Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:10]1=[O:20].[CH3:30][O:31][C:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)=[O:33].C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.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>[CH3:30][O:31][C:32]([C:34]1[CH:39]=[CH:38][C:37]([C:4]2[CH:3]=[C:2]([Cl:1])[C:7]([CH2:8][C@@H:9]3[CH2:13][CH2:12][N:11]([CH:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[C:10]3=[O:20])=[C:6]([Cl:21])[CH:5]=2)=[CH:36][CH:35]=1)=[O:33]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: O=C1[C@H](Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1C1CCOCC1
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: [K+]
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(C4CCOCC4)C3=O)c(Cl)c2)cc1
Temperature: 80 °C
Yield: 87.9 %

Procedure:
Treat a solution of trifluoro-methanesulfonic acid 3,5-dichloro-4-[(R)-2-oxo-1-(tetrahydro-pyran-4-yl)-pyrrolidin-3-ylmethyl]-phenyl ester (3.0 g, 6.3 mmol), 4-methoxycarbonylphenylboronic acid (2.3 g, 13 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.73 g, 0.63 mmol) in dimethoxyethane (40 mL) with 2M aqueous potassium carbonate (9.5 mL). Heat the mixture to 80° C. overnight. Cool to room temperature, quench with 1N hydrochloric acid and extract with ethyl acetate. Wash the organic layer with brine, dry over magnesium sulfate, and filter. Purify the crude material by silica gel chromatography using hexanes:ethyl acetate to afford 2.56 g (88%) of desired product: MS (m/z): 462 (M+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]#[C:10][CH2:11][OH:12].[CH3:13][S:14](Cl)(=[O:16])=[O:15].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:13][S:14]([O:12][C:11]#[C:10][CH2:9][CH2:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: OCC#CCOC1CCCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC#CCCOC1CCCCO1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
10.24 ml (15.15 g, 0.1323 mol) of 2-butyne-1,4-diol monotetrahydropyranyl ether was added dropwise to a solution of 15 g (0.088 mol) of methanesulfonyl chloride and 19.79 ml (14.25 g, 0.141 mol) of triethylamine in 250 ml of anhydrous methylene chloride at such a rate to maintain the reaction temperature at 0° C. The reaction mixture was stirred for 30 minutes further at 0° C. Then the reaction mixture was poured into 200 ml of aqueous saturated sodium bicarbonate solution and extracted with methylene chloride. The combined organic extracts were dried over sodium sulfate and the solvent removed in vacuo, to yield crude 4-tetrahydropyranyloxy-butyn-1-ol methanesulfonate. This crude product was dissolved in 50 ml of acetone and treated with a solution of 40.34 g (0.4636 mol) of lithium bromide in 200 ml of acetone, stirring the reaction mixture at room temperature for 1 hour. The solvent was then evaporated and the residue diluted with water (100 ml) and extracted with methylene chloride, the organic extracts were dried over sodium sulfate and evaporated in vacuo. The crude material was purified bysilica gel column chromatography using hexane:ethyl acetate (95:5) as eluant to yield 1-bromobut-2-yn-4-ol-tetrahydropyranyl ether, as an oil.
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:18]3[CH:21]([CH2:22][CH2:23][C:24]=2[P:25](OCC)(OCC)=[O:26])[CH:20]([NH:33][C:34](=[O:43])[CH2:35][O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:19]3=[O:44])=[O:16])C2C=CC=CC=2)C=CC=CC=1.Br[Si](C)(C)C.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl>[O:36]([CH2:35][C:34]([NH:33][CH:20]1[C:19](=[O:44])[N:18]2[CH:21]1[CH2:22][CH2:23][C:24]([PH2:25]=[O:26])=[C:17]2[C:15]([OH:16])=[O:14])=[O:43])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CCOP(=O)(OCC)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)COc3ccccc3)C2CC1
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=[PH2]C1=C(C(=O)O)N2C(=O)C(NC(=O)COc3ccccc3)C2CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 5.5 %

