Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:29])[C@@H:4]([NH2:28])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])=[C:8]([Br:27])[CH:7]=1.[F:30][C:31]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:32]=1[CH:33]=[CH:34][C:35](O)=[O:36]>>[Br:27][C:8]1[CH:7]=[C:6]([CH2:5][C@H:4]([NH:28][C:35](=[O:36])[CH:34]=[CH:33][C:32]2[CH:38]=[CH:39][C:40]([F:42])=[CH:41][C:31]=2[F:30])[C:3]([OH:2])=[O:29])[CH:11]=[CH:10][C:9]=1[O:12][CH2:13][CH2:14][C:15]1[N:16]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:18][C:19]=1[CH3:20]
Reactant: COC(=O)[C@@H](N)Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c(Br)c1
Reactant: O=C(O)C=Cc1ccc(F)cc1F
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](NC(=O)C=Cc2ccc(F)cc2F)C(=O)O)cc1Br
Yield: 31 %

Procedure:
Following the procedures described in Example 1, Intermediate 3B was used in place of Intermediate 3A, and 2,4-difluorocinnamic acid was used in place of cinnamic acid to give (2S)-3-{3-bromo-4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]-phenyl}-2-(3-(2,4-difluorophenyl)-acryloylamino)-propanoic acid as a white solid with the yield of 31% and mp of 221-223° C.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[CH:9][CH:10]=[C:11]3[CH:15]=[CH:14][O:13][C:12]=23)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(O)(=O)C.[H][H]>CO.[Pt](=O)=O>[N:1]1([C:7]2[N:8]=[CH:9][CH:10]=[C:11]3[CH2:15][CH2:14][O:13][C:12]=23)[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]1
Reactant: [H][H]
Reactant: c1cc2ccoc2c(N2CCNCC2)n1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CO
Product: c1cc2c(c(N3CCNCC3)n1)OCC2
Yield: 95.1 %

Procedure:
A mixture of 7-(piperazin-1-yl)-furo[2,3-c]pyridine [CAS-No. 209160-83-8] (1 g, 4.92 mmol), platinum(IV) oxide (0.46 g, 4.32 mmol), acetic acid (2.3 ml) in MeOH (6.9 ml) was stirred in a hydrogen atmosphere at room temperature for 24 h. After removal of the catalyst by filtration the mixture was evaporated, the residue was dissolved in dichloromethane (70 ml), washed with 2N sodium carbonate solution (40 ml), dried (MgSO4) and evaporated to yield 7-(piperazin-1-yl)-2,3-dihydro-furo[2,3-c]pyridine as a light brown oil (0.96 g, 95%), MS (ISP) m/z=206.3 [(M+H)+].
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:24][CH:23]2[CH:21]([CH:22]2[C:25](=[O:32])[CH:26]=[C:27]([S:30][CH3:31])SC)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:41]2[CH:42]=[C:43]([O:48][C:49]([F:52])([F:51])[F:50])[C:44]([NH2:47])=[N:45][CH:46]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>S1C=CC=C1C(O[Cu])=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].O1CCCC1.O>[NH2:47][C:44]1[N:45]=[CH:46][C:41](/[C:27](/[S:30][CH3:31])=[CH:26]\[C:25]([CH:22]2[CH:23]3[CH:21]2[CH2:20][CH:19]([O:18][Si:1]([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:24]3)=[O:32])=[CH:42][C:43]=1[O:48][C:49]([F:52])([F:50])[F:51]
Reactant: CC1(C)OB(c2cnc(N)c(OC(F)(F)F)c2)OC1(C)C
Reactant: CSC(=CC(=O)C1C2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC21)SC
Agent: O=C(O[Cu])c1cccs1
Agent: [Pd]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: CS/C(=C/C(=O)C1C2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC21)c1cnc(N)c(OC(F)(F)F)c1
Temperature: 100 °C
Yield: 27.9 %

