Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][N:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][C:5]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1.C(N)CN>O>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[C:6]3[CH2:11][N:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][C:5]=3[C:4]=2[CH:3]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CCOC(=O)N1Cc2[nH]c3ccc(F)cc3c2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: NCCN
Solvent: O
Product: CCOC(=O)N1Cc2c(n(-c3ccc(F)cc3)c3ccc(F)cc23)C1

Procedure:
A mixture of 6.6 g. (0.028 mole) of 7-fluoro-2-carbethoxy-1,2,3,4-tetrahydropyrrolo[3,4-b]indole, 8.86 g. (0.031 mole) of cuprous bromide, 3.28 g. (0.031 mole) of sodium carbonate and 17.2 g. (0.098 mole) of p-bromofluorobenzene in 75 ml. of N-methyl-2-pyrrolidione is heated to reflux for 4 hrs. The reaction mixture is cooled and poured into ice and water containing 40 ml. of ethylene diamine. The mixture is extracted with benzene, and the benzene extracts subsequently back-washed with water and a saturated brine solution and dried over magnesium sulfate. Removal of the solvent in vacuo provides a gum which on trituration with hexane provides 5.8 g. of product as a brown solid, m.p. 143°-145° C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:26](B3OC(C)(C)C(C)(C)O3)=[CH:25][C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)=[O:12])=[CH:9][N:8]=2)[CH2:3]1.Br[C:37]1[S:38][CH:39]=[CH:40][N:41]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>O>[OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:26]([C:37]3[S:38][CH:39]=[CH:40][N:41]=3)=[CH:25][C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:22])([F:23])[F:24])=[CH:16][CH:15]=3)=[O:12])=[CH:9][N:8]=2)[CH2:3]1
Reactant: CC1(C)OB(c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@@H](O)C2)OC1(C)C
Reactant: Brc1nccs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2nccs2)c1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
(R)-6-(3-Hydroxypyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 9.1, 50 mg, 0.101 mmol), 2-bromothiazole (24.9 mg, 0.152 mmol), PdCl2(dppf)-(CH2Cl2) (8.28 mg, 10.14 μmol), Na2CO3 (32.2 mg, 0.304 mmol), DME (522 μL) and water (92 μL) were added to a MW vial, which was sealed, evacuated/purged with argon, and RM was stirred at 90° C. for 16 h. The RM was diluted with THF (2 mL), treated with Si-Thiol (1.27 mmol/g, 39.9 mg, 0.051 mmol), filtered and the filtrate was evaporated off under reduced pressure to give a residue which was purified by preparative HPLC (Condition 9, 40% for 0.2 min then 40% to 70% in 14 min) to yield the title compound as a white solid. UPLC-MS (Condition 1) tR=2.51 min, m/z=451-452 [M+H]+, m/z=449-450 [M−H]; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.71-1.80 (m, 1H) 1.81-1.92 (m, 1H) 2.94 (d, J=11.74 Hz, 1H) 3.25-3.30 (m, 2H) 3.43-3.53 (m, 1H) 4.18-4.26 (m, 1H) 4.81-4.94 (m, 1H) 7.35 (d, J=8.56 Hz, 2H) 7.83-7.88 (m, 2H) 7.89 (d, J=3.42 Hz, 1H) 7.94 (d, J=3.42 Hz, 1H) 8.19 (d, J=2.45 Hz, 1H) 8.82 (d, J=2.20 Hz, 1H) 10.25 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([OH:24])[CH:18]=1.I[CH:26]([CH3:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:26]([CH3:28])[CH3:27])=[C:19]([OH:24])[CH:18]=1
Reactant: O=C1NC(=O)c2ccc(Br)cc2/C1=C/NCc1ccc(O)c(O)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cc1O
Temperature: 70 °C
Yield: 70.8 %