Procedure:
A solution of 7-[(phenoxyacetyl)amino]-8-oxo-3-(diethoxyphosphinyl)-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (diphenylmethyl)ester (618 mg, 1 mmol) in methylene chloride (20 mL) was cooled to 0° C. under nitrogen. Bromotrimethylsilane (612 mg, 4 mmol) was added and the stirred reaction warmed to room temperature. After two hours, the solvent was removed in vacuo. The residue was stirred at room temperature with methanol-water for 0.5 hours. The reaction product was concentrated and (1 mmol) of the product was treated with trifluoroacetic acid (10 mL) and triethylsilane (4 mL) and stirred vigorously for one hour. The volatiles were removed in vacuo and the residue purified by flash chromatography on silica gel (21/7/7/9 ethyl acetate/acetonitrile/acetic/acid/water) followed by medium pressure liquid chromatography on a C18 column eluted with 10% to 20% acetonitrile/water. The fractions containing pure product were combined and lyophilized to yield 20 mg (5%) 7-[(phenoxyacetyl)amino]-8-oxo-3-phosphinyl-1-azabicyclo[ 4.2.0]-oct-2-ene-2-carboxylic acid:
Reaction SMILES: OCCCN1C=C(C2C=CC(NC3C(C(F)(F)F)=CN=C(NC4C=CC(CP(=O)(OCC)OCC)=CC=4OC)N=3)=C3C=2CN(C)C3=O)C=N1.[NH2:50][C:51]1[C:52]([C:66]([NH:68][CH3:69])=[O:67])=[N:53][C:54]([C:57]2[CH:58]=[N:59][N:60]([CH2:62][CH2:63][CH2:64][OH:65])[CH:61]=2)=[CH:55][CH:56]=1.ClC1C(C(F)(F)F)=CN=C(NC2C=CC(CP(=O)(OCC)OCC)=CC=2OC)N=1.[Cl:99][C:100]1[CH:101]=[C:102]([CH:112]=[CH:113][C:114]=1[NH:115][C:116]1[N:121]=[C:120](Cl)[C:119]([C:123]([F:126])([F:125])[F:124])=[CH:118][N:117]=1)[CH2:103][P:104](=[O:111])([O:108][CH2:109][CH3:110])[O:105][CH2:106][CH3:107]>>[Cl:99][C:100]1[CH:101]=[C:102]([CH:112]=[CH:113][C:114]=1[NH:115][C:116]1[N:117]=[C:118]([NH:50][C:51]2[C:52]([C:66](=[O:67])[NH:68][CH3:69])=[N:53][C:54]([C:57]3[CH:58]=[N:59][N:60]([CH2:62][CH2:63][CH2:64][OH:65])[CH:61]=3)=[CH:55][CH:56]=2)[C:119]([C:123]([F:126])([F:124])[F:125])=[CH:120][N:121]=1)[CH2:103][P:104](=[O:111])([O:108][CH2:109][CH3:110])[O:105][CH2:106][CH3:107]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(Cl)c1)OCC
Reactant: CNC(=O)c1nc(-c2cnn(CCCO)c2)ccc1N
Agent: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Agent: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)nc3C(=O)NC)n2)c(Cl)c1)OCC
Yield: 25 %

Procedure:
Prepared analogously to Compound 1B replacing Compound 1C with 3-amino-6-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-n-methylpyridine-2-carboxamide (Compound 6C, 278 mg, 1.01 mmol) and Compound 1E with diethyl (3-chloro-4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (Compound 24C, 463 mg, 1.01 mmol) to afford 176 mg of the title compound (25%). 1H NMR (400 MHz, CD3OD) δ=8.64-8.79 (m, 1H), 8.55 (s, 1H), 8.44 (s, 1H), 8.35 (s, 1H), 7.73 (d, J=9.1 Hz, 1H), 7.65 (t, J=2.3 Hz, 1H), 7.60 (d, J=8.3 Hz, 1H), 7.44-7.49 (m, 1H), 4.28-4.35 (m, 2H), 4.08-4.18 (m, 4H), 3.56 (t, J=6.2 Hz, 2H), 3.42 (d, J=21.0 Hz, 2H), 3.00 (s, 3H), 2.11 (quin, J=6.5 Hz, 2H), 1.26 (t, J=7.1 Hz, 6H). MS (ESI): m/z=697.72 [M+H]+. UPLC: tR=1.28 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:20].[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl>[O:9]=[C:8]1[N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3](=[O:20])[CH:2]1[NH:1][C:28]([NH:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:29]
Reactant: O=C=Nc1ccccc1
Reactant: NC1C(=O)Nc2ccccc2N(c2ccccc2)C1=O
Solvent: ClCCl
Product: O=C(Nc1ccccc1)NC1C(=O)Nc2ccccc2N(c2ccccc2)C1=O
Temperature: 25 °C
Yield: 71.9 %

