Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].[C:2]1([S:8]([C:11]2[C:12]([S:25][CH3:26])=[N:13][N:14]3[C:19](Cl)=[CH:18][C:17]([CH2:21][N:22]([CH3:24])[CH3:23])=[N:16][C:15]=23)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.CN(C=O)C>[C:2]1([S:8]([C:11]2[C:12]([S:25][CH3:26])=[N:13][N:14]3[C:19]([NH2:1])=[CH:18][C:17]([CH2:21][N:22]([CH3:24])[CH3:23])=[N:16][C:15]=23)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: CSc1nn2c(Cl)cc(CN(C)C)nc2c1S(=O)(=O)c1ccccc1
Solvent: CO
Solvent: CN(C)C=O
Product: CSc1nn2c(N)cc(CN(C)C)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
20 ml of a 50% solution of NH3 in MeOH were added to a solution of 1.20 g (3 mmol) of (3-benzenesulphonyl-7-chloro-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-5-ylmethyl)-dimethyl-amine in 30 ml of DMF and stirred at RT for 4 hrs. The reaction solution was evaporated and the residue was partitioned between 2N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2, and the combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (silica gel, CH2Cl2/MeOH 6:1) yielded 0.90 g (78%) of 3-benzenesulphonyl-5-dimethylaminomethyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ylamine as colorless crystals, m.p. 216-218°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][C:2]=1[CH3:10].[C:11]([C:13]1([NH:16][C:17]([C@@H:19]2[CH2:23][C@@H:22]([S:24]([C:27]3[CH:32]=[CH:31][C:30](Br)=[CH:29][C:28]=3[C:34]([F:37])([F:36])[F:35])(=[O:26])=[O:25])[CH2:21][C@H:20]2[O:38][CH3:39])=[O:18])[CH2:15][CH2:14]1)#[N:12].C(C1(NC([C@H]2C[C@H](S(C3C=CC(Br)=CC=3C(F)(F)F)(=O)=O)C[C@@H]2OC)=O)CC1)#N>>[C:11]([C:13]1([NH:16][C:17]([C@@H:19]2[CH2:23][C@@H:22]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([C:4]4[CH:5]=[CH:6][N:1]=[C:2]([CH3:10])[CH:3]=4)=[CH:29][C:28]=3[C:34]([F:35])([F:36])[F:37])(=[O:25])=[O:26])[CH2:21][C@H:20]2[O:38][CH3:39])=[O:18])[CH2:14][CH2:15]1)#[N:12]
Reactant: Cc1cc(B(O)O)ccn1
Reactant: CO[C@@H]1C[C@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)C[C@H]1C(=O)NC1(C#N)CC1
Agent: CO[C@H]1C[C@@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)C[C@@H]1C(=O)NC1(C#N)CC1
Product: CO[C@@H]1C[C@H](S(=O)(=O)c2ccc(-c3ccnc(C)c3)cc2C(F)(F)F)C[C@H]1C(=O)NC1(C#N)CC1

Procedure:
The title compound was prepared in analogy to example 62 using 2-picoline-4-boronic acid instead of 2.4-difluorophenylboronic acid and (1R,2R,4R)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-methoxy-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (example 137) instead of (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-methoxy-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide. Pink solid. MS (EI): 508.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:20]=2[NH:19][C:18]1=[O:29]>>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([NH:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:20]=2[NH:19][C:18]1=[O:29])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NC1CCc2ccc(Cl)cc2NC1=O
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Product: CC(C)(CC(=O)NC1CCc2ccc(Cl)cc2NC1=O)NC(=O)OC(C)(C)C

