness. The residue was purified by flash chromatography on silica eluting with a heptane/ethylacetate gradient to yield the title compound (1.04 g, 73%) as a yellow oil. MS (ESI, m/z): 237.3 (M+H+).
Reaction SMILES: [CH2:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([CH3:20])([CH3:19])[C:16]([OH:18])=[O:17])=[CH:10][C:9]=1[F:21])=[O:7])[CH2:2][CH2:3][CH3:4].[C:22]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.O>[CH2:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([CH3:20])([CH3:19])[C:16]([O:18][CH3:22])=[O:17])=[CH:10][C:9]=1[F:21])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)c1ccc(NC(C)(C)C(=O)O)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CCCCNC(=O)c1ccc(NC(C)(C)C(=O)OC)cc1F
Temperature: 55 °C
Yield: 42.4 %

Procedure:
The title compound was prepared according to General Method 5. A solution of 2-(4-(butylcarbamoyl)-3-fluorophenylamino)-2-methylpropanoic acid (900 mg, 3.04 mmol) and K2CO3 (1.38 mg, 10 mmol) in DMF (10 mL) was stirred at RT for 10 minutes. Methyl iodide (647 mg, 4.5 mmol) was added and heated at 55° C. for 4 h. The solvent was removed and reaction mixture was poured in water, extracted with ethyl acetate (100 mL, 2 times), dried over Na2SO4, concentrated and purified with column chromatography to obtain 400 mg of methyl 2-(4-(butylcarbamoyl)-3-fluorophenylamino)-2-methylpropanoate.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[C:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[N:15]1>C1CCCCC1.CCOC(C)=O>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]#[C:6][CH2:5][CH2:4][CH2:3][CH2:2][N:15]1[CH:16]=[C:17]2[C:22]([CH:21]=[CH:20][CH:19]=[CH:18]2)=[N:14]1
Reactant: BrCCCCC#Cc1ccccn1
Reactant: c1ccc2[nH]ncc2c1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: C(#Cc1ccccn1)CCCCn1cc2ccccc2n1
Yield: 9 %

Procedure:
The title compounds were prepared in accordance with the general method of Example 109(D), from 2-(6-bromo-hex-1-ynyl)-pyridine (250 mg, 1.05 mmol, Example 124(B)) and indazole (124 mg, 1.05 mmol). The crude product was purified by flash chromatography (cyclohexane/AcOEt 75:25) to yield 2-(6-(pyridin-2-yl)hex-5-ynyl)-2H-indazole (26 mg, 94 μmol, 9%) as a brown oil and (cyclohexane/AcOEt 1:1) to yield 1-(6-(pyridin-2-yl)hex-5-ynyl)-1H-indazole (15 mg, 54 μmol, 5%) as a brown oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[O:13]=[C:14]1[N:20]([CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C@@H:30]([C:44](O)=[O:45])[CH2:31][C:32]3[CH:42]=[C:41]([CH3:43])[C:35]4[NH:36][C:37]([O:39][CH3:40])=[N:38][C:34]=4[CH:33]=3)=[O:28])[CH2:23][CH2:22]2)[CH2:19][CH2:18][C:17]2[CH:47]=[CH:48][CH:49]=[CH:50][C:16]=2[NH:15]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[O:13]=[C:14]1[N:20]([CH:21]2[CH2:22][CH2:23][N:24]([C:27]([O:29][C@H:30]([CH2:31][C:32]3[CH:42]=[C:41]([CH3:43])[C:35]4[NH:36][C:37]([O:39][CH3:40])=[N:38][C:34]=4[CH:33]=3)[C:44]([N:1]3[CH2:6][CH2:5][CH:4]([N:7]4[CH2:12][CH2:11][O:10][CH2:9][CH2:8]4)[CH2:3][CH2:2]3)=[O:45])=[O:28])[CH2:25][CH2:26]2)[CH2:19][CH2:18][C:17]2[CH:47]=[CH:48][CH:49]=[CH:50][C:16]=2[NH:15]1
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: COc1nc2cc(C[C@@H](OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)C(=O)O)cc(C)c2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1nc2cc(C[C@@H](OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)C(=O)N3CCC(N4CCOCC4)CC3)cc(C)c2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
40 mg (0.24 mmol) 4-piperidin-4-yl-morpholine were added to a solution of 90 mg (0.16 mmol) (R)-1-carboxy-2-(2-methoxy-7-methyl-1H-benzimidazol-5-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 60 mg (0.19 mmol) TBTU and 30 μL (0.22 mmol) triethylamine in 1 mL DMF and the reaction mixture was stirred overnight at RT. The reaction mixture was purified by HPLC without working up; the fractions containing the product were combined and lyophilised.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][C:7](=[CH2:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[C:21]([O:25][C:26]([NH:28][CH:29]1[CH2:33][CH2:32][NH:31][CH2:30]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>CS(C)=O>[C:21]([O:25][C:26]([NH:28][CH:29]1[CH2:33][CH2:32][N:31]([C:3]2[C:2]([F:1])=[CH:15][C:14]3[C:13](=[O:16])[C:12]([C:17]([OH:19])=[O:18])=[CH:11][N:6]4[C:7](=[CH2:10])[CH2:8][O:9][C:4]=2[C:5]=34)[CH2:30]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: C=C1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Solvent: CS(C)=O
Product: C=C1COc2c(N3CCC(NC(=O)OC(C)(C)C)C3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Yield: 60.3 %