Procedure:
To a solution of (4Z)-6-bromo-4-{[(3,4-dihydroxybenzyl)-amino]methylene}isoquinoline-1,3(2H,4H)-dione (0.74 g, 1.9 mmol) in 5 mL of N,N′-dimethylformamide is added 2-iodopropane (0.19 mL, 1.9 mmol) and 0.52 g (3.8 mmol) of potassium carbonate. The reaction mixture is heated at 70° C. under N2. Mass spectroscopy indicated the completion of reaction after 3.5 h. The reaction mixture is filtered through a pad of celite, and water is added to give a precipitate. It is filtered and washed successively with MeOH, Et2O and hexane, dried in oven (60° C.) overnight to afford 0.58 g (70.7% yield) of tan solid: mp 212-213° C.; MS (ESI) m/z 431.2 and 433.2 (M+H)+1
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:15](=[O:30])[C:16]1[CH:21]=[C:20]([C:22](F)(F)F)N=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=1.[CH3:36][S:37](C1C=C(C=C(C(F)(F)F)C=1)C(O)=O)(=[O:39])=[O:38]>>[CH3:35][O:34][C:32](=[O:33])[CH2:31][N:14]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[C:15](=[O:30])[C:16]1[CH:17]=[C:18]([C:26]([F:27])([F:29])[F:28])[CH:22]=[C:20]([S:37]([CH3:36])(=[O:39])=[O:38])[CH:21]=1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: COC(=O)CN(C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1)c1cnccc1-c1ccccc1F
Product: COC(=O)CN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1cnccc1-c1ccccc1F

Procedure:
The title compound was prepared in analogy to example 90, from [4-(2-fluoro-phenyl)-pyridin-3-ylamino]-acetic acid methyl ester (example 196, intermediate) and 3-methanesulfonyl-5-trifluoromethyl-benzoic acid (280 mg, 1.05 mmol, example 114, intermediate a) after a reaction time of 22 hours. The compound was purified by silica gel chromatography on a 20 g column using an MPLC (Flashmaster) system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light brown foam (323 mg, 61%). MS (ESI): m/z=511.094 [M+H]+.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH:12]([NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[N:57][O:58][CH3:59])[C:21]([NH:23][CH:24]2[C:55](=[O:56])[N:26]3[CH:27]([C:31]([O:33][CH:34]([CH2:45][O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:35][O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[O:32])[CH:28]=[CH:29][S:30][C@H:25]23)=[O:22])[N:19]=1)=[O:13]>C(Cl)Cl>[CH:12]([NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[N:57][O:58][CH3:59])[C:21]([NH:23][CH:24]2[C:55](=[O:56])[N:26]3[C:27]([C:31]([O:33][CH:34]([CH2:35][O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:45][O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[O:32])=[CH:28][CH2:29][S:30](=[O:9])[C@H:25]23)=[O:22])[N:19]=1)=[O:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCCCCCOCC(COCCCCCCCC)OC(=O)C1C=CS[C@@H]2C(NC(=O)C(=NOC)c3csc(NC=O)n3)C(=O)N12
Solvent: ClCCl
Product: CCCCCCCCOCC(COCCCCCCCC)OC(=O)C1=CCS(=O)[C@@H]2C(NC(=O)C(=NOC)c3csc(NC=O)n3)C(=O)N12
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 79.5 %

Procedure:
A solution of 3-chloroperbenzoic acid (0.9 g) in methylene chloride (10 ml) was dropwise added to a stirred solution of 2-n-octyloxy-1-n-octyloxymethylethyl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-2-cephem-4-carboxylate (syn isomer, 3.0 g) in methylene chloride (30 ml) at -7° to -3° C. over 30 minutes, and then stirred at 0° C. for 35 minutes. The resultant mixture was washed with a diluted aqueous solution of sodium bicarbonate and saturated aqueous solution of sodium chloride in turn, and dried over anhydrous magnesium sulfate. After removing the solvent from the solution in vacuo, the residue was subjected to column chromatography on silica gel (120 g) with a mixture of chloroform and methanol (20:1). The eluate was evaporated in vacuo to give powder [2.44 g] of 2-n-octyloxy-1-n-octyloxymethylethyl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate-1-oxide (syn isomer).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12](=[O:14])[CH3:13])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C(N(CC)CC)C.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>ClCCl>[C:12]([C:3]1[C:2]([O:1][S:28]([C:25]2[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=2)(=[O:30])=[O:29])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)(=[O:14])[CH3:13]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)c1nc2ccccc2cc1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1nc2ccccc2cc1OS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.9 %

