Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[P:10]([O:17]CC)([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]>CCOC(C)=O>[I:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]
Reactant: CCOP(OCC)OCC
Reactant: BrCc1ccccc1I
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1ccccc1I)OCC
Temperature: 160 °C
Reaction time: 4 h
Yield: 38.6 %

Procedure:
A mixture of 2-iodobenzyl bromide 10 (5 g, 16.84 mmol) and triethyl phosphite (3.3 g, 20 mmol) was stirred at 160° C. After 4 h, the mixture was cooled to room temperature. The residue was subjected to flash chromatography (EtOAc: Hex, 1:4), and gave 2.3 g of 11 (39%). 1H NMR (200 MHz, CDCl3): δ1.24 (t, J=7.04 Hz, 6H), 3.40 (d, J=22.00 Hz, 2H), 4.03 (m, 4H), 6.91 (m, 1H), 7.32 (m, 1H), 7.44 (m, 1H), 7.82 (m, 1H); 13C NMR (50 MHz, CDCl3): δ 16.27 (J=6.00 Hz), 38.31 (J=137.50 Hz), 62.16 (J=6.70 Hz), 101.16 (J=9.45 Hz), 128.23 (J=3.35 Hz), 128.45 (J=3.55 Hz), 130.60 (J=5.10 Hz), 135.36 (J=8.80 Hz), 139.60 (J=2.85 Hz).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](O)=[O:41])=[CH:33][CH:32]=2)=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.[NH2:46][C:47]([CH3:51])([CH3:50])[CH2:48][OH:49].NC(C)(C)C(N)=O>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](=[O:41])[NH:46][C:47]([CH3:51])([CH3:50])[CH2:48][OH:49])=[CH:33][CH:32]=3)=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(C)(N)CO
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCC(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(C)(N)C(N)=O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(OCCC(=O)NC(C)(C)CO)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 78 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)phenyl]-methyl}-5-isopropyl-1H-pyrazole and 2-amino-2-methyl-1-propanol instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]-methyl}-5-isopropyl-1H-pyrazole and 2-amino-2-methyl-propionamide, respectively.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[S:32](Cl)([CH3:35])(=[O:34])=[O:33]>ClCCl>[CH3:1][N:2]([CH2:3][C:4]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[S:32]([CH3:35])(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: CNCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1)S(C)(=O)=O
Reaction time: 8 h
Yield: 71 %

Procedure:
To a stirred solution of methyl-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-ylmethyl}amine (200 mg, 0.60 mmol) and triethylamine (102 μL, 0.72 mmol) in anhydrous dichloromethane (8 mL) under nitrogen atmosphere was added dropwise a solution of mesyl chloride (56 μL, 0.72 mmol) in anhydrous dichloromethane (2 mL). After stirring overnight, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3. The organic layer was separated, washed with water then dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (175 mg, 71%). 1H NMR (400 MHz, CDCl3) δ 7.22 (d, 2H), 6.92-6.90 (d, 2H), 4.03 (t, 2H), 3.83-3.78 (m, 2H), 3.52 (t, 2H), 3.16 (s, 2H), 2.68 (s, 3H), 2.64 (t, 2H), 2.54 (m, 4H), 2.19-2.15 (m, 5H), 2.05-1.91 (m, 4H), 1.81-1.78 (m, 4H).
Reaction SMILES: [C:1]([C:3]1[CH:8]([C:9]2[O:17][C:16]3[CH:15]=[CH:14][N:13]=[C:12]([NH:18][C:19](=[O:26])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:11]=3[CH:10]=2)[C:7]([C:27]#[N:28])=[C:6]([CH3:29])[NH:5][C:4]=1[CH3:30])#[N:2].[C:31](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[C:27]([C:7]1[CH:8]([C:9]2[O:17][C:16]3[CH:15]=[CH:14][N:13]=[C:12]([NH:18][C:19](=[O:26])[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:11]=3[CH:10]=2)[C:3]([C:1]#[N:2])=[C:4]([CH3:30])[N:5]([CH3:31])[C:6]=1[CH3:29])#[N:28]
Reactant: CC1=C(C#N)C(c2cc3c(NC(=O)c4ccccc4)nccc3o2)C(C#N)=C(C)N1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC1=C(C#N)C(c2cc3c(NC(=O)c4ccccc4)nccc3o2)C(C#N)=C(C)N1C
Reaction time: 0.5 h

