Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:13]([NH2:17])[CH2:14][CH2:15][CH3:16]>C(O)C>[CH2:13]([NH:17][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCOC(=O)c1cccnc1Cl
Reactant: CCCCN
Solvent: CCO
Product: CCCCNc1ncccc1C(=O)OCC

Procedure:
Ethyl 2-chloropyridine-3-carboxylate (8.00 g) was heated at 100° C. for 5 hours with 16 mL of n-butylamine and 34 mL of ethanol in an autoclave. The product was chromatographed on silica gel to give 7.69 g of ethyl 2-butylaminopyridine-3-carboxylate. This compound was reacted with N-triphenylmethyl-5-[2-(4'-bromomethyl-biphenyl)]tetrazole, prepared as described by P. E. Aldrich, et al., in European Patent Application Number 291969, using the procedure described in Example 87 to give ethyl 2-{N-butyl-N-[(2'-[N-triphenylmethyl-1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}pyridine-3-carboxylate in 61% yield. m.p. 90°-94° C. Treatment of 1.50 g of this compound with 14 mL of methylene chloride and 21 mL of 88% formic acid for 1 hour at ambient temperature gave 690 mg of the title compound. m.p. 120°-121° C. 1H NMR (CDCl3, 300 MHz) d 0.85 (t, J=7 Hz, 3H), 1.22 (m, 2H), 1.36 (t, J=7 Hz, 3H), 1.55 (m, 2H), 3.29 (t, J=7 Hz, 2H), 4.31 (q, J=7 Hz, 2H), 4.60 (s, 2H), 6.69 (dd, J=4 Hz, 8 Hz, 1H), 7.11 (d, J=8 Hz, 2H), 7.25 (d, J=8 Hz, 2H), 7.45 (dd, J=8 Hz, 2 Hz, 1H), 7.50-7.70 (m, 4H), 7.92 (dd, J=8 Hz, 1 Hz, 1H), 8.05 (dd, J=4 Hz, 2 Hz, 1H), 8.17 (dd, J=8 Hz, 1 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][NH:9][CH:10]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)=[O:20].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:18][C:19]([N:21]2[CH2:22][CH2:23][N:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH2:25][CH2:26]2)=[O:20])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)c1cnn(CC(=O)N2CCN(c3ccc(F)cc3)CC2)c1

Procedure:
Protocol T was followed using 1H-Pyrazole-4-carboxylic acid ethyl ester, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/1) afforded the title compound as a white solid. 1H NMR (400 MHz, CDCl3): 8.2 (s, 1H), 7.92 (s, 1H), 6.94–7.0 (m, 2H), 6.82–6.88 (m, 2H), 5.0 (s, 2H), 4.1–4.2 (q, 2H), 3.74–3.82 (t, 2H), 3.62–3.72 (t, 2H), 3.0–3.12 (m, 4H), 1.28–1.42 (t, 3H). MS (ES) M+H expected 360.39, found 361.1.
Reaction SMILES: O.[CH3:2][C:3]1[C:4]([CH2:15][S:16][C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)=[N:5][CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].ClC1C=CC=C(C(OO)=[O:34])C=1.C(N(CC)CC)C.O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN1CCCC1=O.O>[CH3:2][C:3]1[C:4]([CH2:15][S:16]([C:17]2[NH:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[N:21]=2)=[O:34])=[N:5][CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]([F:13])([F:12])[F:14]
Reactant: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Temperature: 2.5 °C
Yield: 105.7 %

