Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][C:32]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)/[C:27](O)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([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.P(Cl)(Cl)(Cl)(Cl)Cl.Cl.[NH2:58][CH:59]1[C:85](=[O:86])[N:61]2[C:62]([C:69]([O:71][CH:72]([C:79]3[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=3)[C:73]3[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=3)=[O:70])=[C:63](/[CH:66]=[CH:67]\[CH3:68])[CH2:64][S:65][C@H:60]12.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C>ClCCl>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][C:32]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)/[C:27]([NH:58][CH:59]2[C:85](=[O:86])[N:61]3[C:62]([C:69]([O:71][CH:72]([C:73]4[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=4)[C:79]4[CH:80]=[CH:81][CH:82]=[CH:83][CH:84]=4)=[O:70])=[C:63](/[CH:66]=[CH:67]\[CH3:68])[CH2:64][S:65][C@H:60]23)=[O:28])[N:25]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C/C=C\C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Reactant: O=C(O)/C(=N\OC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: C/C=C\C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 2-(2-tritylaminothiazol-4-yl)-2-(Z)-trityloxyiminoacetic acid (III, R2a =Tr) (873 mg, 1.30 m moles) and dichloromethane (5 ml) was added phosphorus pentachloride (297 mg, 1.43 m moles) at -5° C. The mixture was allowed to stand for 20 min at the same temperature and added dropwise to a solution of diphenylmethyl 7-amino-3-(1-propenyl)-3-cephem-4-carboxylate hydrochloride (XIII, R3 =H: 443 mg, 1 m mole) and N,O-bis(trimethylsilyl)acetamide (0.74 ml, 4.4 m moles) in dichloromethane (5 ml) at -5° C. The reaction mixture was allowed to stand for 20 min. at the same temperature and poured into ice-water. Extraction of the mixture with ethyl acetate and evaporation of the extracts under reduced pressure gave the crude product as an oil, which was chromatographed on a column of silica gel (eluted with chloroform) to give the title compound as an amorphous powder. Yield 510 mg (48%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](/[N+]([O-])=O)\[CH3:10])=[C:4]([F:14])[CH:3]=1.[N+:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])#[C-:16].C1COCC1>CC(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH3:10])=[CH:16][NH:15][C:17]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:4]([F:14])[CH:3]=1
Reactant: C/C(=C\c1ccc(Cl)cc1F)[N+](=O)[O-]
Reactant: [C-]#[N+]CC(=O)OCC
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]cc(C)c1-c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 120 h
Yield: 87.2 %

Procedure:
To a suspension of (E)-4-chloro-2-fluoro-1-(2-nitroprop-1-enyl)benzene (5 g, 23.2 mmol) and ethyl 2-isocyanoacetate (2.65 mL, 24.4 mmol) in a mixture of dry THF (20 mL) and i-PrOH (20 mL) was added 2.6 mmol TBD/g polymer (9.8 g, 25.5 mmol). The suspension was stirred at room temperature for 5 d. The reaction mixture was filtered off and the residue was washed with i-PrOH/THF (1:1, 30 mL). The filtrate was concentrated to give the desired product (5.7 g, 87%) as a yellow oil.
Reaction SMILES: C(O[C:5]1[C:6]([CH3:24])=[C:7]([CH3:23])[C:8]2[O:12][CH:11](CSC3C=CC=CC=3)[CH2:10][C:9]=2[C:21]=1[CH3:22])(=O)C.[OH-].[Na+].Cl>CO.O>[CH3:22][C:21]1[C:9]2[CH2:10][CH2:11][O:12][C:8]=2[C:7]([CH3:23])=[C:6]([CH3:24])[CH:5]=1
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CC(CSc1ccccc1)O2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C)c2c(c1C)OCC2
Yield: 149.7 %