Procedure:
A microwave vial charged with 1-(3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexan-6-yl)-3,3-bis(methylthio)prop-2-en-1-one (2.0 g, 4.1 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoro-methoxy)-pyridin-2-amine (1.89 g, 6.23 mmol), ((thiophene-2-carbonyl)oxy)copper (1.58 g, 8.29 mmol), cesium carbonate (2.7 g, 8.3 mmol) and tetra(triphenylphosphine)palladium (0) (957 mg, 0.83 mmol) in 10:1 tetrahydrofuran/water (22 mL) was purged with nitrogen for 3 min. The reaction mixture was sealed and heated by microwave irradiation at 100° C. for 1.5 h. The reaction mixture was concentrated in vacuo, and the resulting residue was purified by flash column chromatography (40% ethyl acetate in petroleum ether) to provide product as a yellow oil (0.70 g, 26% yield). LCMS (ESI) [MH]+=613.1.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1)=[O:15]>CN(C=O)C>[F:28][C:25]1[CH:24]=[CH:23][C:22]([N:19]2[CH2:18][CH2:17][N:16]([C:14](=[O:15])[CH2:13][N:1]3[CH:5]=[CH:4][CH:3]=[N:2]3)[CH2:21][CH2:20]2)=[CH:27][CH:26]=1
Reactant: c1cn[nH]c1
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Cn1cccn1)N1CCN(c2ccc(F)cc2)CC1
Temperature: 80 °C

Procedure:
Pyrazole (112.33 mg, 1.65 mmol) was dissolved in DMF (10 mL). K2CO3 (228.05 mg, 1.65 mmol) and 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone (300 mg, 1.67 mmol) were added to it. The reaction was heated to 80° C. for 14 h. After completion, the reaction was cooled to room temperature, quenched with brine and then extracted with ethyl acetate. The organic layer was further washed with water (2×25 mL) and brine (2×25 mL) and dried over magnesium sulfate. The solvent was removed by rotary evaporation to give the crude product which was purified by column chromatography on silica gel using a solvent mixture (hexane/ethyl acetate=1/1) to afford the title compound as white solid. 1H NMR (400 MHz, CDCl3): 7.2-7.58 (d, 2H), 6.94-7.2 (t, 2H), 6.84-6.9 (dd, 2H), 6.32-6.36 (t, 1H), 5.6 (s, 2H), 3.76-3.82 (m, 2H), 3.68-3.74 (m, 2H), 3.04-3.1 (m, 2H), 3.0-3.04 (m, 2H). 13C NMR (400 MHz, CDCl3):165, 158, 146.5, 140, 130, 118.4, 118.2, 116, 115.8, 107, 54, 51, 50.8 45.8, 42.8.
Reaction SMILES: CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.[C:19]([NH:23][C:24](=[O:39])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][N:32]2[CH2:37][CH2:36][NH:35][CH2:34][C@H:33]2[CH3:38])[CH:26]=1)([CH3:22])([CH3:21])[CH3:20].[NH2:40][C:41]1[CH:49]=[CH:48][C:44]([C:45](O)=[O:46])=[CH:43][C:42]=1[F:50].C(N(CC)CC)C>ClCCl>[NH2:40][C:41]1[CH:49]=[CH:48][C:44]([C:45]([N:35]2[CH2:36][CH2:37][N:32]([CH2:31][C:27]3[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=3)[C:24]([NH:23][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:39])[C@H:33]([CH3:38])[CH2:34]2)=[O:46])=[CH:43][C:42]=1[F:50]
Reactant: Nc1ccc(C(=O)O)cc1F
Reactant: C[C@@H]1CNCCN1Cc1cccc(C(=O)NC(C)(C)C)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(C(=O)c2ccc(N)c(F)c2)CCN1Cc1cccc(C(=O)NC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.4 %