Procedure:
To a cooled (5° C.) solution of 1-(3-Hydroxy-quinolin-2-yl)-ethanone (1.96 g, 10.5 mmol) in 100 mL dichloromethane was added triethylamine (1.59 g, 2.19 mL. 15.75 mmol). After 10 minutes p-toluenesulfonyl chloride (2.191 g, 11.5 mmol) was added and the mixture was stirred at room temperature for 18 hours. The mixture was washed with 1N HCl, water, and brine, dried (MgSO4) and concentrated under reduced pressure to afford 3.58 g of toluene-4-sulfonic acid 2-acetyl-quinolin-3-yl ester.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:3][CH:2]=1.Cl>C(O)C.[H][H].[Pt]=O>[NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3][CH2:2]1
Reactant: CCOC(=O)Cc1ccncc1
Reactant: [H][H]
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CC1CCNCC1
Reaction time: 1 h
Yield: 162.3 %

Procedure:
16.5 g (0.1 mol) Ethyl 4-pyridylacetate, 8.4 mL (0.1 mol) 12 N hydrochloric acid and 2.5 g platinum oxide were dissolved in absolute ethanol and hydrogenated at 40 psi hydrogen on a Parr shaker. After 1 hour, the contents of the vessel were filtered and concentrated in vacuo yielding 27.79 g of ethyl 4-piperidinylacetate.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[F:25])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:25][C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][C:15]=1[O:14][CH2:13][CH:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1ccc(OCC2CCCN2C(=O)OC(C)(C)C)c(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(OCC2CCCN2)c(F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.5 %

Procedure:
To a stirred solution of methyl 4-[1-(tert-butoxycarbonyl)-2-pyrrolidinyl ]methoxy-3-fluorobenzoate (323.0 mg, 0.914 mmol) in CH2Cl2 (6.5 mL) was added TFA (1.3 mL) at 0° C., and the mixture was stirred 1.5 hr at room temp. The solvent was removed under a reduced pressure and the residue was made basic by the addition of 1 N NaOH. The mixture was extracted with CHCl3. The extract was washed with brine, dried over Na2SO4, and concentrated under a reduced pressure to afford 174.8 mg (76%) methyl 3-fluoro4-(2-pyrrolidinyl)methoxybenzoate as a brownish oil. 1H-NMR (400 MHz, CDCl3) δ 1.54–1.63 (m, 1H), 1.76–2.02 (m, 3H), 2.93–3.07 (m, 2H), 3.57 (ddd, J=4.9, 6.9, 14.3 Hz, 1H), 3.89 (s, 3H), 3.97 (dd, J=6.8, 9.3 Hz, 1H), 4.04 (dd, J=5.0, 8.8 Hz, 1H), 6.98 (t, J=17.6 Hz, 1H), 7.73 (dd, J=2.0, 11.7 Hz, 1H), 7.78 (dt, J=2.0, 8.8 Hz, 1H); MS (FAB) m/z 253 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+].C(#N)C>CCOCC>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:10][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: BrCCCCCBr
Reactant: O=Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: O=Cc1cc(Cl)ccc1OCCCCCBr
Yield: 81.8 %