Procedure:
A solution of 100 mg (0.253 mmol) N-[2-(3,5-dicyano-2,6-dimethyl-1,4-dihydropyridin-4-yl)furo-[3,2-c]pyridin-4-yl]benzamide (Example 4) in DMF (1.4 ml) was cooled to 0° C., and 99 mg (0.30 mmol) caesium carbonate were added at this temperature. After stirring for 30 min, 19 μl (0.30 mmol) methyl iodide were added dropwise at room temperature, and the mixture was stirred at rt overnight. After this, additional methyl iodide (20 μL) was added, and stirring at rt was continued for further 48 h. The reaction mixture was then filtered, and the filtrate was directly purified by preparative RP-HPLC (acetonitrile/water+0.1% TFA, isocratic 40:60 v/v) to give 5.6 mg (5% of th.) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C(N1CCN(C2C=C(N[C:30]([C:32]3[C:33]4[N:34]=[CH:35][CH:36]=[N:37][C:38]=4[C:39]([C:42]4[C:51]5[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=5)[CH:45]=[N:44][CH:43]=4)=[CH:40][CH:41]=3)=[O:31])C=CC=2)CC1)C>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([NH:14][C:30]([C:32]3[C:33]4[N:34]=[CH:35][CH:36]=[N:37][C:38]=4[C:39]([C:42]4[C:51]5[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=5)[CH:45]=[N:44][CH:43]=4)=[CH:40][CH:41]=3)=[O:31])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccc(N)cn2)CC1
Reactant: CCN1CCN(c2cccc(NC(=O)c3ccc(-c4cncc5ccccc45)c4nccnc34)c2)CC1
Product: CN1CCN(c2ccc(NC(=O)c3ccc(-c4cncc5ccccc45)c4nccnc34)cn2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but stirring the reaction mixture for 20 h at rt and using 6-(4-methylpiperazin-1-yl)-pyridin-3-ylamine (prepared as described in Example 33 but using N-methyl-piperazine in Step 33.2) and 8-isoquinolin-4-yl-quinoxaline-5-carboxylic acid (Example 52). Title compound: ESI-MS: 476.1 [M+H]+; tR=1.98 min (System 1).
Reaction SMILES: O.Cl.[C:3]([NH2:11])(=[NH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Na].[CH3:13][O:14][C:15](=[O:24])[C:16]([CH:19](OC)OC)=[CH:17]O.O>CN(C=O)C>[CH3:13][O:14][C:15]([C:16]1[CH:17]=[N:10][C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[N:11][CH:19]=1)=[O:24]
Reactant: N=C(N)c1ccccc1
Reactant: COC(=O)C(=CO)C(OC)OC
Agent: Cl
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cnc(-c2ccccc2)nc1
Temperature: 100 °C
Yield: 74.7 %

Procedure:
To a solution of benzamidine hydrochloride hydrate (2 mmol) in anhydrous DMF (4 mL) is added sodium salt of 2-dimethoxymethyl-3-hydroxy-acrylicacid methyl ester (0.46 g, 2.32 mmol) and the reaction mixture heated at 100° C. under N2 for 1 hour. The reaction is cooled to rt and water (15 mL) is added. After addition of water, immediate precipitation of the product is observed. The solids are collected by filtration, washed with water (2.5 mL) and vacuum dried to yield 2-phenyl-pyrimidine-5-carboxylic acid methyl ester (0.32 g, 74%). (see: P. Zhichkin, D. J. Fairfax, S. A. Eisenbeis, Synthesis, 2002, 720-722.)
Reaction SMILES: CS([C:5]1[N:6]=[C:7]([O:34][CH3:35])[C:8]2[N:13]=[C:12]([NH:14][C:15]([N:17]3[CH2:22][CH2:21][C:20]([OH:33])([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)[CH2:19][CH2:18]3)=[O:16])[S:11][C:9]=2[N:10]=1)(=O)=O.[OH-:36].[K+]>C1COCC1.O>[OH:36][C:5]1[N:6]=[C:7]([O:34][CH3:35])[C:8]2[N:13]=[C:12]([NH:14][C:15]([N:17]3[CH2:22][CH2:21][C:20]([OH:33])([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)[CH2:19][CH2:18]3)=[O:16])[S:11][C:9]=2[N:10]=1
Reactant: COc1nc(S(C)(=O)=O)nc2sc(NC(=O)N3CCC(O)(c4cccc(C(F)(F)F)c4)CC3)nc12
Reactant: [OH-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1nc(O)nc2sc(NC(=O)N3CCC(O)(c4cccc(C(F)(F)F)c4)CC3)nc12
Temperature: 75 °C
Reaction time: 4 h
Yield: 14.5 %