Procedure:
20 g (0.0538 mole) of 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]thio]-1H-benzimidazole hydrate was dissolved at room temperature in 60 ml of 1-methyl-2-pyrrolidone (NMP) and the reaction mixture was cooled to a temperature of from 0 to 5° C. 12.07 g (0.070 mole) of 3-chloroperbenzoic acid were suspended (optionally per partes) and the reaction was carried out at a temperature of from 0 to 10° C. for half an hour, then at 10-15° C. until the reaction was completed. At the end of the reaction 0.5 ml of triethylamine and a solution of 11.36 g sodium thiosulphate pentahydrate in 12 ml of water were added. The product was precipitated with water (120 ml at 20±5° C.) and filtered off to obtain 21 g of wet lansoprazole.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:30])[NH:6][C:7]1[N:11]([C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH2:18][O:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][O:21]3)[CH:16]=2)[N:10]=[C:9]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:8]=1.C(C1C=C(NC([NH:53][C@@H:54]2[C:63]3[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=3)[C@H:57]([O:64][C:65]3[CH:66]=[CH:67][C:68]4[N:69]([C:71]([N:74]5[CH2:79][CH2:78][CH2:77][CH2:76][CH2:75]5)=[N:72][N:73]=4)[CH:70]=3)[CH2:56][CH2:55]2)=O)N(C2C=CC(CO)=CC=2)N=1)(C)(C)C>>[C:26]([C:9]1[CH:8]=[C:7]([NH:6][C:5]([NH:53][C@@H:54]2[C:63]3[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=3)[C@H:57]([O:64][C:65]3[CH:66]=[CH:67][C:68]4[N:69]([C:71]([N:74]5[CH2:75][CH2:76][CH2:77][CH2:78][CH2:79]5)=[N:72][N:73]=4)[CH:70]=3)[CH2:56][CH2:55]2)=[O:30])[N:11]([C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH2:18][O:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][O:21]3)[CH:16]=2)[N:10]=1)([CH3:27])([CH3:29])[CH3:28]
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2ccc(CO)cc2)n1
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cnn(CCOC3CCCCO3)c2)n1
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2cnn(CCOC3CCCCO3)c2)n1

Procedure:
The title compound was prepared starting from Intermediate 3c and Intermediate 108b using analogous procedures to those described in Intermediate 106a. LCMS (Method 4): Rt 3.27 min, m/z 723.5 [MH+].
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]([CH2:4][C:5]([OH:7])=O)=[CH2:3].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:15][NH2:16]>[OH-].[Na+]>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:15][N:16]1[CH2:3][CH:2]([C:1]([OH:9])=[O:8])[CH2:4][C:5]1=[O:7]
Reactant: COc1ccc(CN)cc1OC
Reactant: C=C(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(CN2CC(C(=O)O)CC2=O)cc1OC
Temperature: 130 °C
Yield: 67.7 %

Procedure:
A mixture of 6.0 g (46 mmols) of itaconic acid and 7.7 g (46 mmols) of 3,4-dimethoxybenzylamine was heated at 130° C. for 2 hours in a nitrogen atmosphere. After cooling to about 100° C., 70 ml of 10% sodium hydroxide were added to the viscous reaction mixture, while mechanically stirring, and the resulting mixture was then cooled to room temperature. In order to remove any insoluble matter, the sodium salt solution was extracted with 50 to 100 ml of ethyl acetate, and the aqueous phase was acidified with dilute hydrochloric acid. The oil precipitated thereby was taken up in methylene chloride, and the methylene chloride phase was dried and concentrated by evaporation. The residue crystallized when ether was added. 8.7 g (68% of theory) of 1-(3,4-dimethoxybenzyl)-4-carboxy-pyrrolidin-2-one were obtained. Melting point: 176°-178° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH2:10][CH:9]([N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])[CH2:8]2)(OC)=[O:2].CC(C[AlH]CC(C)C)C>C1COCC1>[CH:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH2:10][CH:9]([N:16]([CH2:17][CH2:18][CH3:19])[CH2:20][CH2:21][CH3:22])[CH2:8]2)=[O:2]
Reactant: CCCN(CCC)C1Cc2cc(OC)c(C(=O)OC)cc2C1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: CCCN(CCC)C1Cc2cc(C=O)c(OC)cc2C1