Procedure:
1-Propanephosphonic acid cyclic anhydride (1.967 g, 3 mmol, 1.840 mL, 50% solution in ethyl acetate) was added dropwise to a solution of (R)N-tert-butyl-3-((2-methylpiperazin-1-yl)methyl)benzamide (500 mg, 1.7 mmol), 4-amino-3-fluorobenzoic acid (239.7 mg, 1.5 mmol) and triethylamine (469 mg, 4.5 mmol, 1.84 mL) in dichloromethane. The reaction was stirred at room temperature for 2 hours. The dichloromethane was removed under reduced pressure and the residue was taken up in ethyl acetate, washed with water, sodium hydrogen carbonate and brine. The organic layer was concentrated under vacuum to afford the title compound (476.3 mg).
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[C:11]1([CH3:19])[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Mg]Cl.[Cl-].[NH4+].CCCCCC.C(OCC)(=O)C>C1COCC1>[CH3:19][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:2]([C:1]([O:8][CH2:9][CH3:10])=[O:7])=[O:4]
Reactant: Cc1ccccc1[Mg]Cl
Reactant: CCOC(=O)C(=O)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)C(=O)c1ccccc1C
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
A solution of diethyl oxalate (30 g) in anhydrous THF (300 ml) was cooled to -30° C. A solution of o-tolyl magnesium chloride in THF (1 M, 140 ml) was added to the above solution at a temperature of the reaction solution of -20° C. After stirring at -30° C. for 30 minutes, the mixture was allowed to warm up to 0° C. and combined with an aqueous ammonium chloride solution. The mixture was concentrated under reduced pressure. The residue was treated with water and diethyl ether and phases were separated. The organic phase was washed with water, dried over anhydrous magnesium sulfate and concentrated to give a yellow oil. The oil was subjected to silica gel column chromatography (eluent: hexane/ethyl acetate=10/1) to give the desired ethyl 2-methylbenzoylformate (18 g, yield: 87%).
Reaction SMILES: [OH:1][C:2]1([C:10]#[N:11])[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.C(N(CC)CC)C.[N:19]([C:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([CH3:33])=[CH2:32])[CH:26]=1)([CH3:24])[CH3:23])=[C:20]=[O:21]>C(#N)C.O1CCOCC1>[CH2:32]=[C:31]([C:27]1[CH:26]=[C:25]([C:22]([NH:19][C:20](=[O:21])[O:1][C:2]2([C:10]#[N:11])[CH:7]3[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]3)[CH2:3]2)([CH3:24])[CH3:23])[CH:30]=[CH:29][CH:28]=1)[CH3:33]
Reactant: N#CC1(O)CN2CCC1CC2
Reactant: C=C(C)c1cccc(C(C)(C)N=C=O)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: C1COCCO1
Product: C=C(C)c1cccc(C(C)(C)NC(=O)OC2(C#N)CN3CCC2CC3)c1
Reaction time: 0.25 h
Yield: 65 %