Procedure:
A magnetically stirred mixture of 4-hydroxy-4-[3-(trifluoromethy)phenyl]piperidine-1-carboxylic acid (5-methanesulfonyl-7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-amide (250 mg, 0.47 mmol) in THF (10 mL) and water (5 mL) was treated with a 2N aqueous KOH solution (0.5 mL, 0.94 mmol). The reaction mixture was stirred at 75° C. for 4 h. The reaction was then cooled to room temperature and poured into water and extracted with methylene chloride. The organics were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo to afford 4-hydroxy-4-[3-(trifluoromethy)phenyl]piperidine-1-carboxylic acid (5-hydroxy-7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-amide (32 mg, 15%) as a white solid. LRMS for C19H18F3N5O4S2 (M+H)+ at m/z=469. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [CH:1]1([O:4][N:5]=[C:6]([C:38]2[N:39]=[C:40]([NH:43][CH:44]=[O:45])[S:41][CH:42]=2)[C:7]([NH:9][C@@H:10]2[C:36](=[O:37])[N:12]3[C:13]([C:20]([O:22][CH:23]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:21])=[C:14]([CH2:18]Cl)[CH2:15][S:16](=[O:17])[C@H:11]23)=[O:8])[CH2:3][CH2:2]1.[I-:46].[Na+].[C:48]([NH2:56])(=[O:55])[C:49]1[CH:54]=[CH:53][N:52]=[CH:51][CH:50]=1.C(OC(C)C)(C)C>CN(C)C=O>[I-:46].[CH:1]1([O:4][N:5]=[C:6]([C:38]2[N:39]=[C:40]([NH:43][CH:44]=[O:45])[S:41][CH:42]=2)[C:7]([NH:9][C@@H:10]2[C:36](=[O:37])[N:12]3[C:13]([C:20]([O:22][CH:23]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:21])=[C:14]([CH2:18][N+:52]4[CH:53]=[CH:54][C:49]([C:48](=[O:55])[NH2:56])=[CH:50][CH:51]=4)[CH2:15][S:16](=[O:17])[C@H:11]23)=[O:8])[CH2:3][CH2:2]1
Reactant: NC(=O)c1ccncc1
Reactant: O=CNc1nc(C(=NOC2CC2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CCl)CS(=O)[C@H]23)cs1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1cc[n+](CC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)C(=NOC4CC4)c4csc(NC=O)n4)[C@H]3S(=O)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of benzhydryl 7β-[2-cyclopropyloxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-chloromethyl-3-cephem-4-carboxylate 1-oxide (syn isomer) (2.5 g) and sodium iodide (3.4 g) in N,N-dimethylformamide (20 ml) was stirred at ambient temperature for 30 minutes. To the mixture was added isonicotinamide (0.91 g) under ice-cooling and the mixture was stirred for 2 hours at the same temperature. The mixture was poured into diisopropyl ether to give an oil. The oil was separated by decantation and triturated with water. The solid was dissolved in tetrahydrofuran, dried over magnesium sulfate, concentrated under reduced pressue, and triturated in diisopropyl ether to give benzhydryl 7β-[2-cyclopropyloxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(4-carbamoyl-1-pyridinio)methyl-3-cephem-4-carboxylate 1-oxide iodide (syn isomer) as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:11])=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[CH3:12][C:13]([CH3:18])([CH3:17])[C:14](Cl)=[O:15]>>[NH2:1][C:2]1[C:3]([F:11])=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH:6][C:14](=[O:15])[C:13]([CH3:18])([CH3:17])[CH3:12]
Reactant: NCc1ccc(Cl)c(N)c1F
Reactant: CC(C)(C)C(=O)Cl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(N)c1F
Yield: 36 %