Procedure:
To a solution of 5-acetoxy-2-(phenylthiomethyl)-4,6,7-trimethyl-2,3-dihydrobenzofuran [1.2 g (3.5 mmol)] in methanol (8 ml) was added a solution of sodium hydroxide (0.6 g) in water (5 ml). The mixture was heated for one hour under reflux under argon atmosphere. The reaction mixture was, after cooling, diluted with water and, then, neutralized with 2N-HCl and followed by extraction with ethyl acetate. The extract solution was washed with water, and dried, then the solvent was distilled off. The residue was crystallized from isopropyl ether-hexane to obtain 5-hydroxy-2-phenylthiomethyl)-4,6,7-trimethyl-2,3-dihydrobenzofuran (Compound 3) (0.85 g).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:23])[N:9]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:3]=1.[C:24]([NH:27][C:28]1[CH:37]=[CH:36][C:31]([S:32](Cl)(=[O:34])=[O:33])=[CH:30][CH:29]=1)(=[O:26])[CH3:25]>>[Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:23])[N:9]([CH:10]2[CH2:11][CH2:12][N:13]([S:32]([C:31]3[CH:30]=[CH:29][C:28]([NH:27][C:24](=[O:26])[CH3:25])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH2:14][CH2:15]2)[C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)=[N:4][CH:3]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(Cl)s2)C2CCNCC2)CC1
Product: CC(=O)Nc1ccc(S(=O)(=O)N2CCC(N(C(=O)Nc3ncc(Cl)s3)[C@H]3CC[C@H](C)CC3)CC2)cc1

Procedure:
Prepared in a similar manner to Example 554 using 3-(5-chloro-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-1-piperidin-4-yl-urea and N-acetylsulfanilyl chloride.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[CH3:6][N:7]([CH3:21])/[CH:8]=[CH:9]/[C:10]([C:12]1[CH:13]=[N:14][N:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=12)=O.[F:22][P-:23]([F:28])([F:27])([F:26])([F:25])[F:24].[Na+]>C(Cl)Cl.CO>[F:22][P-:23]([F:28])([F:27])([F:26])([F:25])[F:24].[Cl:3]/[C:10](/[C:12]1[CH:13]=[N:14][N:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=12)=[CH:9]\[CH:8]=[N+:7]([CH3:21])[CH3:6]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)/C=C/C(=O)c1cnn2ccccc12
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: C[N+](C)=C/C=C(\Cl)c1cnn2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
POCl3 (0.951 mL, 10.20 mmol) was added to a solution of (E)-3-(dimethylamino)-1-(pyrazolo[1,5-a]pyridin-3-yl)prop-2-en-1-one (2.153 g, 10 mmol) in CH2Cl2 (15 mL) at 20° C. (using ice/water cooling) over a period of 3 minutes under N2. The resulting solution was stirred at r.t. for 0.5 h and was then concentrated in vacuo. The residue was dissolved into a minimum amount of CH3OH (100 mL). This solution was added over a period of 2 minutes to a solution of sodium hexafluorophosphate(V) (3.36 g, 20.00 mmol) in CH3OH (40 mL). After 5 minutes the precipitate was collected by filtration, washed well with CH3OH cooled to −50° C. and dried by suction under a stream of N2 to give the title compound (3.40 g, 90%) as a yellow powder, which was used without further purification; 1H NMR: 3.63 (6H, d), 7.36 (2H, m), 7.71-7.90 (1H, m), 8.45 (1H, d), 8.81 (1H, d), 9.05 (2H, d); m/z: ES+ M+ 234.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][C:18]=1[OH:26]>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)=[CH:19][C:18]=1[OH:26]
Reactant: OB(O)c1ccc(F)c(O)c1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(F)c(O)c1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile (PREPARATION 2) and 4-fluoro-3-hydroxyphenyl boronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C16H11FN4O, 295. Found, 295.
Reaction SMILES: C12N(C3C=NC4C(=CC=CC=4)N=3)CC1CCNC2.[C@@H:19]12[NH:26][CH2:25][C@@H:24]1[CH2:23][CH2:22][N:21]([C:27]([C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[N:36]1[N:40]=[CH:39][CH:38]=[N:37]1)=[O:28])[CH2:20]2.Cl[C:42]1[N:47]=[CH:46][N:45]=[C:44]([N:48]([CH3:50])[CH3:49])[CH:43]=1>>[F:35][C:33]1[CH:32]=[CH:31][C:30]([N:36]2[N:40]=[CH:39][CH:38]=[N:37]2)=[C:29]([C:27]([N:21]2[CH2:22][CH2:23][C@@H:24]3[C@@H:19]([N:26]([C:42]4[N:47]=[CH:46][N:45]=[C:44]([N:48]([CH3:50])[CH3:49])[CH:43]=4)[CH2:25]3)[CH2:20]2)=[O:28])[CH:34]=1
Reactant: O=C(c1cc(F)ccc1-n1nccn1)N1CC[C@H]2CN[C@H]2C1
Reactant: CN(C)c1cc(Cl)ncn1
Agent: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Product: CN(C)c1cc(N2C[C@@H]3CCN(C(=O)c4cc(F)ccc4-n4nccn4)C[C@@H]32)ncn1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 2, Step A, using (1R,6S)-3,8-diazabicyclo[4.2.0]octan-3-yl(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and (6-chloro-pyrimidin-4-yl)-dimethyl-amine. MS (ESI) mass calcd. for C21H23FN8O, 422.5; m/z found, 423.2 [M+H]+.
Reaction SMILES: [Li][CH2:2]CCC.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14]([CH:22]=O)=[CH:15][C:16]([N:19]([CH3:21])[CH3:20])=[CH:17][CH:18]=2)=[CH:9][CH:8]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][C:14]=2[CH:22]=[CH2:2])=[CH:9][CH:8]=1
Reactant: CN(C)c1ccc(-c2ccc(Br)cc2)c(C=O)c1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1cc(N(C)C)ccc1-c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.4 %