Procedure:
Prepared from 3-t-butoxycarbonylamino-3-methylbutanoic acid (Example 31, Step E) and the amine obtained in Step F by the procedure described in Example 1, Step F. 1H NMR (300MHz, CDCl3): 1.35 (s,6H), 1.42 (s,9H), 1.95 (m,1H), 2.4-2.8 (m,5H), 4.51 (m,1H), 5.22 (br s,1H), 6.73 (d,7Hz,1H), 7.02 (s,1H), 7.14 (br s,2H), 8.21 (br s,1H). FAB-MS: calculated for C20H28C1N3O4 409; found 410 (M+H,55%).
Reaction SMILES: C([O:8][C:9](=[O:29])[CH:10]([NH:25][C:26](=[O:28])[CH3:27])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:14][CH:13]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[C:26]([NH:25][CH:10]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:16][CH:17]=1)[C:9]([OH:29])=[O:8])(=[O:28])[CH3:27]
Reactant: CC(=O)NC(Cc1ccc(C(=O)OC(C)(C)C)cc1)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(=O)NC(Cc1ccc(C(=O)OC(C)(C)C)cc1)C(=O)O
Yield: 89 %

Procedure:
A suspension of rac.-2-acetamido-3-[4-((1,1-dimethylethoxy)carbonyl]phenyl]propanoic acid benzyl ester (3.3 g, 8 mmol) and 10% Pd/C (320 mg) in ethanol (100 mL) was blanketed with hydrogen (1 atm) at room temperature. Upon the consumption of 1 equivalent of hydrogen, the mixture was filtered through celite. The celite pad was washed with ethanol (50 mL) and the filtrates were combined and concentrated. The resultant solid was purified by recrystallization from ethyl acetate/hexane to give rac.-2-acetamido-3-[4-[(1,1-dimethylethoxy)carbonyl]phenyl]propanoic acid, (2.3 g. 7.4 mmol) in 89% yield, mp. 187°-188° C.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][SH:11].[ClH:12].[C:13]([NH:15][C:16](=[N:19][CH3:20])SC)#[N:14]>N1C=CC=CC=1.O>[ClH:12].[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][S:11][C:16](=[N:19][CH3:20])[NH:15][C:13]#[N:14]
Reactant: Cc1[nH]cnc1CSCCS
Reactant: CN=C(NC#N)SC
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CN=C(NC#N)SCCSCc1nc[nH]c1C