Procedure:
The sub-title compound is prepared from crude 3-amino-4-chloro-2-fluoro-benzylamine, 2,2-dimethyl-propionic acid chloride and TEA in analogy to step Ae.
Reaction SMILES: [CH2:1]([C@@H:8]([C@@H:13]([OH:15])[CH3:14])[C:9](OC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:17][NH2:18]>CC(O)C>[CH2:1]([C@@H:8]([C@@H:13]([OH:15])[CH3:14])[C:9]([NH:17][NH2:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: COC(=O)[C@@H](Cc1ccccc1)[C@H](C)O
Solvent: O
Solvent: CC(C)O
Product: C[C@H](O)[C@H](Cc1ccccc1)C(=O)NN
Reaction time: 8 h
Yield: 64.3 %

Procedure:
A 0.70 g (3.36 mmol) of methyl (2S,3S)-2-benzyl-3-hydroxybutyrate (optical purity: 96%e.e.; anti/syn=98/2) was dissolved in 1 ml of 2-propanol, and 0.34 g (6.72 mmol) of hydrazine monohydrate was added thereto dropwise at room temperature. After the addition, the mixture was refluxed for 8 hours, and then stirred overnight to obtain a concentrate. The obtained concentrate was crystallized by using a mixed solvent of ethyl acetate and hexane to give 0.45 g (64%) of the title compound. Melting point: 167.1° C. Optical purity: >99.9%e.e. anti/syn>99/1
Reaction SMILES: [F:1]/[C:2](=[CH:8]\[CH3:9])/[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:10][CH2:9]/[CH:8]=[C:2](\[F:1])/[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: C/C=C(\F)C(=O)OCC
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)/C(F)=C/CBr
Yield: 79.3 %

Procedure:
Ethyl 2-fluorocrotonate (6.0 g) (prepared according to E. D. Bergmann and I. Shahak, J.Chem.Soc., 4033, 1961) N-bromosuccinimide (8.1 g) and benzoyl peroxide (0.15 g) was dissolved in carbon tetrachloride (120 ml) and heated at reflux for 3-5 hours. The mixture was cooled, filtered and the filtrate evaporated to dryness under reduced pressure. Chromatography on silica eluting with 10% diethyl ether: hexane gave ethyl 4-bromo-2-fluorocrotonate as a yellow oil (7.6 g). NMR 1H: 1.5(3H,t), 4.1(2H,dd), 4.4(2H,q), 6.4(1H,dt).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:72])=[N:14][C:15]2[N:16]([N:50]=[C:51]([CH:53]=[CH:54][CH2:55][C:56]3[CH:61]=[CH:60][C:59]([F:62])=[CH:58][C:57]=3B3OC(C)(C)C(C)(C)O3)[CH:52]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([O:32][Si:33]([C:46]([CH3:49])([CH3:48])[CH3:47])([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH3:31])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH:73]OS([O-])=O.[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CC(C)=O.O>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:72])=[N:14][C:15]2[N:16]([N:50]=[C:51]([CH:53]=[CH:54][CH2:55][C:56]3[CH:61]=[CH:60][C:59]([F:62])=[CH:58][C:57]=3[OH:73])[CH:52]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([O:32][Si:33]([C:46]([CH3:48])([CH3:49])[CH3:47])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH3:31])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: O=S([O-])OO
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C=CCc3ccc(F)cc3B3OC(C)(C)C(C)(C)O3)nn2c1N1CCC(C)(OCCCC[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Agent: O=S([O-])([O-])=S
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C=CCc3ccc(F)cc3O)nn2c1N1CCC(C)(OCCCC[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
To a solution of (S)-ethyl 2-(tert-butoxy)-2-(7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-2-(3-(4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)prop-1-en-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (450 mg, 0.449 mmol) in Acetone (6 mL) was added solution of oxone (276 mg, 0.449 mmol) in water (6 mL) and the resulting mixture was stirred at room temp for 1 h. Sat. sodium thiosulfate was then added and the mixture was extracted with ethyl acetate, dried (Na2SO4), filtered and concentrated to afford (S)-ethyl 2-(tert-butoxy)-2-(7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-2-(3-(4-fluoro-2-hydroxyphenyl)prop-1-en-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (370 mg, 0.414 mmol, 92% yield) as viscous oil. Product is a mixture of isomers LCMS (M+H)=893.4. Used as is in the next reaction without further purification.
Reaction SMILES: Cl.[NH:2]([C:4]1[N:9]=[C:8]([NH2:10])[N:7]=[C:6]([NH2:11])[C:5]=1[N:12]=O)[NH2:3].C(O[CH:17](OCC)[CH2:18][Cl:19])C>CN(C=O)C>[Cl:19][CH2:18][C:17]1[N:3]=[N:2][C:4]2[C:5](=[C:6]([NH2:11])[N:7]=[C:8]([NH2:10])[N:9]=2)[N:12]=1
Reactant: NNc1nc(N)nc(N)c1N=O
Reactant: CCOC(CCl)OCC
Agent: Cl
Solvent: CN(C)C=O
Product: Nc1nc(N)c2nc(CCl)nnc2n1
Temperature: 85 °C
Reaction time: 0.08 h