Procedure:
To a slurry of 3-amino-1-phenyl-1,5-dihydro-benzo [b] [1,4]-diazepine-2,4-dione (0.398 g) in dichloromethane (5 ml) was added phenyl isocyanate (0.177 g) gradually with stirring at ambient temperature. The reaction mixture was stirred two hours at ambient temperature after which time a cream precipitate Was separated by filtration to provide the title compound (0.413 g). 1H NMR (300 MHz, DMSO-d6): d 4.97 (d, J=7.5 Hz, 1H), 6.88-6.97 (m, 3H), 7.13-7.47 (m, 12H), 9.16 (s, 1H), 10.78 (br s, 1H); TLC (CH2Cl2 /CH3OH, 19:1 ): Rf =0.21.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)=[O:3].N1C=CC=CC=1.[S:17](Cl)([CH3:20])(=[O:19])=[O:18]>ClCCl>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:6][CH:5]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)c1ccc(NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 84 h
Yield: 59.8 %

Procedure:
Ex-100A: A solution of 4-aminoacetophenone (5.0 g, 37.0 mmol) and pyridine (3.0 mL) in anhydrous dichloromethane (300 mL) was treated with mesyl chloride (2.86 mL, 37.0 mmol). The reaction was stirred for 84 hours at room temperature under nitrogen, and then quenched with saturated NH4Cl solution (100 mL). The organic phase was collected, washed with water (100 mL) and brine, dried over sodium sulfate, and concentrated over silica. The material was purified by silica gel chromatography (50% ethyl acetate/hexanes) to give 4.72 g (60%) of N-(4-acetyl-phenyl)-methanesulfonamide as a yellowish oil. 1H-NMR (DMSO-d6) δ 10.28 (s, 1H), 7.90 (d, 1H), 7.24 (d, 1H), 3.06 (s, 3H), 2.48 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.O.[OH-].[Li+].Cl>C1COCC1.CO.O>[CH3:17][C:16]1[O:15][N:14]=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[C:12]=1[CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:24])=[O:2])=[CH:5][N:6]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccn3)noc2C)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
To a suspension of 6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (330 mg, 1.0 mmol) in THF (3 mL) and methanol (3 mL) was added a solution of lithium hydroxide monohydrate (85.1 mg, 2.0 mmol) in water (3 mL) added and the resulting mixture stirred at room temperature overnight. The mixture was acidified to pH 4 with HCl (1 N, 30 mL) and the resulting mixture was filtered. The solid was dried to afford the title compound (284 mg, 90%) which was obtained as a white solid. MS: m/e=310.5 [M−H]−.
Reaction SMILES: [NH3:1].[N:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([CH3:17])[N:14]=[N:15][CH:16]=2)=[C:7]([O:18][CH3:19])[CH:6]=1)=[C:3]=[S:4]>>[CH3:19][O:18][C:7]1[CH:6]=[C:5]([NH:2][C:3]([NH2:1])=[S:4])[CH:10]=[CH:9][C:8]=1[C:11]1[CH:12]=[C:13]([CH3:17])[N:14]=[N:15][CH:16]=1
Reactant: N
Reactant: COc1cc(N=C=S)ccc1-c1cnnc(C)c1
Product: COc1cc(NC(N)=S)ccc1-c1cnnc(C)c1
Reaction time: 4 h
Yield: 99.4 %