Procedure:
2-(5-Methyl-4-imidazolylmethylthio)ethanethiol (4.0 g) (prepared from the hydrochloride as in Example 1(b) and N-cyano-N', S-dimethylisothiourea (4.0 g) were heated together under nitrogen in pyridine (100 ml) at 100° for 20 hours. After this time the mixture was evaporated to dryness to give the crude title product. This residue taken up in water acidified to pH2 with concentrated hydrochloric acid. After extracting with ethyl acetate the volume of the aqueous fraction was reduced and on cooling gave S-[2-(5-methyl-4-imidazolylmethylthio)-ethyl]-N-cyano-N'-methylisothiourea hydrochloride, m.p. 225°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([N:15]([CH2:25][CH3:26])CC3C=CC(OC)=CC=3)[C:12]3=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:11]3[N:10]=2)=[CH:6][C:5]([C:32]#[N:33])=[CH:4][C:3]=1[N:34]1[CH2:39][CH2:38][C@@H:37]([NH:40][C:41](=[O:44])[O:42][CH3:43])[C@H:36]([OH:45])[CH2:35]1.C([O:53][P:54]([O:64][CH:65]([CH3:69])[C:66](O)=[O:67])([O:56]CC1C=CC=CC=1)=[O:55])C1C=CC=CC=1.C1CCC(N=C=NC2CCCCC2)CC1.ClC1C(NC2N=C(N(CC)CC3C=CC(OC)=CC=3)C3=NC=C(C#N)N3N=2)=CC(C#N)=CC=1N1CC[C@@H](NC(OC)=O)[C@H](C(OP(OCC2C=CC=CC=2)(OCC2C=CC=CC=2)=O)(C)C([O-])=O)C1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[P:54]([O:64][CH:65]([CH3:69])[C:66]([O:45][C@H:36]1[C@H:37]([NH:40][C:41]([O:42][CH3:43])=[O:44])[CH2:38][CH2:39][N:34]([C:3]2[CH:4]=[C:5]([C:32]#[N:33])[CH:6]=[C:7]([NH:8][C:9]3[N:14]=[C:13]([NH:15][CH2:25][CH3:26])[C:12]4=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:11]4[N:10]=3)[C:2]=2[Cl:1])[CH2:35]1)=[O:67])([OH:56])([OH:55])=[O:53]
Reactant: CC(OP(=O)(OCc1ccccc1)OCc1ccccc1)C(=O)O
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC(=O)OC)[C@H](O)C3)c2Cl)nn2c(C#N)cnc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN(Cc1ccc(OC)cc1)c1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC(=O)OC)[C@H](C(C)(OP(=O)(OCc4ccccc4)OCc4ccccc4)C(=O)[O-])C3)c2Cl)nn2c(C#N)cnc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC(=O)OC)[C@H](OC(=O)C(C)OP(=O)(O)O)C3)c2Cl)nn2c(C#N)cnc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl ((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate (0.040 g, 0.063 mmol), 2-((bis(benzyloxy)phosphoryl)oxy)propanoic acid (0.067 g, 0.19 mmol) in DCM (2 mL) was added DCC (0.039 g, 0.190 mmol) followed DMAP (0.77 mg, 0.006 mmol) and stirred at room temperature for 30 min. After completion of starting material (by LC-MS), reaction mixture was diluted with DCM (50 mL), filtered through celite and filtrate was washed with water and brine solution (5 mL). Combined organic extracts were dried over anhydrous Na2SO4, concentrated and purified by flash chromatography on silica gel using an ISCO system (eluted with 1:1 Hexanes and EtOAc) to give diastereomeric mixture of (3R,4R) 1-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4((methoxycarbonyl)amino)piperidin-3-yl-2-((bis(benzyloxy)phosphoryl)oxy)propanoate (0.060 g) as gummy liquid.
Reaction SMILES: [CH2:1]([N:5]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[S:6]([C:9]1[C:14]([F:15])=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:10]=1[F:19])(=[O:8])=[O:7])[CH2:2][CH:3]=[CH2:4].O.B(O[O-])=[O:30].[Na+]>C1COCC1>[OH:30][CH2:4][CH2:3][CH2:2][CH2:1][N:5]([C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[S:6]([C:9]1[C:10]([F:19])=[C:11]([F:18])[C:12]([F:17])=[C:13]([F:16])[C:14]=1[F:15])(=[O:7])=[O:8]
Reactant: C=CCCN(c1ccc(OC)cc1)S(=O)(=O)c1c(F)c(F)c(F)c(F)c1F
Reactant: O=BO[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(N(CCCCO)S(=O)(=O)c2c(F)c(F)c(F)c(F)c2F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
To a solution of 1-(N-(3-butenyl)pentafluorophenylsulfonamido)-4-methoxybenzene (410 mg, 1.01 mmol) in THF (6.5 mL) at −78° C. was added BH3. THF (1.00 mL of a 1 M solution in THF, 1.00 mmol). After stirring at −78° C. for 1 h and at 0° C. for 1 h, the reaction mixture was treated with H2O (20 ml) and sodium perborate (513 mg, 5.14 mmol). After stirring at rt for 2 h, the mixture was poured onto H2O (20 mL) and extracted with CH2Cl2 (3×15 mL). The combined organic extracts were washed with sat. NaCl (20 mL) and dried (MgSO4). Concentration followed by chromatography (2:1/hexanes:EtOAc) afforded 270 mg (64%) of product as a white solid, mp 88–90° C. 1H NMR (CDCl3): d 7.08 (m, 2H), 6.85 (m, 2H), 3.80 (s, 3H), 3.77 (m, 2H), 3.64 (t, J=6.0; 2H), 1.63–1.55 (m, 5H), 1.50 (bs, 1H). Anal. Calcd. for C17H16F5NO4S: C, 48.00; H, 3.79; N, 3.29; S, 7.54. Found: C, 48.08; H, 3.76; N, 3.34; S, 7.46.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.C(N(C(C)C)CC)(C)C.[F:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[N:29]=[C:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:27]([CH2:37][NH2:38])=[CH:26]2>C(O)CCC>[F:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[N:29]=[C:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:27]([CH2:37][NH:38][C:2]1[N:10]=[CH:9][N:8]=[C:7]3[C:3]=1[N:4]=[CH:5][NH:6]3)=[CH:26]2
Reactant: Brc1ncnc2nc[nH]c12
Reactant: NCc1cc2cccc(F)c2nc1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Fc1cccc2cc(CNc3ncnc4[nH]cnc34)c(-c3ccccc3)nc12
Temperature: 110 °C