Procedure:
A solution of 5-carbomethoxy-6-methoxy-2-(di-n-propylamino)indan (Example 57) in THF under nitrogen is treated with DIBAL-H at -78° C. After work-up and purification, the title compound is obtained.
Reaction SMILES: [OH2:1].[C:2](#[N:5])[CH:3]=[CH2:4]>CC(C)=O>[CH:4]1[C:2]([NH2:5])=[CH:3][CH:4]=[C:2]([N+:5]([O-:1])=[O:1])[CH:3]=1
Reactant: O
Reactant: C=CC#N
Solvent: CC(C)=O
Product: Nc1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of 120 parts of acrylonitrile and 1000 parts of acetone is introduced into the solution of the diazo derivative obtained from 276 parts of p-nitraniline. Then 40 parts of cupric chloride cyrstallised with 2 molecules of water are added and the mixture is kept vigorously stirred. The evolution of nitrogen is exothermal and the temperature must be maintained at 30°-32° C. by means of a cooling bath. After the diazonium chloride has disappeared (six hours), the yellow flakes which melt at 108° C. are filtered off. After recrystallising from methanol, 330 parts of 2-chloro-4'-nitro-3-phenyl-propionitrile are obtained which melts at 112° C. The product obtained is then dehydrohalogenated by means of 200 parts of crystalline sodium acetate in a mixture of 340 parts of water and 800 parts of ethyl alcohol. The mixture is heated under reflux for 12 hours and 225 parts of 4-nitro-cinnamonitrile which melts at 202° C. are isolated in the cold.
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([CH2:28][NH:29][C:30]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=3)=[O:31])[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:18][CH:19]1[CH2:20][N:21]([C:23]2[S:24][CH:25]=[C:26]([CH2:28][NH:29][C:30]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=3)=[O:31])[N:27]=2)[CH2:22]1
Reactant: CC(C)(C)[Si](OC1CN(c2nc(CNC(=O)OCc3ccc([N+](=O)[O-])cc3)cs2)C1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(NCc1csc(N2CC(O)C2)n1)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 4.5 h
Yield: 87.1 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-[4-(p-nitrobenzyloxycarbonylaminomethyl)-1,3-thiazol-2-yl]azetidine (867.2 mg, 1.44 mmol) (obtained as described in Reference Example 62(2)) in anhydrous tetrahydrofuran (45 ml) were added acetic acid (0.1 ml, 1.75 mmol) and 1.0 M tetra-n-butylammonium fluoride in tetrahydrofuran (1.72 ml, 1.72 mmol) in an ice bath and the mixture was stirred in an ice bath for 4.5 hours. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate methanol (15:1) as the eluant to afford 3-hydroxy-1-[4-(p-nitrobenzyloxycarbonylaminomethyl)-1,3-thiazol-2-yl]azetidine (457 mg, yield 87%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[S:10](Cl)(=[O:12])=[O:11].[NH2:14][C:15]1[CH:16]=[C:17]([C:21]2[NH:25][N:24]=[N:23][N:22]=2)[CH:18]=[CH:19][CH:20]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[S:10]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[NH:25][N:24]=[N:23][N:22]=2)[CH:16]=1)(=[O:12])=[O:11]
Reactant: O=S(=O)(Cl)c1cc(Cl)c(Cl)cc1Cl
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1cc(Cl)c(Cl)cc1Cl
Yield: 57 %

Procedure:
The product was prepared according to General Procedure 6, described in Example 65, with 2,4,5-trichlorobenzenesulfonyl chloride (15.4 mg, 0.055 mmol) and 5-(3-aminophenyl)tetrazole (8.0 mg, 0.050 mmol). The title compound was obtained in 57% yield (11.4 mg). MS (ESI+) calcd mass for C13H8Cl3N5O2S 402.946428, found 402.946388.
Reaction SMILES: C([O:8][CH2:9][C@:10]12[S:18](=[O:20])(=[O:19])[N:17]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([C:29]([F:32])([F:31])[F:30])[CH:22]=3)[CH2:16][C@H:15]1[C@@H:14]1[CH2:33][C@H:11]2[CH:12]=[CH:13]1)C1C=CC=CC=1.[H][H]>CCOC(C)=O.CO.[Pd]>[OH:8][CH2:9][C@:10]12[S:18](=[O:20])(=[O:19])[N:17]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([C:29]([F:31])([F:32])[F:30])[CH:22]=3)[CH2:16][C@H:15]1[C@@H:14]1[CH2:33][C@H:11]2[CH2:12][CH2:13]1
Reactant: N#Cc1ccc(N2C[C@H]3[C@H]4C=C[C@H](C4)[C@@]3(COCc3ccccc3)S2(=O)=O)cc1C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N2C[C@H]3[C@H]4CC[C@H](C4)[C@@]3(CO)S2(=O)=O)cc1C(F)(F)F
Yield: 82.3 %