Procedure:
BuLi (2.5M in hexanes, 2.96 mL, 7.40 mmol) was added to a solution of methyltriphenylphosphonium bromide (2.94 g, 8.22 mmol) in THF (20 mL). The mixture was stirred at 0° C. for 1 hr. A solution of 4′-bromo-4-(dimethylamino)biphenyl-2-carbaldehyde (1.25 g, 4.11 mmol) in THF (20 mL) was added dropwise at 0° C. The mixture was stirred overnight from 0° C. to r.t. The reaction was filtered and evaporated. The residue was diluted with diethyl ether and washed with water and brine. The ether layer was dried (MgSO4), filtered and evaporated to give the crude material. The crude material was purified on the Biotage (5-15% EtOAc:Hex) to give 4′-bromo-N,N-dimethyl-2-vinylbiphenyl-4-amine (725 mg, 2.399 mmol, 58% yield) as a yellow solid. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 2.97-3.07 (m, 6H) 5.20 (d, J=10.99 Hz, 1H) 5.69 (d, J=17.40 Hz, 1H) 6.70 (dd, J=17.40, 10.99 Hz, 1H) 6.76 (dd, J=8.55, 2.75 Hz, 1H) 6.95 (d, J=2.44 Hz, 1H) 7.16 (d, J=8.55 Hz, 1H) 7.21 (m, J=8.24 Hz, 2H) 7.50 (m, J=8.55 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([N:16]2[CH2:21][CH2:20][CH2:19][C@@H:18]([CH3:22])[C@@H:17]2[CH2:23][NH:24]C(=O)OC(C)(C)C)=[O:15])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:24][CH2:23][C@H:17]1[C@H:18]([CH3:22])[CH2:19][CH2:20][CH2:21][N:16]1[C:14]([C:9]1[N:10]=[C:11]([CH3:13])[S:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:15]
Reactant: Cc1nc(C(=O)N2CCC[C@@H](C)[C@@H]2CNC(=O)OC(C)(C)C)c(-c2ccc(F)cc2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(C(=O)N2CCC[C@@H](C)[C@@H]2CN)c(-c2ccc(F)cc2)s1

Procedure:
To a solution of rac-trans-tert-butyl ((3-methylpiperidin-2-yl)methyl)carbamate (1 eq) from the previous step in DMF was added DIPEA (2 eq) followed by 5-(4-fluorophenyl)-2-methylthiazole-4-carboxylic acid (1.5 eq) and HATU (2 eq). The reaction was allowed to stir at rt for 15 h, and was then concentrated in vacuo to remove the DMF. The crude residue was taken up in EtOAc and washed with 1M HCl, sat aq. NaHCO3, brine, dried (MgSO4), and concentrated. The crude residue was purified by chromatography on silica gel (EtOAc/hex) to give tert-butyl (((2R,3R)-1-(5-(4-fluorophenyl)-2-methylthiazole-4-carbonyl)-3-methylpiperidin-2-yl)methyl)carbamate as a light yellow oil. To a solution of this carbamate in CH2Cl2 was added TFA (1:1 v/v). The reaction was aged at rt and monitored for disappearance of starting material by analytical reverse-phase HPLC. When starting material was consumed, the reaction was concentrated in vacuo. The crude residue was taken up in EtOAc, and washed with sat aqueous NaHCO3, brine, dried (MgSO4), and concentrated to afford the title compound as a pale yellow oil which crystallized. MS (ESI) 348.2 (M+H).
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH:14]=O)=[CH:10][C:9]([CH2:16][CH2:17][CH2:18][CH3:19])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:14][CH2:13][CH2:12][C:11]2[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=[C:9]([CH2:16][CH2:17][CH2:18][CH3:19])[CH:10]=2)[CH2:29][CH2:28]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CCCCc1cc(CCC=O)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCCCc1cc(CCCN2CCN(c3ccccc3F)CC2)n(-c2ccccc2)n1