Procedure:
To a solution of 3-hydroxyquinuclidine-3-carbonitrile (38 mg, 0.25 mmol) in acetonitrile/dioxane (3 mL) at room temperature was added triethylamine (7.0 uL, 0.05 mmol). The reaction mixture was stirred for 15 min and 1-(2-isocyanatopropan-2-yl)-3-(prop-1-en-2-yl)benzene (49.0 uL, 0.248 mmol) was added dropwise. The reaction was stirred for a period of 18 h at 65° C. and concentrated. The crude material was purified on a combiflash (SiO2 cartridge, CHCl3 and 2N NH3 in MeOH) to afford the corresponding carbamate as a clear oil (57 mg, 65%). 1H NMR (400 MHz, CDCl3) δ 7.42-7.20 (s, 5H), 6.61 (s, 1H), 5.11 (s, 1H), 3.29 (d, J=12.0 Hz, 1H), 3.09 (d, J=12.0 Hz, 1H), 2.93 (d, J=4.0 Hz, 2H), 2.79-2.68 (m, 2H), 2.13 (s, 6H) 2.05-2.00 (m, 2H), 1.91 (s, 3H), 1.87 (s, 2H), 1.50-1.37 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3) δ 135.4, 128.7, 125.2, 124.5, 124.0, 122.0, 112.9, 61.2, 47.0, 46.2, 32.4, 31.8, 29.9, 29.4, 29.2, 26.6, 25.7, 23.7, 22.8, 22.2, 19.2 ppm. Purity: >99% UPLCMS (210 nm); retention time 0.81 min; (M+1) 354.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:15])[CH2:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])=[C:4]([N+:16]([O-])=O)[CH:3]=1.Cl[Sn]Cl.CCOC(C)=O.C(=O)(O)[O-].[Na+]>CCO>[Br:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([N:8]([CH2:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])[CH3:15])=[CH:6][CH:7]=1
Reactant: CN(C)CCCN(C)c1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(C)CCCN(C)c1ccc(Br)cc1N
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To N-(4-Bromo-2-nitro-phenyl)-N,N′,N′-trimethyl-propane-1,3-diamine (made by a method similar to that of Example 103-Step 1) (0.54 g, 1.7 mmol) in 20 ml EtOH was added SnCl2 (0.51 g, 2.67 mmol). The mixture was sealed and was heated to 80° C. for 12 h. An additional amount of SnCl2 (0.51 g, 2.67 mmol) was added and heating continued for 12 h. The reaction was cooled to ambient temperature, and was poured into a mixture of EtOAc and saturated aqueous sodium bicarbonate. The mixture was filtered through celite, and the organic layer was removed. The aqueous layer was extracted twice with EtOAc, and the combined organic layers were dried with Na2SO4, filtered, and concentrated to give a cloudy oil. This material was filtered through silica gel with 90/10/1 dichloromethane/MeOH/conc. NH4OH and concentrated in vacuo to give the title compound as a red oil. MS (ES+): 285.9 (M+H)+. Calc'd for C12H20BrN3: 286.21.
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:91]=[C:92]([F:94])[CH:93]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[CH:67][C:68]([N:71]5[CH2:76][CH2:75][N:74]([CH2:77][C@@H:78]([OH:80])[CH3:79])[CH2:73][CH2:72]5)=[N:69][CH:70]=4)[CH:63]=3)[N:58](S(C3C=CC(C)=CC=3)(=O)=O)[CH:57]=2)[CH:53]=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([CH:91]=[C:92]([F:94])[CH:93]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[CH:67][C:68]([N:71]5[CH2:72][CH2:73][N:74]([CH2:77][C@@H:78]([OH:80])[CH3:79])[CH2:75][CH2:76]5)=[N:69][CH:70]=4)[CH:63]=3)[NH:58][CH:57]=2)[CH:53]=[N:52]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)cc(F)c4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)nc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](O)CN1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cc(F)cc(F)c6)c5)c4c3)cn2)CC1
Yield: 100.9 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, (S)-1-(4-(5-(3-(1-(3,5-difluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazin-1-yl)propan-2-ol (90 mg, 0.131 mmol) was hydrolyzed with lithium hydroxide (28 mg, 0.658 mmol) in THF/methanol/water (2/2/1 mL) to yield 70 mg (100% yield) of desired product. 1H NMR (CD3OD, 300 MHz): δ 8.74-8.73 (d, 1H), 8.61-8.56 (m, 2H), 8.31-8.25 (m, 2H), 8.02 (s, 1H), 7.83 (s, 1H), 7.30-7.27 (d, 1H), 7.10-6.85 (m, 2H), 5.44 (s, 2H), 4.30-4.20 (m, 1H), 3.60-3.50 (bs, 4H), 3.23-3.15 (m, 2H), 1.27-1.25 (d, 3H). MS: m/z=530.2 (M+1), HPLC: 97.51% in method A.
Reaction SMILES: [F:1][C:2]1[C:11]2[N:10]=[N:9][C:8]3[C:12](=[O:24])[N:13]([C:15]4[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=4)[NH:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[NH2:34][CH2:35][CH2:36][CH2:37][CH2:38][N:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1.O>CC(N(C)C)=O.C(O)CCC>[F:1][C:2]1[C:11]2[N:10]=[N:9][C:8]3[C:12](=[O:24])[N:13]([C:15]4[CH:23]=[CH:22][C:18]([C:19]([NH:34][CH2:35][CH2:36][CH2:37][CH2:38][N:39]5[CH2:43][CH2:42][CH2:41][CH2:40]5)=[O:20])=[CH:17][CH:16]=4)[NH:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(-n2[nH]c3c(nnc4c(F)cccc43)c2=O)cc1
Reactant: NCCCCN1CCCC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O=C(NCCCCN1CCCC1)c1ccc(-n2[nH]c3c(nnc4c(F)cccc43)c2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.2 %