Procedure:
Concentrated HCl (14 mL) was added to stirred ice cooled DMF (350 mL) followed by 7.14 g of 6-Hydrazino-5-nitroso-pyrimidine-2,4-diamine. After 5 min., chloroacetaldehyde diethylacetal (15.4 mL) was added over a ca. 2 min. period. The cooling bath was removed and the mixture allowed to come to room temperature. After 1 h, the mixture was warmed to 85° C. for 1.5 h and then allowed to cool to room temp over a 2.5 h period. The mixture was filtered to remove a small amount of brown insoluble material, the filtrate made alkaline with concentrated NH4OH solution and then diluted with an equal volume of water. The mixture was set aside for 1 h and then filtered to collect the orange/brown solid which was further dried in vacuo over P2O5 to give 3.50 g of 3-Chloromethyl-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine 3.
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[S:32][CH:33]=[CH:34][CH:35]=4)[CH2:28][CH2:27][C:26]([C:36]([OH:38])=O)=[CH:25][C:24]=3[CH:39]=2)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH3:9].S(Cl)(Cl)=O>O1CCCC1>[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:39]=[CH:24][C:23]3[N:29]([CH2:30][C:31]4[S:32][CH:33]=[CH:34][CH:35]=4)[CH2:28][CH2:27][C:26]([C:36]([NH:29][C:23]4[CH:24]=[CH:39][C:20]([CH2:4][N:2]([CH3:1])[CH:3]5[CH2:12][CH2:11][O:10][CH2:6][CH2:7]5)=[CH:21][CH:22]=4)=[O:38])=[CH:25][C:22]=3[CH:21]=2)=[CH:18][CH:19]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CN(C)C=O
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2cccs2)cc1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2cccs2)cc1
Reaction time: 1 h

Procedure:
One droplet of DMF was added to a solution of 7-(4-butoxyethoxyphenyl)-1-(2-thienylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (110 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (82 mg) was added at 0° C., the temperature was returned to room temperature, and the mixture was stirred under nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were evaporated under reduced pressure, the resulting residue was suspended in tetrahydrofuran (20 ml), and the suspension was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (61 mg) and triethylamine (279 mg) in tetrahydrofuran (10 ml) at 0° C. The suspension was stirred under nitrogen atmosphere at room temperature for 3 hours, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:8), which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-(2-thienylmethyl)-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 60) (86 mg) as yellow crystals.
Reaction SMILES: [OH:1][CH:2]([PH:4](=[O:6])[OH:5])[CH3:3].[CH2:7](O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>C1C=CC=CC=1>[OH:1][CH:2]([PH:4](=[O:5])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:3]
Reactant: CC(O)[PH](=O)O
Reactant: OCc1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: CC(O)[PH](=O)OCc1ccccc1
Yield: 87.2 %