Procedure:
196.6 mg (86%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-3-butyl-1H-pyrazol-5-yl)propanal (140 mg, 0.546 mmol), 1-(2-fluorophenyl)piperazine (130 mL, 0.819 mmol), and NaBH(OAc)3 (excess amount).
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([C:13](Cl)=[O:14])=[CH:8][CH:9]=2)[N:4]=[CH:3]1.[S:16]1[CH:20]=[CH:19][N:18]=[C:17]1[NH2:21].O>C1COCC1.C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([C:13]([NH:21][C:17]3[S:16][CH:20]=[CH:19][N:18]=3)=[O:14])=[CH:8][CH:9]=2)[N:4]=[CH:3]1
Reactant: Cn1cnc2cc(C(=O)Cl)ccc2c1=O
Reactant: Nc1nccs1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Product: Cn1cnc2cc(C(=O)Nc3nccs3)ccc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-methyl-4-oxo-3,4-dihydroquinazoline-7-carbonyl chloride prepared as described in Example 22.1a was dissolved in anhydrous THF and added to a solution of thiazol-2-amine (81 mg, 0.81 mmol) in CHCl3 (10 mL). The reaction was stirred at room temperature for 30 min and then poured into water. The mixture was extracted with ethyl acetate, and the organic layer was washed with brine, dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was purified by silica gel chromatography purification to provide the desired product. MS (ESI): 287 (MH+); 1H NMR (300 MHz, DMSO-d6) δ 12.95 (s, 1H), 8.46 (s, 1H), 8.38-8.37 (d, J=1.44 Hz, 1H), 8.29-8.26 (m, 1H), 8.15-8.12 (dd, J=8.36, 1.60 Hz, 1H), 7.60-7.59 (d, J=3.57 Hz, 1H), 7.33-7.32 (d, J=3.45 Hz, 1H), 3.53 (s, 3H).
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[N:14][O:15][CH:16]=2)=[N:6][CH:5]=1.[NH2:25][CH:26]([CH2:29][OH:30])[CH2:27][OH:28]>>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:25][CH:26]([CH2:29][OH:30])[CH2:27][OH:28])=[O:24])=[CH:5][N:6]=3)=[CH:16][O:15][N:14]=2)=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(OCc2conc2-c2ccc(F)cc2)nc1
Reactant: NC(CO)CO
Product: O=C(NC(CO)CO)c1ccc(OCc2conc2-c2ccc(F)cc2)nc1
Yield: 49 %

Procedure:
As described for example 325, 6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (200 mg, 0.61 mmol) was converted, using 2-amino-1,3-propandiol instead of rac-2-amino-1-propanol, to the title compound (117 mg, 49%) which was obtained as a white solid MS: m/e=388.2 [M+H]+.
Reaction SMILES: C([O:5][C:6](=[O:28])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:27])[CH:13]([S:25][CH3:26])[CH2:14][S:15]CC1C=CC(OC)=CC=1)(C)(C)C.FC(F)(F)S(O)(=O)=O>ClCCl.C1(OC)C=CC=CC=1>[SH:15][CH2:14][CH:13]([S:25][CH3:26])[C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([OH:28])=[O:5])=[O:27]
Reactant: COc1ccc(CSCC(SC)C(=O)N2CCC[C@H]2C(=O)OC(C)(C)C)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: CSC(CS)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C