Procedure:
A solution-suspension of Example 30 (50 mg, 0.11 mmol) and Degussa-type Pd/C (10 mg; 20 wt %) in 4 mL EtOAc/MeOH (2:1) was stirred under 1 atmosphere of hydrogen at ambient temp for 5 hrs. The reaction vessel was then purged with N2 to give a black suspension that was then filtered. The resulting colorless filtrate was concentrated in vacuo to give 35 mg of a mixture of starting material and product in a 2:1 ratio. The mixture was dissolved in CH2Cl2, loaded onto a preparative TLC plate, and eluted with 30% acetone/heptane to afford 15 mg Example 32 (36% yield) as a colorless film. HPLC: 98% at 3.015 min (retention time) (YMC ODS-A column 4.6×50 mm eluting with 10-90% aqueous MeOH over 4 min containing 0.1% H3PO4, 4 mL/min, monitoring at 220 nm); and MS (ES): m/z 445.11 [M−H+ OAc]−.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22])=[CH:17][C:16]=2[NH2:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[N:29]([O-])=O.[Na+].C([O-])(O)=O.[Na+].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(N(C(C)C)C(C)C)C>CO.O.ClCCl>[CH2:24]([O:23][C:21]([C:18]1[CH:19]=[CH:20][C:15]2[N:14]([CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]3)[N:29]=[N:27][C:16]=2[CH:17]=1)=[O:22])[CH:25]=[CH2:26]
Reactant: C=CCOC(=O)c1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)c1
Reactant: O=N[O-]
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: C=CCOC(=O)c1ccc2c(c1)nnn2C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
To a solution of 4-(4-allyloxycarbonyl-2-amino-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (50.0 g, 133.17 mmol, 1.0 equiv; example 1/step 4) in methanol (400 mL) was added conc. HCl (27.7 mL, 266.33 mmol, 2.0 equiv) and the reaction mixture stirred at 0° C. for 2 h. Another portion of conc. HCl (27.7 mL, 266.33 mmol, 2.0 equiv) was added and stirring was continued for an additional time period of 3 h. The reaction mixture was cooled to 0° C., diluted with water (25 mL), treated with a sat. solution of NaNO2 (10.11 g, 146.48 mmol, 1.1 equiv) and stirred at rt for 30 min. The reaction mixture was cooled to 0° C., basified by addition of a sat. solution of NaHCO3, concentrated by evaporation under reduced pressure and the aqueous phase extracted with ethyl acetate (3×150 mL). The organic solvents were to a large extent evaporated under reduced pressure and the aqueous layer was extracted with ethyl acetate (3×150 ml). The organic phase was washed with water, dried over Na2SO4 and evaporated under reduced pressure. The residue which was a mixture of the desired product and the de-boc analogue was treated with di-tert-butyl dicarbonate (29.06 g, 133.17 mmol, 1.0 equiv) and N-ethyl-diisopropylamine (20.65 g, 159.80 mmol, 1.2 equiv) in dichloromethane (200 mL). The solvent was evaporated under reduced pressure, water was added and the reaction mixture extracted with ethyl acetate (3×100 mL). The organic layer was washed with water, dried over Na2SO4 and evaporated under reduced pressure. The crude material was purified with silica column chromatography eluting with a gradient of hexane/ethyl acetate (9:1→4:1) to obtain 37.1 g (72%) of the title compound. 1H NMR (400 MHz, DMSO): δ 1.44 (s, 9H), 2.02-2.16 (m, 4H), 3.05 (br s, 2H), 4.12-4.15 (m, 2H), 4.87 (d, J=5.2 Hz, 2H), 5.16-5.22 (m, 1H), 5.30 (d, J=10.7, 1H), 5.45 (dd, J=17.2 Hz, J=1.0 Hz, 1H), 6.06-6.13 (m, 1H), 8.08-8.15 (m, 2H), 8.68 (s, 1H). 13C-NMR (100 MHz, DMSO): δ 28.91, 32.21, 56.66, 66.25, 79.82, 112.04, 118.86, 122.44, 126.56, 128.09, 133.42, 135.42, 145.66, 154.72, 165.86. MS (ISP): 387.3 [M+H]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10](=[O:13])[NH:9][C:7]=2[N:8]=1.[Br:14]N1C(=O)CCC1=O>CN(C)C=O>[Br:14][C:11]1[C:10](=[O:13])[NH:9][C:7]2[N:8]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=2[CH:12]=1
Reactant: CSc1ncc2ccc(=O)[nH]c2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CSc1ncc2cc(Br)c(=O)[nH]c2n1
Reaction time: 18 h
Yield: 48.3 %