Procedure:
4-(6-fluoro-3-oxo-1,3-dihydro-2H-pyrazolo[4,3-c]cinnolin-2-yl)benzoyl chloride (100 mg, 0.29 mmol) was dissolved in anhydrous DMA (2 ml). Diisopropylethylamine (75 mg, 101 μl, 0.58 mmol) was added followed by 1-(4-aminobutyl)pyrrolidine (41 mg). The mixture was stirred at room temperature overnight. Water (5 ml) and n-butanol (5 ml) were added. The phases were separated. The organic phase was washed with water (2×5 ml). The volatiles were removed under vacuum. The product was isolated as a brown powder (50 mg, 0.11 mmol, 37%). LCMS: m/z [M+H]+ 463.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:15]([CH:18]=O)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28]C(C)C(=O)C(P(=O)([O-])[O-])=[N+]=[N-].C(=O)([O-])[O-].[K+].[K+].O>CO.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:15]([C:18]#[CH:28])=[CH:16][N:17]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)C(=O)C(=[N+]=[N-])P(=O)([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(C=O)n1COCC[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C#Cc1cnc(C2CCCN2C(=O)OC(C)(C)C)n1COCC[Si](C)(C)C
Reaction time: 3.33 h
Yield: 76.7 %

Procedure:
2-[5-Formyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (1.625 g, 4.11 mmol) and dimethyl-1-diazo-2-oxopropylphosphonate (1.056 g, 5.50 mmol) were dissolved in 1:1 MeOH/THF (10 mL) and potassium carbonate (1.14 g, 8.25 mmol) was added. After stirring for 200 min, more potassium carbonate (1.14 g, 8.25 mmol) was added. 45 min later, the reaction mixture was poured into 100 mL 1:1 water/saturated aqueous sodium bicarbonate. The aqueous phase was extracted 3 times with diethyl ether. The combined organic phases were dried with magnesium sulfate and concentrated. The crude residue was purified by silica column chromatography (20% to 45% EtOAc/hexanes) to afford 2-[5-Ethynyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (1.234 g, 77%).
Reaction SMILES: [Br:1][C:2]1[C:7]2[O:8][CH2:9][C@@H:10]3[C@@H:15]([CH2:16][OH:17])[CH2:14][NH:13][CH2:12][C@H:11]3[C:6]=2[CH:5]=[C:4]([O:18][CH3:19])[CH:3]=1.[CH2:20]=O>C(O)=O>[Br:1][C:2]1[C:7]2[O:8][CH2:9][C@@H:10]3[C@@H:15]([CH2:16][OH:17])[CH2:14][N:13]([CH3:20])[CH2:12][C@H:11]3[C:6]=2[CH:5]=[C:4]([O:18][CH3:19])[CH:3]=1
Reactant: COc1cc(Br)c2c(c1)[C@@H]1CNC[C@H](CO)[C@H]1CO2
Reactant: C=O
Solvent: O=CO
Product: COc1cc(Br)c2c(c1)[C@@H]1CN(C)C[C@H](CO)[C@H]1CO2