Procedure:
1-[3-(4-Methoxybenzylmercapto)-2-(methylthio)propanoyl]-L-proline tert-butyl ester (0.5 g.) is dissolved in a mixture of dichloromethane (2 ml.) and anisole (1.1 ml.) under a blanket of argon in an ice bath. Trifluoromethanesulfonic acid (1 g.) is added and the mixture is stirred at room temperature for thirty minutes. The solvent is removed in vacuo and the residue is distributed between water and ethyl acetate. The organic layer is washed six times with water, dried and concentrated to dryness in vacuo to yield 1-[3-mercapto-2-(methylthio)propanoyl]-L-proline.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:16][CH2:15][NH:14][C:13]1=[O:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[CH3:20][O:21][CH:22]([O:26][CH3:27])[CH2:23][CH2:24]Br>CC(N(C)C)=O.C(Cl)Cl>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:16][CH2:15][N:14]([CH2:24][CH2:23][CH:22]([O:26][CH3:27])[O:21][CH3:20])[C:13]1=[O:17])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCCN1CCNC1=O
Reactant: COC(CCBr)OC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: COC(CCN1CCN(CCCO[Si](C)(C)C(C)(C)C)C1=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.7 %

Procedure:
1-[3-(tert-Butyldimethylsilanyloxy)propyl]imidazolidin-2-one (17.65 g, 68.30 mmol; prepared as described in Preparation 1) was slowly added to a suspension of NaH (8.20 g, 204.9 mmol, 3.0 eq, 40% mineral oil) in DMA (400 mL). Deprotonation was monitored with a bubbler, and bubbling was ceased after one hour of stirring at room temperature. A solution of 3-bromopropionaldehyde dimethyl acetal (25.0 g, 136.6 mmol, 2.0 eq) in DMA (100 mL) was slowly added to the reaction mixture over a period of 2 hours via an addition funnel. Following an additional hour of stirring at room temperature, the solution was concentrated in vacuo and the crude reaction mixture was taken up in DCM (200 mL) and washed with water (2×200 mL) and brine (2×200 mL). The organic phase was dried over Na2SO4, filtered and concentrated to afford the title compound (24.53 g, 68.8 mmol) as light yellow oil. The material was used without further purification.
Reaction SMILES: [N:1]#[C:2][NH2:3].[CH3:4][C:5]([C:8]1[CH:9]=[C:10]([CH:19]=[C:20]2[N:24]([CH3:25])[C:23](SC)=[N:22][C:21]2=[O:28])[CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])([CH3:7])[CH3:6].CC(C)([O-])C.[K+].P(=O)(O)(O)O>C(O)C.O>[CH3:4][C:5]([C:8]1[CH:9]=[C:10]([CH:19]=[C:20]2[N:24]([CH3:25])[C:23]([NH:3][C:2]#[N:1])=[N:22][C:21]2=[O:28])[CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])([CH3:7])[CH3:6]
Reactant: CSC1=NC(=O)C(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)N1C
Reactant: N#CN
Agent: CC(C)(C)[O-]
Agent: O=P(O)(O)O
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CN1C(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C(=O)N=C1NC#N
Reaction time: 2.5 h
Yield: 50.6 %

Procedure:
Cyanamide (0.2 g, 4.8 mmols) is added to a solution of 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene-1,5-dihydro-1-methyl-2-(methylthio)-4H-imidazol-4-one (1.5 g, 3.9 mmols) and potassium tert-butoxide (0.5 g, 4.3 mmols) in ethanol (25 mL) and the mixture is stirred under an inert atmosphere and heated to reflux. After 2.5 hours the mixture is allowed to cool, and is then poured into water (200 mL), acidified with phosphoric acid, and stirred. After half an hour the product is filtered off, washed three times with water, and dried. Recrystallization from acetonitrile gave the 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-4,5-dihydro-1-methyl-4-oxo-1H-imidazol-2-yl-cyanamide (0.7 g), mp 257°-259° C. (dec).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[CH2:9][C:10]1[N:18]2[C:13]([C:14]([NH2:19])=[N:15][CH:16]=[N:17]2)=[CH:12][CH:11]=1)=[O:5])[CH3:2].[Br:20]C1C(=O)C(C)(C)C(Br)C1=O>C1COCC1>[CH2:1]([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[CH2:9][C:10]1[N:18]2[C:13]([C:14]([NH2:19])=[N:15][CH:16]=[N:17]2)=[C:12]([Br:20])[CH:11]=1)=[O:5])[CH3:2]
Reactant: CC1(C)C(=O)C(Br)C(=O)C1Br
Reactant: CCOC(=O)C1CC1Cc1ccc2c(N)ncnn12
Solvent: C1CCOC1
Product: CCOC(=O)C1CC1Cc1cc(Br)c2c(N)ncnn12
Temperature: -20 °C
Reaction time: 2 h
Yield: 102.8 %