Procedure:
To a reaction flask was added 6-bromopurine (19 mg, 95 μmol, 1.2 eq), diisopropylethylamine (42 μl, 238 μmol, 3 eq), (8-fluoro-2-phenylquinolin-3-yl)-methanamine (20 mg, 79 μmol, 1 eq), and n-butanol (0.75 mL). The reaction was heated to 110° C. for 8 h. The reaction was cooled to rt and the solvent was removed in vacuo. The compound was purified by reverse phase HPLC. The fractions were concentrated and freebased with sat. NaHCO3. The organic layer was extracted into DCM, dried over MgSO4, filtered, and concentrated to afford a white solid,
Reaction SMILES: [C:1]1([C:7]2([CH2:26][CH2:27]CS([O-])(=O)=O)[CH2:11][CH2:10][N:9]([C:12](=[O:25])[C:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:34]1([C:40]2([C:46]([NH2:48])=[O:47])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[C:1]1([C:7]2([CH2:26][CH2:27][N:43]3[CH2:42][CH2:41][C:40]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)([C:46]([NH2:48])=[O:47])[CH2:45][CH2:44]3)[CH2:11][CH2:10][N:9]([C:12](=[O:25])[C:13]3[CH:14]=[C:15]([O:23][CH3:24])[C:16]([O:21][CH3:22])=[C:17]([O:19][CH3:20])[CH:18]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccccc3)C2)cc(OC)c1OC
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccccc3)C2)cc(OC)c1OC

Procedure:
Prepared by the method of example 3.3 using 2-[3-phenyl-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (2.59 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (3.3 mmol). Chromatography on silica gel (100 g) eluting sequentially with ethyl acetate, 6% methanol in dichloromethane, and 10% methanol in dichloromethane gave the title compound: Rf =0.41 (silica gel, 10% methanol in dichloromethane).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]([O:7][CH:8]([O:10][C:11]([C:13]1[N:18]2[C:19]([C@@H:21]([NH:22][C:23](/[C:25](/[C:29]3[N:33]=[C:32]([NH2:34])[S:31][CH:30]=3)=[N:26]\[O:27][CH3:28])=[O:24])[C@H:17]2[S:16][CH2:15][C:14]=1[CH2:35][O:36][CH3:37])=[O:20])=[O:12])[CH3:9])=[O:6])[CH3:3].[CH:38]([O:41]C(OC(OC(C1N2C(=O)C(N)[C@H]2SC(C)C=1OC)=O)C)=O)(C)C.CO/N=C(/C1N=C(NC=O)SC=1)\C(O)=O>>[CH:2]([O:4][C:5]([O:7][CH:8]([O:10][C:11]([C:13]1[N:18]2[C:19](=[O:20])[CH:21]([NH:22][C:23](=[O:24])/[C:25](/[C:29]3[N:33]=[C:32]([NH:34][CH:38]=[O:41])[S:31][CH:30]=3)=[N:26]\[O:27][CH3:28])[C@H:17]2[S:16][CH2:15][C:14]=1[CH2:35][O:36][CH3:37])=[O:12])[CH3:9])=[O:6])([CH3:1])[CH3:3]
Reactant: COC1=C(C(=O)OC(C)OC(=O)OC(C)C)N2C(=O)C(N)[C@H]2SC1C
Reactant: COCC1=C(C(=O)OC(C)OC(=O)OC(C)C)N2C(=O)[C@@H](NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Agent: CO/N=C(\C(=O)O)c1csc(NC=O)n1
Product: COCC1=C(C(=O)OC(C)OC(=O)OC(C)C)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(NC=O)n3)[C@H]2SC1