Procedure:
130 mg of 9,10-difluoro-3-methylene-7-oxo-2,3-dihydro-7H-pyrido(1,2,3-de)-1,4-benzoxazine-6-carboxylic acid and 300 mg of 3-tertiary-butoxycarbonylaminopyrrolidine were added to 3 ml of dimethyl sulfoxide and the mixture was allowed to react for 3 hours at 100°-110° C. (bath temperature). The solvent was distilled off in vacuo. The residue was washed with diethyl ether and purified by silica gel column chromatography and then recrystallized from benzene to give 125 mg of 10-(3-tertiary-butoxycarbonylamino-1-pyrrolidinyl)-9-fluoro-3-methylene-7-oxo-2,3-dihydro-7H-pyrido(1,2,3-de)-1,4-benzoxazine-6-carboxylic acid with mp 219°-220° C. as luster yellow crystals.
Reaction SMILES: [CH:1](/OC1C=CC=CC=1C1(CNC(=O)CCC)CC1)=[CH:2]\[CH3:3].[OH:21][C:22]1[CH:23]=[C:24]([C@@H:28]2[CH2:30][C@H:29]2[CH2:31][NH:32][C:33](=[O:37])[CH2:34][CH2:35][CH3:36])[CH:25]=[CH:26][CH:27]=1.[OH-].[K+].C(I)C=C>C(O)C.CCOCC>[CH2:3]([O:21][C:22]1[CH:23]=[C:24]([C@@H:28]2[CH2:30][C@H:29]2[CH2:31][NH:32][C:33](=[O:37])[CH2:34][CH2:35][CH3:36])[CH:25]=[CH:26][CH:27]=1)[CH:2]=[CH2:1]
Reactant: C/C=C/Oc1ccccc1C1(CNC(=O)CCC)CC1
Reactant: CCCC(=O)NC[C@@H]1C[C@H]1c1cccc(O)c1
Agent: C=CCI
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: C=CCOc1cccc([C@@H]2C[C@H]2CNC(=O)CCC)c1
Reaction time: 18 h
Yield: 34 %

Procedure:
(trans)-N-[[(2-Propen-1-yloxyphenyl)cyclopropyl]methyl]butanamide: To a rapidly stirred solution of (trans)-N-[[2-(3 hydroxyphenyl)cyclopropyl]methyl]butanamide (0.8 g, 3.4 mmol) and KOH (210 mg, 3.74 mmol) in ethanol (15 mL) was added allyl iodide (622 mg, 3.7 mmol). After stirring for 18 h, the suspension was diluted with Et2O (100 mL), and washed with H2O, 2N NaOH, brine, dried (K2CO3), and concentrated to a give a crude residue. The resulting material was purified by chromatography (silica gel, 40% EtOAc/hexane) to afford 320 mg (34%) of the title compound: 1H NMR (300 MHz, CDCl3) δ 0.70-0.94 (m, 5H), 1.12-1.32 (m, 1H), 1.58-1.84 (m, 3H), 2.20 (t, J=6.0 Hz, 2H), 3.15-3.36 (m, 2H), 4.48 (d, J=5.6 Hz, 2H), 5.24 (d, J=10.0 Hz, 1H), 5.40 (d, J=17.2 Hz, 1H), 5.56 (br s, 1H), 5.96-6.07 (m, 1H), 6.57-6.70 (m, 3H), 7.13 (t, J=7.2 Hz, 1H); IR (NaCl Film) 3296, 2962, 1644, 1607, 1548, 1494 cm-1 ; MS m/e 273; Analysis calc'd for C17H23NO2 0.20(H2O): C, 73.72; H, 8.52; N, 5.06; found: C, 73.77; H, 8.63; N, 5.00.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=4)=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([N:34](CC)CC)C.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.[Cl-].[NH4+]>C(OCC)(=O)C.CN(C)C=O>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:24]=[CH:25][C:26]([C:27]([NH2:34])=[O:28])=[CH:30][CH:31]=4)=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCN(CC)CC
Reactant: CN1C(=O)C(F)(F)CN(C2CCCCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc21
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)C(F)(F)CN(C2CCCCC2)c2nc(Nc3ccc(C(N)=O)cc3)ncc21
Reaction time: 0.25 h
Yield: 85.8 %