Procedure:
Step L (5): Methanolic ammonia (2.0 M, 20 mL, 40 mmol) was added to a flask charged with 5-(4-isothiocyanato-2-methoxyphenyl)-3-methylpyridazine (650 mg, 2.53 mmol). After 4 h, the reaction mixture was concentrated in vacuo to afford 1-(3-methoxy-4-(6-methylpyridazin-4-yl)phenyl)thiourea (690 mg, 100% yield). LC-MS (M+H)+ 275.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][C:8]([CH3:23])([CH3:22])[N:9]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)[CH2:10]2)=[CH:5][C:4]=1[O:24][Si](C(C)C)(C(C)C)C(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[CH3:21][O:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][N:9]1[C:8]([CH3:23])([CH3:22])[CH2:7][C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[C:4]([OH:24])[CH:5]=2)[CH2:10]1
Reactant: COc1cccc(CN2Cc3cc(OC)c(O[Si](C(C)C)(C(C)C)C(C)C)cc3CC2(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(CN2Cc3cc(OC)c(O)cc3CC2(C)C)c1
Yield: 47.5 %

Procedure:
To a solution of 226 (237 mg, 0.45 mmol) in THF (10 ml) at 0° C. (ice-bath) was added TBAF (1.0 M in THF, 0.53 ml, 0.53 mmol). The reaction mixture was stirred at 0° C. for 18 h. water (10 ml) was added and the aqueous layer was extracted with EtOAc (3×). The combined organic layer were washed with brine (10 ml), dried (MgSO4) and concentrated in vacuo. Purification (flashmaster: 20 g, 100% hex to 100% EtOAc over 25 min) afforded the title compound (70 mg, 43%) as a colourless oil. 1H NMR (270 MHz; CDCl3) 1.18 (6H, s, 2×CH3), 2.66 (2H, s, CH2), 3.50 (2H, s, CH2), 3.65 (2H, s, CH2), 3.79 (3H, s, OCH3), 3.83 (3H, s, OCH3), 6.47 (1H, s, CH), 6.52 (1H, s, CH), 6.75-6.79 (1H, m, CH), 6.95-6.97 (2H, m, 2×CH), 7.21 (1H, t, J=8.0 Hz, CH). 13C NMR (100 MHz; CDCl3) 23.72 (CH3), 45.54 (CH2), 49.97 (CH2), 52.49 (C), 53.45 (CH2), 55.13 (OCH3), 55.86 (OCH3), 110.69 (CH), 111.73 (CH), 111.90 (CH), 114.09 (CH), 120.88 (CH), 125.60 (C), 126.86 (C), 129.11 (C), 142.41 (C), 143.49 (C), 144.99 (C), 159.59 (C). LC/MS (ES−) tr=1.85 min, m/z 326.27 (M−H)−. HRMS (ES+) calcd. for C20H26NO3 (M++H) 328.1907, found 328.1904.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH:8][C:9]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[O:7].[O:20]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28](O)=[O:29])=[CH:21]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C(=O)C.C(OCC)(=O)C>[Cl:19][C:16]1[CH:17]=[CH:18][C:9]([NH:8][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][NH:2][C:28]([C:27]2[CH:31]=[CH:32][CH:33]=[C:25]([C:22]3[CH:23]=[CH:24][O:20][CH:21]=3)[CH:26]=2)=[O:29])=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)CCCN
Reactant: O=C(O)c1cccc(-c2ccoc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cc(Cl)ccc1NC(=O)CCCNC(=O)c1cccc(-c2ccoc2)c1
Yield: 83.9 %