Procedure:
A solution of α-hydroxyethylphosphinic acid (5.5 g) and benzyl alcohol (2.26 g) in benzene (50 ml) was heated for 8 hours with removal of water through a Dean-Stark apparatus. After cooling, the reaction mixture was washed with water, dried over magnesium sulfate and concentrated in vacuo to give 3.65 g (91.2%) of benzyl α-hydroxyethylphosphinate (Compound No. 36).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]([OH:45])([C:21]3[N:22]=[CH:23][N:24](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:25]=3)[CH:18]([CH3:20])[CH3:19])[CH:13]=2)[CH:8]=1)(=O)=O.C([Sn](CCCC)(CCCC)[C:53]1[S:54][CH:55]=[CH:56][CH:57]=1)CCC>>[NH:24]1[CH:25]=[C:21]([C:17]([C:12]2[CH:11]=[CH:10][C:9]3[C:14](=[CH:15][CH:16]=[C:7]([C:53]4[S:54][CH:55]=[CH:56][CH:57]=4)[CH:8]=3)[CH:13]=2)([OH:45])[CH:18]([CH3:20])[CH3:19])[N:22]=[CH:23]1
Reactant: CC(C)C(O)(c1ccc2cc(OS(=O)(=O)C(F)(F)F)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Product: CC(C)C(O)(c1ccc2cc(-c3cccs3)ccc2c1)c1c[nH]cn1

Procedure:
In a similar manner to that described in Example 2-(i), the reaction was carried out by using 6-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-2-naphthyl trifluoromethanesulfonate (2.0 g) and 2-(tributylstannyl)thiophene (1.27 mL) to give the titled compound (1.43 g) as a colorless powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([N:18]3[CH2:22][CH:21]([OH:23])[CH:20]([NH2:24])[CH2:19]3)=[C:12]([F:17])[CH:13]=2)[N:8]([CH2:25][CH2:26][C:27]#[N:28])[CH:7]=1)=[O:5])[CH3:2].[CH:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([N:18]3[CH2:22][CH:21]([OH:23])[CH:20]([NH:24][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:19]3)=[C:12]([F:17])[CH:13]=2)[N:8]([CH2:25][CH2:26][C:27]#[N:28])[CH:7]=1)=[O:5])[CH3:2]
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)c1cn(CCC#N)c2nc(N3CC(N)C(O)C3)c(F)cc2c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)c1cn(CCC#N)c2nc(N3CC(O)C(NCc4ccccc4)C3)c(F)cc2c1=O
Reaction time: 18 h

Procedure:
A solution of EXAMPLE 199A (0.12 g) and benzaldehyde (0.063 mL) in methanol (10 mL) and acetic acid (2 drops) was stirred for 30 minutes at 25° C., treated with sodium triacetoxyborohydride (0.196 g), stirred for 18 hours, and concentrated; and the concentrate chromatographed on silica gel with 5% methanol/dichloromethane.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9]([CH3:11])=O>>[CH:9]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:11])[CH3:8]
Reactant: Nc1ccccc1
Reactant: CC(C)=O
Product: CC(C)Nc1ccccc1

Procedure:
N-Isopropylaniline [NMR (200 MHz, DMSO-d6): δ1.13 (d, J=6.3 Hz, 6H); 3.58 (m, 1H); 5.30 (d, J=8.0 Hz, 1H); 6.49 (t, J=7.2 Hz, 1H); 6.55 (d, J=7.8 Hz, 2H); 7.06 (t, J=7,6 Hz, 2H)] was prepared from aniline and acetone via reductive amination using the general method described by Schellenberg (Schellenberg, K. A. J. Org. Chem. 1963, 28, 3259).