Procedure:
A mixture of 0.120 g (0.26 mmole) of 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoic acid (I-256), 0.105 g (1.04 mmole) of triethylamine, 0.148 g (0.39 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate and 5 mL of dimethylformamide was stirred for 15 minutes, then 0.045 g (0.84 mmole) of ammonium chloride was added. The mixture was stirred for 3 hours, then taken up in 100 mL of ethyl acetate and washed twice with 100 mL of water and then 100 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol-ammonium hydroxide (gradient 100:0:0-92:8:0.3) to give 0.096 g of 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzamide (I-257).
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH:19]([CH3:21])[CH3:20])([CH3:3])=[CH2:2].C12CCCC(CCC1)B12[H]B2(C3CCCC2CCC3)[H]1.[CH3:42][O:43][C:44](=[O:55])[CH2:45][O:46][C:47]1[CH:52]=[CH:51][C:50](Br)=[CH:49][C:48]=1[CH3:54].ClCCl.C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.B1C2CCCC1CCC2>O.[Cl-].[Na+].O.CN(C)C=O.O1CCCC1>[CH3:42][O:43][C:44](=[O:55])[CH2:45][O:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:2][CH:1]([C:4]2[O:8][C:7]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:18])[F:16])=[CH:11][CH:10]=3)=[N:6][C:5]=2[CH:19]([CH3:21])[CH3:20])[CH3:3])=[CH:49][C:48]=1[CH3:54]
Reactant: COC(=O)COc1ccc(Br)cc1C
Reactant: C=C(C)c1oc(-c2ccc(C(F)(F)F)cc2)nc1C(C)C
Agent: B1C2CCCC1CCC2
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)COc1ccc(CC(C)c2oc(-c3ccc(C(F)(F)F)cc3)nc2C(C)C)cc1C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 5-Isopropenyl-4-isopropyl-2-(4-trifluoromethyl-phenyl)-oxazole (0.5 g, 1.695 mmol), 9-BBN dimer (0.46 g, 1.865 mmol), and tetrahydrofuran (5 mL) is stirred at room temperature 6 hr. The mixture is diluted with water (1 mL). In another flask, a mixture of (4-bromo-2-methyl-phenoxy)-acetic acid methyl ester (0.53 g, 2.03 mmol), [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (0.14 g, 0.17 mmol), triphenylarsine (0.1 g, 0.339 mmol), and N,N-dimethylformamide (5 mL) is stirred in ice/water. The previously described 9-BBN solution is added via cannula and the resulting mixture is stirred at room temperature 18 hr. The black reaction mixture is diluted with water (50 mL) and brine (50 mL), and the product is extracted to ethyl acetate (3×75 mL). The combined extracts are dried over anhydrous magnesium sulfate, filtered, and concentrated. The black residue is purified via silica chromatography eluting with 1:1 hexanes:dichloromethane to 1:1:0.5 hexanes:dichloromethane:ethyl acetate to afford the product as a colorless oil, 0.136 g, 17%. MS M++1 476. The structure is confirmed by 1H NMR spectroscopy.
Reaction SMILES: [I-].[CH:2](P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:4])[CH3:3].C([Li])CCC.[CH3:29][C:30]1[CH:35]=[C:34]([C:36]#[C:37][CH:38]=O)[N:33]=[C:32]([O:40][C:41]2[N:45]([CH3:46])[N:44]=[C:43]([C:47]([F:50])([F:49])[F:48])[CH:42]=2)[CH:31]=1>C1COCC1>[CH3:29][C:30]1[CH:35]=[C:34]([C:36]#[C:37][CH:38]=[C:2]([CH3:4])[CH3:3])[N:33]=[C:32]([O:40][C:41]2[N:45]([CH3:46])[N:44]=[C:43]([C:47]([F:50])([F:49])[F:48])[CH:42]=2)[CH:31]=1
Reactant: Cc1cc(C#CC=O)nc(Oc2cc(C(F)(F)F)nn2C)c1
Reactant: CC(C)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)=CC#Cc1cc(C)cc(Oc2cc(C(F)(F)F)nn2C)n1
Temperature: -70 °C
Reaction time: 0.75 h
Yield: 44.7 %