Procedure:
One process in the production of cefpodoxime proxetil may be carried out via acylation of 7-amino-3-methoxy-methyl-3-cephem-4-carboxylic acid-1-(isopropoxycarbonyloxy)ethyl-ester of formula with activated Z-2-(methoxyimino)-2-(2-formylaminothiazol-4-yl)-acetic acid to obtain 7-[2-(2-formylaminothiazol-4-yl)-2-(Z)-(methoxyimino)acetamido]-3-methoxymethyl-3-cephem-4-carboxylic acid 1-(isopropoxycarbonyloxy)ethyl ester (N-formyl cefpodoxime proxetil) of formula
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH:20]2[O:32][CH2:33][C:34]2[CH:43]=[CH:42]C3[C:36](=[CH:37]C(CBr)=CC=3)[CH:35]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1[CH2:51][CH2:50][CH2:49][CH2:48][CH:47]1[O:52][CH2:53][CH2:54][OH:55].C(OCCCOC1C=CC(C2CCN(C(OC(C)(C)C)=O)CC2OCC2C=CC3C(=CC(CN(C)C)=CC=3)C=2)=CC=1)C1C=CC=CC=1>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH:20]2[O:32][CH2:33][C:34]2[CH:35]=[C:36]3[C:51]([CH:50]=[CH:49][C:48]([CH2:47][O:52][CH2:53][CH2:54][OH:55])=[CH:37]3)=[CH:42][CH:43]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCOC1CCCCO1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3ccccc3)cc2)C(OCc2ccc3ccc(CBr)cc3c2)C1
Agent: CN(C)Cc1ccc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOCc4ccccc4)cc3)cc2c1
Product: OCCOCc1ccc2ccc(COC3CNCCC3c3ccc(OCCCOCc4ccccc4)cc3)cc2c1

Procedure:
by reaction of tert-butyl (3RS,4RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-(7-bromomethyl-naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with rac-2-[(tetrahydro-2H-pyran-2-yl)oxy]-1-ethanol, a mixture of (3RS,4RS)- and (3SR,4SR)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-{7-[2-[(RS)-tetrahydro-pyran-2-yloxy]-ethoxymethyl]-naphthalen-2-ylmethoxy}-piperidine-1-carboxylate [colourless oil, MS: 740 (M+H)+ ] and tert-butyl (3RS,4RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-(7-dimethylaminomethyl-naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [byproduct, colourless oil, MS: 639 (M)+ ]. Simultaneous cleavage of the BOC and tetrahydropyranyl groups from the main product gave 2-(7-{(3RS,4RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-piperidin-3-yloxymethyl}-naphthalen-2-ylmethoxy)-ethanol as a colourless oil; MS: 556 (M+H)+. Cleavage of the BOC group from the byproduct gave (7-{(3RS,4RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-piperidin-3-yloxymethyl}-naphthalen-2-ylmethyl)-dimethyl-amine as a colourless oil; MS: 539 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.[Br:23][C:24]1[CH:29]=[C:28]([CH2:30]Br)[CH:27]=[CH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:23][C:24]1[CH:29]=[C:28]([CH2:30][O:19][C:13]2[CH:12]=[C:11]3[C:16]([C:7]([NH:6][C:5]4[CH:20]=[CH:21][C:2]([Cl:1])=[CH:3][C:4]=4[F:22])=[N:8][CH:9]=[N:10]3)=[CH:15][C:14]=2[O:17][CH3:18])[CH:27]=[CH:26][N:25]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: BrCc1ccnc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCc1ccnc(Br)c1
Temperature: 80 °C
Yield: 44 %