Procedure:
A mixture of 7.82 g (50 mmol) of 5-chlorosalicylaldehyde, 92.1 g (0.4 mol) of 1,5-dibromopentane, 22.1 g (0.15 mol) of anhydrous granular potassium carbonate, and 360 mL of acetonitrile was stirred and refluxed for 20 hr. The resulting slurry was cooled and diluted with 300 mL of ether. The solids were removed by suction filtration and washed thoroughly with ether. The filtrate and washes were combined and concentrated under water aspirator pressure. The excess 1,5-dibromopentane was removed by distillation under high vacuum. Flash chromatography of the residue on silica gel (eluting with 4:1 hexane-ether) afforded 12.5 g (81.8%) of 2-[(5-bromopentyl)oxy]-5-chlorobenzaldehyde as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16]2[N:20]=[C:19]([C:21]3[O:29][C:28]4[CH:27]=[CH:26][N:25]=[C:24]([CH2:30]O)[C:23]=4[CH:22]=3)[O:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[CH2:33][N:34](CC)[CH2:35]C.CS(Cl)(=O)=O.N(C)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][CH2:15][C:16]2[N:20]=[C:19]([C:21]3[O:29][C:28]4[CH:27]=[CH:26][N:25]=[C:24]([CH2:30][N:34]([CH3:35])[CH3:33])[C:23]=4[CH:22]=3)[O:18][N:17]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCC(OCc2noc(-c3cc4c(CO)nccc4o3)n2)CC1
Agent: CNC
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: CN(C)Cc1nccc2oc(-c3nc(COC4CCN(C(=O)OC(C)(C)C)CC4)no3)cc12
Reaction time: 0.08 h

Procedure:
To a solution of 4-[5-(4-hydroxymethylfuro[3,2-c]pyridine-2-yl)-[1,2,4]oxadiazole-3-ylmethoxy]piperidine-1-carboxylic acid tert-butyl ester (Example 24, 50 mg, 116 μmol) in THF was added NEt3 (50 mL, 361 μmol), followed by MsCl (15 μL, 194 μmol). After 5 min, of Me2NH (0.3 mL of a 2M solution in THF, 600 μmol) was added and stirring continued for a further 2 h. The mixture was adsorbed onto SiO2 and purified via column chromatography to give the title compound: RT=1.82 min; m/z (ES+)=458.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:37][N:38]([CH3:43])[CH2:39][C:40](Cl)=[O:41]>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([F:22])=[CH:11][C:12]([CH:16]3[CH2:17][CH2:18][N:19]([C:40](=[O:41])[CH2:39][N:38]([CH3:43])[CH3:37])[CH2:20][CH2:21]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: CN(C)CC(=O)Cl
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(C(=O)CN(C)C)CC4)cc3F)ncc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (0.12 mmol) and triethylamine (50 uL, 0.36 mmol) in DMF (1.5 mL) was added 2-(dimethylamino)acetyl chloride (38 mg, 0.24 mmol). The mixture was stirred at room temperature for 1 hour. The reaction was filtered and the filtrate was purified by preparative RP-HPLC to give 1-(4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-methylphenyl)piperidin-1-yl)-2-(dimethylamino)ethanone as a white solid: 1H NMR (400 MHz, MeOD-d4) δ 8.08 (s, 1H), 7.71 (d, 1H), 7.03 (d, 1H), 6.26 (s, 1H), 4.71-4.67 (m, 2H), 3.81-3.77 (m, 2H), 3.14-3.12 (m, 2H), 2.98 (s, 3H), 2.96 (s, 3H), 2.90-2.83 (m, 1H), 2.34 (s, 3H), 2.28 (s, 3H), 1.87 (d, 2H), 1.76-1.55 (m, 2H); ESMS m/z 501.2 (M+H+).
Reaction SMILES: [CH3:1][NH2:2].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH2:11][C:12]([O:14]C)=O)=[N:8][CH:9]=1>CO>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH2:11][C:12]([NH:2][CH3:1])=[O:14])=[N:8][CH:9]=1
Reactant: COC(=O)CNc1ccc(Br)cn1
Reactant: CN
Solvent: CO
Product: CNC(=O)CNc1ccc(Br)cn1
Reaction time: 24 h
Yield: 100 %