Procedure:
A mixture of isopropyltriphenylphosphine iodide (0.43 g, 1 mmol) in a dry THF (15 ml) is cooled to −70° C. under an inert gas atmosphere. A 2.5 M solution of butyl lithium (0.44 ml) is added and after stirring at −70° C. for 45 min the mixture is heated at 0° C. for 1 h. Then the mixture is cooled to −70° C. and 4-methyl-6-for-mylethynyl-2-(1-methyl-3-trifluoromethylpyrazol-5-yloxy)pyridine 0.3 g, 1 mmol) is added. After stirring for 30 min at −70° C. the reaction mixture is stirred at ambient temperature for 2 days. The mixture is quenched with water, evaporated and to the water containing residue is added ethyl acetate. The mixture is washed with diluted hydrochloric acid and with water. After drying and evaporation, the product (0.15 g) is obtained by flash chromatogy as nearly colorless crystals of mp 85° C.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:18][C:17]2[C:16]([NH2:19])=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C=C(O[C:27](OC2N=CC=CC=2)=[S:28])N=CC=1>ClCCl>[C:4]([Si:1]([O:8][CH:9]1[CH2:10][CH2:11][C:12]2[C:17](=[C:16]([N:19]=[C:27]=[S:28])[CH:15]=[CH:14][CH:13]=2)[CH2:18]1)([CH3:3])[CH3:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)OC1CCc2cccc(N)c2C1
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CCc2cccc(N=C=S)c2C1
Yield: 72 %

Procedure:
A solution of the product of Example 18B, 2-(tert-butyldimethylsilyl)-ol (1.4 g, 5.07 mmol) and di-2-pyridyl thionocarbonate (1.07 g, 4.61 mmol) in 30 mL dichloromethane was stirred at room temperature overnight. The mixture was evaporated, then the residue was taken up in 2 mL dichloromethane and filtered through silica gel, eluting with 5% ethyl acetate-hexane. Evaporation of the filtrate afforded the product as a dark red oil (1.165 g, 72%). 1H NMR (DMSO-d6) δ 7.21 (m, 3H), 4.27 (m, 1H), 2.58-3.09 (m, 4H), 1.90 (m, 1H), 1.77 (m, 1H), 0.90 (s, 9H), 0.14 (s, 6H).
Reaction SMILES: [H-].[Na+].C1OCCOCCOCCOCCOC1.[C:18]1([OH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl[C:26]1[C:27](=[O:43])[N:28]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)[C:29]2[C:34]([N:35]=1)=[CH:33][CH:32]=[CH:31][CH:30]=2>C1(C)C=CC=CC=1.O>[Cl:42][C:39]1[CH:38]=[CH:37][C:36]([N:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:35]=[C:26]([O:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:27]2=[O:43])=[CH:41][CH:40]=1
Reactant: O=c1c(Cl)nc2ccccc2n1-c1ccc(Cl)cc1
Reactant: Oc1ccccc1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1c(Oc2ccccc2)nc2ccccc2n1-c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 62.6 %

Procedure:
A mixture of sodium hydride (0.65 g), "15-crown-5" (1,4,7,10,13-pentaoxacyclopentadecane) (0.5 ml), phenol (2.2 g), and dry toluene was stirred for 30 minutes. To this was added a suspension of 3-chloro-1-(4-chlorophenyl)-1,2-dihydroquinoxalin-2-one (6.0 g) in dry toluene (30 ml) and stirring was continued for 2 hours. Water was added and the product was extracted into chloroform. Evaporation of the solvent and crystallisation from ethanol gave the title compound (4.5 g) mp 239°-241° C.