Procedure:
1.00 g (3.3 mmol) of methyl 2-[(4-aminobutanoyl)amino]-5-chlorobenzoate hydrochloride, 0.61 g (3.3 mmol) of 3-(furan-3-yl)benzoic acid, 0.75 g (3.9 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, and 0.53 g (3.9 mmol) of 1-hydroxybenzotriazole were stirred in 10 mL of N,N-dimethylacetamide (DMAc) for 2 hours. After the completion of the reaction, ethyl acetate was added, and the mixture was diluted and washed with saturated sodium bicarbonate solution and saturated saline. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained crude product was recrystallized using a mixed solvent of ethyl acetate and n-hexane, thereby giving 1.22 g of methyl 5-chloro-2-{[4-({[3-(furan-3-yl)phenyl]carbonyl}amino)butanoyl]amino}benzoate (yield: 85%).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=3)[C@H:20]([CH2:30]OS(C)(=O)=O)[CH2:19][CH2:18][O:17]2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[CH2:39]1[C:43]2([CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH:42]([OH:49])[CH2:41][O:40]1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[F:1][C:2]([F:36])([F:37])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=3)[C@H:20]([CH2:30][N:46]3[CH2:45][CH2:44][C:43]4([CH2:39][O:40][CH2:41][CH:42]4[OH:49])[CH2:48][CH2:47]3)[CH2:19][CH2:18][O:17]2)[CH3:14])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: OC1COCC12CCNCC2
Reactant: C[C@@H](O[C@H]1OCC[C@@H](COS(C)(=O)=O)[C@@H]1c1ccc(F)c(F)c1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: C[C@@H](O[C@H]1OCC[C@@H](CN2CCC3(CC2)COCC3O)[C@@H]1c1ccc(F)c(F)c1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
A mixture of methanesulfonic acid [(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)-phenyl)ethoxy]-3-(3,4-difluorophenyl)-tetrahydropyran-4-yl]methyl ester (Description 16; 0.275 g, 0.49 mmol), 2-oxa-8-aza-spiro[4.5]decan-4-ol hydrochloride (Description 8; 0.1 g, 0.37 mmol), potassium carbonate (237 g, 1.7 mmol) and acetonitrile (3 ml) was stirred at 55° C. overnight and then at 65° C. for 18 hours. The mixture was treated with water and extracted into dichloromethane. The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by preparative TLC (dichloromethane:methanol) to give the title compound.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[NH:8][C:7](=O)[C@@H:6]([CH3:10])[NH:5][C:4]1=O.B.C1COCC1.[ClH:18]>CO>[ClH:18].[CH3:10][C@@H:6]1[CH2:7][NH:8][C@@H:3]([CH2:2][OH:1])[CH2:4][NH:5]1
Reactant: C[C@H]1NC(=O)[C@H](CO)NC1=O
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H]1CN[C@@H](CO)CN1
Temperature: 70 °C

Procedure:
To (3S,6R)-3-hydroxymethyl-6-methyl-piperazine-2,5-dione (34 g, 0.215 mol) was added a solution of borane in THF (1 M, 1.6 L, 1.6 mol) and the mixture was heated to 70° C. for 18 h. The solution was cooled in ice, then MeOH (425 mL) was gradually added, followed by 5 M hydrochloric acid (113 mL). The mixture was heated to 70° C. for 2 h and then cooled to ambient temperature. The resulting solid was filtered, cake washed with THF (200 mL) and dried in vacuo at 40° C., to give the title compound (39.3 g) as a colourless solid. 1H NMR (DMSO-d6): 9.79 (3H, s), 5.59 (1H, s), 3.76-3.40 (5H, m), 3.19-2.94 (2H, m), 1.28 (3H, d).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Cl:35][C:36]1[CH:37]=[C:38]([CH:40]=[CH:41][C:42]=1[Cl:43])[NH2:39]>CN(C=O)C>[Cl:35][C:36]1[CH:37]=[C:38]([NH:39][C:9](=[O:11])[CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=2)[CH:40]=[CH:41][C:42]=1[Cl:43]
Reactant: O=C(O)Cc1cccc(O)c1
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cc1cccc(O)c1)Nc1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 61.9 %