Procedure:
A solution of 1.65 g (±)-[4R*,4aS*,10bR*]-7-bromo-4-(hydroxymethyl)-1,3,4,4a,5,10b-hexahydro-9-methoxy-2H-[1]benzopyrano[4,3-c]pyridine in 0.5 ml 37% HCHO and 2.2 ml HCO2H is heated at 100° for 20 min. The reaction mixture is concentrated in vacuo and partitioned between 10 ml 2N NaOH and 50 ml CH2Cl2. The organic phase is dried over Na2SO4, filtered and concentrated under reduced pressure to yield the title compound; m.p. of HCl salt 262° dec.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][N:10]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])[CH2:9][CH2:8][N:7]1[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[CH3:29])=[O:5])C.[Li+].[OH-].CO.OS([O-])(=O)=O.[K+]>O1CCCC1>[Cl:21][C:17]1[CH:16]=[C:15]([S:12]([N:10]2[CH2:9][CH2:8][N:7]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=3[CH3:29])[CH:6]([C:4]([OH:5])=[O:3])[CH2:11]2)(=[O:13])=[O:14])[CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)C1CN(S(=O)(=O)c2cccc(Cl)c2)CCN1c1ccc(F)cc1C
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1N1CCN(S(=O)(=O)c2cccc(Cl)c2)CC1C(=O)O

Procedure:
To a solution of 4-(3-chloro-benzenesulfonyl)-1-(4-fluoro-2-methyl-phenyl)-piperazine-2-carboxylic acid ethyl ester (730 mg) in tetrahydrofuran (20 mL) was added 1 M aqueous LiOH solution (16.6 mL) and methanol until a clear solution was obtained. The mixture was stirred at reflux for 1 h, 1M KHSO4 (20 mL) was added and the inorganic phase was extracted with ethyl acetate. The combined organic phases were dried (Na2SO4), filtered and evaporated to yield 4-(3-chloro-benzenesulfonyl)-1-(4-fluoro-2-methyl-phenyl)-piperazine-2-carboxylic acid as a light yellow solid, MS: 411.0 ([M−H, 1Cl]−).
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C:14]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([Cl:26])[CH:20]=2)[N:16]([CH3:27])[N:15]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:34][C:35]1[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[CH:39][C:36]=1[CH2:37]Cl>O>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C:14]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:37][C:36]3[CH:39]=[CH:40][C:41]([C:43]([F:44])([F:46])[F:45])=[CH:42][C:35]=3[Cl:34])=[C:21]([Cl:26])[CH:20]=2)[N:16]([CH3:27])[N:15]=1
Reactant: FC(F)(F)c1ccc(CCl)c(Cl)c1
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(OCc2ccc(C(F)(F)F)cc2Cl)c(Cl)c1
Temperature: 25 °C
Yield: 72.8 %

Procedure:
To 20 ml of N,N-dimethylformamide are added 3-(2-chloro-6-fluorophenyl)-5(3-chloro-4-hydroxyphenyl)-1-methyl-1H-1,2,4-triazole (0.70 g) and potassium carbonate (0.31 g) and 2-chloro-4-trifluoromethylbenzyl chloride (0.50 g) is added thereto at room temperature with stirring, which is stirred at 120° C. for 5 hours. On completion of the reaction, the reaction solution is cooled to room temperature, poured into water and extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography to give 0.80 g of desired compound (melting point: 156.0°-159.0° C.).
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[C:9]([I:11])[N:8]([CH2:12][C:13]#[CH:14])[C:7](=[O:15])[C:6]=1[CH3:16])[CH2:3][CH3:4].CCN(CC)CC.Br[Si:25]([CH:44]([CH3:46])[CH3:45])([CH:41]([CH3:43])[CH3:42])[CH2:26][CH2:27][C:28]([F:40])([F:39])[C:29]([F:38])([F:37])[C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:44]([Si:25]([CH:41]([CH3:43])[CH3:42])([CH2:26][CH2:27][C:28]([F:40])([F:39])[C:29]([F:37])([F:38])[C:30]([F:35])([F:36])[C:31]([F:32])([F:33])[F:34])[O:1][CH:2]([C:5]1[CH:10]=[C:9]([I:11])[N:8]([CH2:12][C:13]#[CH:14])[C:7](=[O:15])[C:6]=1[CH3:16])[CH2:3][CH3:4])([CH3:45])[CH3:46]
Reactant: C#CCn1c(I)cc(C(O)CC)c(C)c1=O
Reactant: CC(C)[Si](Br)(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCn1c(I)cc(C(CC)O[Si](CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(C(C)C)C(C)C)c(C)c1=O
Reaction time: 12 h
Yield: 83.4 %