Procedure:
A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (950 mg, 3 mmol), (prepared as described for the starting material in Example 24), 2-bromo-4-bromomethylpyridine (765 mg, 3 mmol) and potassium carbonate (2.38 g 17 mmol) in DMF (10 ml) was heated at 80° C. for 2 hours. The mixture was allowed to cool, poured into water and extracted with ethyl acetate. The combined extracts were dried (MgSO4) and the solvent removed by evaporation and azeotroped with toluene. The residue was triturated with ethyl acetate/hexane and the solid product collected by filtration, washed with ethyl acetate/hexane and dried to give 7-((2-bromo-4-pyridyl)methoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline (647 mg, 44%).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:36]=[CH:35][C:25]([C:26]([NH:28][CH:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[O:27])=[CH:24][C:23]=4[O:37][CH3:38])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:39][N:40]([CH3:45])[CH2:41][C:42](Cl)=[O:43]>>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:36]=[CH:35][C:25]([C:26]([NH:28][CH:29]5[CH2:34][CH2:33][N:32]([C:42](=[O:43])[CH2:41][N:40]([CH3:45])[CH3:39])[CH2:31][CH2:30]5)=[O:27])=[CH:24][C:23]=4[O:37][CH3:38])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)NC2CCNCC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN(C)CC(=O)Cl
Product: COc1cc(C(=O)NC2CCN(C(=O)CN(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(piperidin-4-yl)benzamide in accordance with scheme 6 using 2-(dimethylamino)acetyl chloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38 (dd, J=13.1, 4.0 Hz, 1 H) 1.58 (m, 5 H) 1.71 (m, 2 H) 1.83 (m, 2 H) 1.93 (m, 2 H) 2.21 (s, 5 H) 2.52 (d, J=1.8 Hz, 1 H) 2.63-2.73 (m, 1 H) 3.05 (t, J=12.1 Hz, 2 H) 3.17-3.24 (m, 1 H) 3.32 (s, 5 H) 3.93 (s, 3 H) 4.05 (t, J=14.2 Hz, 3 H) 4.36 (d, J=12.6 Hz, 1 H) 4.77 (q, J=8.3 Hz, 1 H) 7.48 (dd, 1 H) 7.50 (s, 1 H) 7.97 (s, 1 H) 8.17 (d, J=7.8 Hz, 1 H) 8.26 (s, 1 H) 8.29 (d, 1H). [M+H] calc'd for C30H40F2N8O4, 615; found 615.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[CH:8][O-].[Na+].[C:11]([CH2:13][C:14]([NH2:16])=[O:15])#[N:12].N1CCCCC1>O>[OH:1][C:2]12[NH:16][C:14](=[O:15])[CH:13]([C:11]#[N:12])[CH:8]=[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7]2
Reactant: O=C1CCCCC1=C[O-]
Reactant: N#CCC(N)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCNCC1
Product: N#CC1C=C2CCCCC2(O)NC1=O
Temperature: 40 °C
Reaction time: 96 h
Yield: 217.7 %

Procedure:
Sodium 2-oxocyclohexylidenemethanolate (15 g), 2-cyanoacetamide (4.3 g) and piperidine (1.0 ml) were suspended in water (35 ml), and the mixture was stirred at 40° C. for 4 days. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was suspended in methanol, and insoluble material was filtered off. The filtrate was concentrated under reduced pressure to give the object compound (21.4 g).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][C:12]([C:14]3[S:15][C:16](Cl)=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=3)=[CH:13][C:5]1=2)(=[O:3])[CH3:2].[CH3:25][NH:26][CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[C:1]([N:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][C:12]([C:14]3[S:15][C:16]([N:26]([CH3:25])[CH2:27][CH2:28][O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=3)=[CH:13][C:5]1=2)(=[O:3])[CH3:2]
Reactant: CNCCOc1ccccc1
Reactant: CCOC(=O)c1nc(-c2ccc3c(c2)N(C(C)=O)CCO3)sc1Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(-c2ccc3c(c2)N(C(C)=O)CCO3)sc1N(C)CCOc1ccccc1
Temperature: 70 °C
Yield: 51.7 %