Procedure:
A solution of 2.0 M methylamine in MeOH (75 mL) was added to 5-bromo-2-(methoxycarbonylmethyl)aminopyridine (2.9 g, 12 mmole). The reaction was stirred for 24 h then was concentrated to dryness. The residue was triturated with 10% petroleum ether/Et2O (100 mL), then was collected and dried under vacuum to give the title compound (2.96 g, 100%) as an off-white solid: MS (ES) m/e 244.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][Si](C)(C)C)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[K+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]#[CH:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C[Si](C)(C)C#Cc1cc(Cl)cc(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C#Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (3,5-dichloro-phenylethynyl)-trimethylsilane (4.85 g, 19.9 mmol) in methanol (50 mL) was added 1 M potassium hydroxide (30 mL). The reaction mixture was stirred 1 h at room temperature and evaporated. The residue was treated with water (10 mL) and extracted with 3×40 mL diethyl ether. The tried organic phases were evaporated to give the desired 1,3-dichloro-5-ethynyl-benzene product in 2.3 g yield.
Reaction SMILES: [C:1]([N:8]([CH3:14])[C@H:9]([C:11](O)=[O:12])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].B.C1COCC1.O.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[C:4]([O:3][C:1](=[O:2])[N:8]([C@@H:9]([CH3:10])[CH2:11][OH:12])[CH3:14])([CH3:7])([CH3:5])[CH3:6]
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: B
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](CO)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
20.3 g Boc-MeAla-OH (100 mmol; Fluka) were dissolved in 80 ml THF and cooled to 0° C. 150 ml 1M BH3-THF (150 mmol; Fluka) were added at 0° C. over 1 h and after additional stirring at 0° C. for 1 h, 65 ml deionized water were added carefully at 0-5° C. After warming up to RT 160 ml 10% Na2CO3 were added and stirring continued for 1 h. The reaction mixture was extracted with 500 ml and 400 ml ethyl acetate and the organic layers were washed with brine and dried (Na2SO4). Removal of the solvent by rotary evaporation gave 18.5 g (98%) product as a colorless oil, [α]D=−6.1 (CHCl3; c=1). 1H-NMR:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].[F:10][CH:11]([CH3:30])[CH2:12][CH2:13][CH2:14][Si:15]1(C2C=CC=CC=2)[CH2:20][CH2:19][CH:18]([C:21](O)=[O:22])[CH2:17][CH2:16]1>>[F:10][CH:11]([CH3:30])[CH2:12][CH2:13][CH2:14][Si@H:15]1[CH2:16][CH2:17][C@H:18]([C:21]([O:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)=[O:22])[CH2:19][CH2:20]1
Reactant: CC(F)CCC[Si]1(c2ccccc2)CCC(C(=O)O)CC1
Reactant: Oc1ccc(F)c(F)c1
Product: CC(F)CCC[Si@H]1CC[C@H](C(=O)Oc2ccc(F)c(F)c2)CC1

Procedure:
The general procedure of Example 3 was repeated using (3,4-difluorophenol and 4-(4-fluoropentyl)-4-phenyl-4-silacyclohexanecarboxylic acid, thereby obtaining the intended product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Li+].[Li+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[CH2:18]([O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(O)cc1)OCc1ccccc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
4-Hydroxyphenylacetic acid (2.0 kg) is dissolved in DMF (8 L) and lithium carbonate (1.07 kg) is added in one portion followed by benzyl bromide (1.88 L). The mixture is heated to 100° C. over 1 hour, aged for 3 hours. The mixture is cooled to 85° C. and transferred into a 50 L vessel and quenched with 2N HCl (10 L).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([N:8]=[C:9]=S)[CH:7]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:15][C:14]=1[OH:24]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([NH:8][C:9]2[O:24][C:14]3[CH:15]=[C:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH:17]=[CH:18][C:13]=3[N:12]=2)[CH:7]=1
Reactant: Cc1ccc(F)cc1N=C=S
Reactant: COC(=O)Cc1ccc(N)c(O)c1
Solvent: CO
Product: COC(=O)Cc1ccc2nc(Nc3cc(F)ccc3C)oc2c1
Temperature: 25 °C
Reaction time: 27 h
Yield: 45.9 %