Procedure:
To a solution of 4-(1-hydroxypropyl)-6-iodo-3-methyl-1-prop-2-ynyl-1H-pyridin-2-one 4b (44 mg, 0.13 mmol) and 4-dimethylaminopyridine (2 mg, 1.2 μmol) in CH2Cl2 (2 mL) was added NEt3 (53 mg, 74 μL, 0.52 mmol) and bromodiisopropyl(3, 3, 4, 4, 5, 5, 6, 6, 6-nonafluorohexyl)silane (147 mg, 0.33 mmol, prepared by mixing diisopropyl-(3, 3, 4, 4, 5, 5, 6, 6, 6-nonafluorohexyl)silane and Br2) and the mixture was stirred for 12 h. The solvent was evaporated and the residue was purified by flash chromatography (hexanes-EtOAc 15:1) to afford 5b (75 mg, 82%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ6.99 (s, 1H), 5.12 (d, J=16.5, 1H), 5.00 (d, J=16.5, 1H), 4.75 (t, J=6.0 Hz, 1H), 2.33-2.31 (m, 1H), 2.07-1.99 (m, 2H) 2.06 (s, 3H), 1.84-1.60 (m, 2H), 1.00 (s, 14H), 0.88 (t, J=7.4 Hz, 3H), 0.83-0.79 (m, 2H); 13C NMR (75 MHz, CDCl3) δ162.4, 152.5, 123.7, 118.6, 94.2, 72.8, 71.5, 44.3, 31.1, 25.3, 17.5, 12.6, 9.4, 0.3.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:4][N:3]1[P:5](Cl)([N:7]1[CH2:9][C:8]1([CH3:11])[CH3:10])=[O:6].[CH3:14][NH2:15]>C1COCC1>[CH3:1][C:2]1([CH3:13])[CH2:4][N:3]1[P:5]([N:7]1[CH2:9][C:8]1([CH3:11])[CH3:10])(=[O:6])[NH:15][CH3:14]
Reactant: CC1(C)CN1P(=O)(Cl)N1CC1(C)C
Reactant: CN
Solvent: C1CCOC1
Product: CNP(=O)(N1CC1(C)C)N1CC1(C)C
Temperature: -15 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
A solution comprising 0.025 moles of P,P-bis(2,2-dimethyl-1-aziridinyl)phosphinoyl chloride in about 170 milliliters of THF, prepared in accordance with Example 1, was cooled to -15° C. and a saturated excess of gaseous methylamine was introduced to the solution through a bubbler tube in accord with the process of Example 2. The vessel and contents were warmed to about 4° C. and the saturated solution was allowed to sit overnight without stirring at that temperature. The resulting slurry was filtered and the filtrate was concentrated by rotary evaporation at room temperature. The thus concentrated filtrate was vacuum distilled at 94° C. and 0.14 millimeters of mercury providing a 75% yield of P,P-bis(2,2-dimethyl-1-aziridinyl)-N-methylphosphinic amide. NMR and aziridinyl titration characterization of the product indicated a purity of 98.4%.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][NH:12][C:13]([NH:15][NH2:16])=[O:14].C(=O)(O)[O-].[Na+]>C(O)C>[C:1]1([S:7]([NH:11][NH:12][C:13]([NH:15][NH:16][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNC(=O)NN
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=C(NNS(=O)(=O)c1ccccc1)NNS(=O)(=O)c1ccccc1
Reaction time: 0.17 h

Procedure:
175.6 g (1.0 mole) of benzenesulfonyl chloride was added to a stirred mixture of 45 g (0.5 mole) carbohydrazide and 100 g sodium bicarbonate in 1000 ml ethanol in a 3 liter 3 neck flask. The mixture was heated to gentle reflux for six hours. The cooled mixture was filtered and the solid precipitate (containing the desired product along with sodium chloride) was washed with ethanol and dried. Yield: 207 g. This mixture was then suspended in water and stirred for 10 minutes. The insoluble solid was filtered off and washed well with water and dried. Yield: 120.5 g, m.p. 227° C (dec.)