Procedure:
To a solution of 2-(4-amino-pyrrolo[2,1-f][1,2,4]triazin-7-ylmethyl)-cyclopropanecarboxylic acid ethyl ester (4.5 g, 17.2 mmol) in THF (73 mL) cooled to −20° C. was added 2,5-dibromo-4,4-dimethyl-cyclopentane-1,3-dione (2.4 g, 8.6 mmol) in four portions over 15 mins. The mixture was allowed to stir at −20° C. for 2 hours. The mixture was quenched with sodium thiosulfate solution (20 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layer was washed with water, brine, dried by Na2SO4, filtered and concentrated. The residue was purified by Biotage® to give 3.0 g (51%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 7.80 (s, 1 H), 8.75 (bs, 2 H), 6.60 (s, 1 H), 4.0 (m, 2 H), 2.9 (d, 2 H), 1.5 (m, 2 H), 1.2 (t, 3 H), 1.0 (m, 2 H); ES-MS m/z 339.19 [M+H]+, HPLC RT (min) 2.58.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([C:11]1[CH:34]=[CH:33][C:14]([O:15][C@@H:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][C@@H:17]2[NH:25][C:26](OC(C)(C)C)=O)=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8].[ClH:35]>O1CCCC1>[ClH:35].[C:7]([C:11]1[CH:34]=[CH:33][C:14]([O:15][C@@H:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][C@@H:17]2[NH:25][CH3:26])=[CH:13][CH:12]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N[C@H]1Cc2ccccc2[C@H]1Oc1ccc(C(C)(C)C)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CN[C@H]1Cc2ccccc2[C@H]1Oc1ccc(C(C)(C)C)cc1

Procedure:
To a solution of LiAlH4 (730 mg, 19 mmol) in dry tetrahydrofuran (30 ml) under argon was added dropwise a solution of (±)cis-1-(4-tert-butylphenoxy)-2-tert-butoxycarbonylaminoindane (1.4 g, 3.7 mmol) in dry tetrahydrofuran (60 ml). The reaction was heated at reflux for 3 h then cooled with an ice/water bath and quenched with the minimum of water. The reaction was filtered and dried over MgSO4. Solvents were removed in vacuo and the residue subjected to column chromatography on silica gel eluting with 5% ethanol in chloroform to afford a colourless oil (618 mg,) which was converted to the HCl salt and crystallised to afford the title compound as a white solid. m.p. >218° C. dec. (from methanol-diethyl ether).
Reaction SMILES: O[C:2]1([C:15]2[NH:16][CH:17]=[CH:18][N:19]=2)[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C(NC(C)C)(C)C.CS(Cl)(=O)=O>CN(C=O)C.O.[OH-].[Na+]>[NH:16]1[CH:17]=[CH:18][N:19]=[C:15]1[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ncc[nH]2)CC1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)N1CC=C(c2ncc[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To a solution of tert-butyl 4-hydroxy-4-(1H-imidazol-2-yl)piperidine-1-carboxylate (10.5 g) and diisopropylamine (13.8 mL, 2.5 equiv.) in anhydrous DMF under N2 at 0° C. was added in one portion of methanesulfonyl chloride (6.19 mL, 2 equiv.). The reaction was stirred at 0° C. for 2 hours when a further 2 equivalents of methanesulfonyl chloride and 2.5 equivalents of diisopropylamine was added and the resulting mixture stirred at room temperature overnight. The mixture was diluted with water (200 mL) and adjusted pH 9 with 1 N NaOH and then extracted with ethyl acetate (3×). The combined ethyl acetate layers was dried over MgSO4, filtered and evaporated. The residue was purified by column chromatography on silica eluting with 5% methanol in dichloromethane with 0.5% ammonium hydroxide to give tert-butyl 4-(1H-imidazol-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (7.5 g).