Procedure:
In methanol (50 ml), 5-fluoro-2-methylphenyl isothiocyanate (2.00 g, 12.0 mmol) was added to methyl 4-amino-3-hydroxyphenylacetate (2.17 g, 12.0 mmol) and the resulting mixture was stirred at room temperature for 27 hours. Mercuric oxide (yellow) (3.12 g, 14.4 mmol) was added to the reaction mixture, followed by stirring at 70° C. for 4 hours. After cooling to room temperature, the reaction mixture was filtered through Celite, followed by washing with methanol. The filtrate was distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from chloroform/ethyl acetate (10/1) eluate fractions, methyl (2-(5-fluoro-2-methylphenylamino)-6-benzoxazolyl)acetate (1.73 g, 46%) was obtained as a brown oil.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[C:11]([C:15]1[N:19]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]([CH3:28])=[C:17]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:16]=1)([CH3:14])([CH3:13])[CH3:12]>O>[C:11]([C:15]1[N:19]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]([CH3:28])=[C:17]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:16]=1[CH:8]=[O:9])([CH3:14])([CH3:12])[CH3:13]
Reactant: CCOC(=O)c1cc(C(C)(C)C)n(CCc2ccccc2)c1C
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCOC(=O)c1c(C=O)c(C(C)(C)C)n(CCc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under ice-cooling, 0.72 ml of phosphorus oxychloride was added to 4 ml of N,N-dimethylformamide at an inner temperature of from 10 to 20° C., followed by stirring at room temperature for 15 minutes. A 5 ml portion of N,N-dimethylformamide solution of 2.00 g ethyl 5-tert-butyl-2-methyl-1-(2-phenylethyl)-1H-pyrrole-3-carboxylate was added to this solution under ice-cooling at an inner temperature of from 10 to 20° C., followed by stirring overnight at 60° C. Water was added at 0° C., pH was adjusted to 8 with potassium carbonate, and extraction was carried out with diethyl ether. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. Then, the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:10-1:8-1:7) to obtain 1.63 g of ethyl 5-tert-butyl-4-formyl-2-methyl-1-(2-phenylethyl)-1H-pyrrole-3-carboxylate as a light yellow solid.
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[C:25]3[C:24](=[O:26])[CH2:23][CH2:22][CH2:21][C:20]=3[N:19]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=3)[C:18](=[O:37])[N:17]2[CH:38]([CH3:42])[C:39]([OH:41])=O)=[CH:12][CH:11]=1)#[N:9].F[B-](F)(F)F.C[N+](C)=C(N(C)C)ON1C2C=CC=CC=2N=N1.[CH2:65]([CH2:67][NH2:68])[OH:66]>CN(C)C=O>[C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[C:25]3[C:24](=[O:26])[CH2:23][CH2:22][CH2:21][C:20]=3[N:19]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:35])([F:36])[F:34])[CH:28]=3)[C:18](=[O:37])[N:17]2[CH:38]([CH3:42])[C:39]([NH:68][CH2:67][CH2:65][OH:66])=[O:41])=[CH:12][CH:11]=1)#[N:9]
Reactant: CC(C(=O)O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1
Reactant: NCCO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C(=O)NCCO)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Triethylamine (55 μL, 0.40 mmol) is added to a solution of 2-(4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,5,6,7,8-hexahydroquinazolin-3(4H)-yl)-propanoic acid (intermediate 59, 50 mg, 0.10 mmol) in N,N-dimethylformamide, and the mixture is stirred for 10 min at room temperature. N,N,N′,N′-Tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate (33 mg, 0.10 mmol) is added, and the mixture is stirred for 15 min. Ethanolamine (15 μL, 0.25 mml) is added, and the mixture is stirred for 1 h, diluted with N,N-dimethylformamide and purified by preparative HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 39 mg; ESI mass spectrum [M+H]+=527; Retention time HPLC: 0.86 min (Z018_S04).