Procedure:
To ethyl 2-(4-acetyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-chlorothiazole-4-carboxylate (7D) (0.15 g, 0.41 mmol) and methyl-(2-phenoxy-ethyl)-amine (1.24 g, 8.1 mmol) was added DMF (10 mL). The reaction mixture was allowed to heat to 70° C. for 48 hours. The reaction mixture was cooled to rt and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel eluting with a gradient of 0 to 80% EtOAc in hexanes to provide 0.102 g (52%) of the desired product ethyl 2-(4-acetyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-(methyl(2-phenoxyethyl)amino)thiazole-4-carboxylate (20A): LC/MS (APCI): m/z 482.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][OH:10])[CH:5]=[CH:4][N:3]=1.N1C=CN=C1.[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17].C(Cl)Cl>CN(C=O)C>[Si:20]([O:10][CH2:9][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[C:7]=1[F:8])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:23])[CH3:22]
Reactant: OCc1ccnc(Cl)c1F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccnc(Cl)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
A mixture of (2-chloro-3-fluoropyridin-4-yl)-methanol (200 mg, 1.24 mmol), imidazole (253 mg, 3.72 mmol) and tert-butyldimethylchlorosilane (373 mg, 2.48 mmol) in DMF was stirred at room temperature for 2 hours. Methylene chloride was then added to the reaction solution, and the solution was washed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. The resultant residue was purified by silica gel column chromatography to yield the title compound (319 mg, 93%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[C:6]([CH3:13])[CH:5]=[C:4]([CH3:14])[C:3]=1[NH2:15].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]=[C:25]=[O:26]>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][C:25]([NH:15][C:3]1[C:4]([CH3:14])=[CH:5][C:6]([CH3:13])=[C:7]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[C:2]=1[CH3:1])=[O:26]
Reactant: COc1ccccc1N=C=O
Reactant: Cc1cc(C)c(N2CCCC2)c(C)c1N
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccccc1NC(=O)Nc1c(C)cc(C)c(N2CCCC2)c1C
Temperature: 25 °C
Yield: 25.5 %

Procedure:
A solution of 2 (0.25 g, 1.22 mmol) and 2-methoxyphenyl isocyanate (0.18 g, 1.22 mmol) in toluene (5 mL) was heated at 80° C. overnight. The mixture was allowed to cool to room temperature and then diluted with EtOAc. The organic layer was washed with water (50 mL) and brine (50 mL) before it was dried (MgSO4) and concentrated on a rotavap. The residue was chromatographed on silica gel to give the title compound (0.11 g) as a solid. ESI [M+H+]=354.22.
Reaction SMILES: [CH3:1][C:2](=[CH2:23])[CH2:3][C:4]1[CH:5]=[C:6]([C:14]2[O:15][C:16]3[C:17]([N:22]=2)=[N:18][CH:19]=[CH:20][CH:21]=3)[CH:7]=[C:8]([CH2:10][C:11]([CH3:13])=[CH2:12])[CH:9]=1.[H][H]>[Pd].CO>[CH2:3]([C:4]1[CH:5]=[C:6]([C:14]2[O:15][C:16]3[C:17]([N:22]=2)=[N:18][CH:19]=[CH:20][CH:21]=3)[CH:7]=[C:8]([CH2:10][CH:11]([CH3:13])[CH3:12])[CH:9]=1)[CH:2]([CH3:1])[CH3:23]
Reactant: [H][H]
Reactant: C=C(C)Cc1cc(CC(=C)C)cc(-c2nc3ncccc3o2)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)Cc1cc(CC(C)C)cc(-c2nc3ncccc3o2)c1

Procedure:
The product from Step B (3 mmoles) is hydrogenated in 25 ml. of methanol in the presence of 500 mg. of 5% palladium on carbon under 3 atmospheres of hydrogen. The catalyst is removed by filtration and the filtrate is concentrated to dryness. The residue is recrystallized from n-hexane to give 2-[3,5-di(isobutyl)phenyl]oxazolo[4,5-b]pyridine.