Procedure:
To a solution of 3-hydroxyphenyl acetic acid (5.0 g, 0.03 mol) in DMF (50 ml) was added 1-hydroxybenzotriazole hydrate (4.86 g, 0.03 mol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (6.9 g, 0.036mol). To the flask was added 3,4-dichloroaniline (4.86 g, 0.03 mol). The reaction was allowed to stir overnight. Solvent was removed and the reaction was diluted with ethyl acetate. The reaction mixture was washed with 1N HCl, 10% sodium carbonate solution, and brine. The organic layer was dried over MgSO4, filtered and concentrated to provide the title compound (5.5 g, 62% yield): ES−MS (m/z) 296 [M+H]+.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.[NH:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)N.CCN(CC)CC>C(O)C.O>[N:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[N:25]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: NNc1ccccn1
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccccn1
Temperature: 100 °C
Reaction time: 5 h
Yield: 50 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (800 mg, 2.4 mmol) in ethanol (20 mL) were added 2-hydrazinopyridine (388 mg, 3.6 mmol) and Et3N (0.66 mL, 4.7 mmol). The mixture was stirred at 100° C. for 5 h. The mixture was diluted with water, extracted with AcOEt, washed with brine, dried over Na2SO4, concentrated in vacuo, purified by HPLC and recrystallized with AcOEt/hexane to yield the title compound as a pale yellow solid (460 mg, 51%).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][OH:13].CNC.Cl>[Cu].CCOCC.O>[CH3:12][O:13][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Reactant: CO
Agent: [Cu]
Agent: CNC
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: COc1cc(Cl)ccc1C(=O)O

Procedure:
A mixture of 2,4-dichlorobenzoic acid (67.4 g), absolute methanol (135 ml), and copper powder (3.37 g) is refluxed for 6-7 hours while introducing gaseous dimethylamine. The reaction mixture is mixed with a large amount of water, acidified with hydrochloric acid, and shaken with ether. The organic layer is washed with water, dried over sodium sulfate, and evaporated to remove the solvent. The residue is washed with isopropyl ether and filtered to give 2-methoxy-4-chlorobenzoic acid (43.6 g) as crystals melting at 139.5° to 141° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([CH2:14][C:15]1[CH:30]=[CH:29][C:18]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[O:20])=[CH:17][CH:16]=1)[CH:7]2O.C(N(S(F)(F)[F:37])CC)C.C([O-])(O)=O.[K+]>C(Cl)Cl>[Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([CH2:14][C:15]1[CH:30]=[CH:29][C:18]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[O:20])=[CH:17][CH:16]=1)[CH:7]2[F:37]
Reactant: CCN(CC)S(F)(F)F
Reactant: Cc1ccccc1NC(=O)c1ccc(CC2CCc3c(ccc(Cl)c3Cl)C2O)cc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Product: Cc1ccccc1NC(=O)c1ccc(CC2CCc3c(ccc(Cl)c3Cl)C2F)cc1
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
A solution containing 0.35 g of 4-[(5,6-dichloro-1-hydroxy-1,2,3,4-tetrahydro-2-naphthalenyl)methyl]-N-(2-methylphenyl)benzamide and 10 cm3 of methylene chloride is cooled down to −65°C.±5° C. 142 mg of DAST (diethylaminosulfur trifluoride) was added. The solution was maintained under agitation for 1 hour at −65° C. The temperature was allowed to rise to 20° C. and the reaction medium was poured into an aqueous solution of potassium acid carbonate, followed by agitation for 30 minutes and extraction with methylene chloride. The organic phases were collected, dried, filtered and concentrated. In this way 340 mg of sought product was obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[CH2:10][N:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:6]=2[N:7]=1.[CH2:21]([NH:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[C:29]([F:42])[CH:28]=1)=[O:25])[CH3:22]>>[CH2:21]([NH:23][C:24](=[O:25])[NH:26][C:27]1[CH:32]=[CH:31][C:30]([C:2]2[N:3]=[C:4]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:5]3[CH2:10][N:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:6]=3[N:7]=2)=[C:29]([F:42])[CH:28]=1)[CH3:22]
Reactant: COC(=O)N1Cc2nc(Cl)nc(N3CCOCC3)c2C1
Reactant: CCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CN(C(=O)OC)C3)c(F)c1
Yield: 16 %

Procedure:
Method as described for example 147 using methyl 2-chloro-4-morpholino-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 25) and 1-ethyl-3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) (intermediate 28) as starting materials. The crude reaction mixture was purified by SCX-2 cartridge (loaded in MeOH eluted with 2M methanolic ammonia). Ammonia eluant was concentrated in vacuo. Residue was then purified by prep. HPLC at high pH to afford an off white solid (34.6 mg, 0.08 mmol, 16%).