Procedure:
To a solution of 2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (1.00 g, 5.18 mmol) in anhydrous dimethylformamide (25 mL) was added N-bromosuccinimide (0.99 g, 5.59 mmol) portionwise at room temperature, and the reaction mixture was stirred for 18 h. The mixture was concentrated, and the solid was triturated with hot water (1×20 mL), filtered, and washed with isopropanol to give title compound as a pale yellow solid (0.68 g, 2.50 mmol, 48%). ESMS m/z 272 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 12.88 (br. S., 1H), 8.84 (s, 1H), 8.47 (s, 1H), 2.57 (s, 3H).
Reaction SMILES: C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]1[CH:22]=[C:23]([O:27][CH2:28][C@@H:29]([C:50]([O:52][CH3:53])=[O:51])[NH:30][C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:24]=[CH:25][CH:26]=1.S(O)(O)(=O)=O.[NH2:59][C:60]1[CH:61]=[C:62](B(O)O)[CH:63]=[CH:64][CH:65]=1.NC1C=C(B(O)O)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.O.C1(C)C=CC=CC=1>[NH2:59][C:60]1[CH:65]=[C:64]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][C@@H:29]([C:50]([O:52][CH3:53])=[O:51])[NH:30][C:31]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:22]=2)[CH:63]=[CH:62][CH:61]=1
Reactant: COC(=O)[C@H](COc1cccc(Br)c1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Nc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Cs+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: COCCOC
Product: COC(=O)[C@H](COc1cccc(-c2cccc(N)c2)c1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Triphenyl arsine (0.31 g, 1.0 mmol, 0.1 equiv) and dichloro-bis(triphenylphosphine)-palladium(II) (0.35 g, 0.50 mmol, 0.05 equiv) were stirred under an argon atmosphere in DME (dimethoxy ethane; 56 mL) at rt for 30 min. Methyl O-(3-bromophenyl)-N-triphenylmethyl-L-serinate (Example 1) (5.16 g, 10.0 mmol, 1.0 equiv) and 3-amino phenyl boronic acid hemisulfate (2.2 g, 6.0 mmol, 1.2 equiv) were added as solids, followed by a 2M aqueous solution of cesium carbonate (15.0 mL, 30.0 mmol, 3 equiv). The reaction mixture was stirred for 3 h at rt and partioned between toluene and water. The organic layer was separated and dried over sodium sulfate. After filtration and evaporation of the solvents in vacuuo the crude product was purified by chromatography on SiO2 (gradient: toluene to toluene/-ethanol 97:3) Yield: 7.3 g, 39.0%. 1H NMR (CDCl3, 200 MHz) δ 7.65-7.40 (m, 10H); 7.25-7.12 (m, 11H); 6.97 (d, 2H); 4.70 (dd, 1H); 4.7 (dd, 1H); 3.75-3.65 (m, 3H); 3.24 (s, 3H); 2.90 (d, 1H). MS (DCI/NH3) 546 (M+NH4+), 529 (M+H); 234 (CPh3).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[I:10].C(O)C.O.CCOCC>C1COCC1>[NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=1[I:10]
Reactant: N#Cc1ccc(N)c(I)c1
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: NCc1ccc(N)c(I)c1

Procedure:
To a solution of (2.44 g, 10 mmol) 4-amino-3-iodobenzonitrile (Helv. Chim. Acta. 54: 1486-1488, 1971, Toth: "Die jodierung von desaktivierten aromatischen aminen in wasseriger phase.") in dry THF (5 ml) was added 30 ml of borane-tetrahydrofuran complex solution (30 mmole) with stirring. The solution was heated at reflux temperature for 1 hr. under argon. Upon cooling, ethanol (2 ml) was added to quench excess borane. After the vigorous reaction subsided, water (30 ml) and ether (40 ml) were added and the mixture was separated. The aqueous layer was again extracted with ether (2×40 ml) and the combined ether extracts were dried. HCl gas was bubbled through the ether solution for 10 min. and the granular white precipitate which resulted was collected and recrystallized from methanol (3.0 g, 94%): mp 185°-195° C. (dec); IR (cm-1) Nujol 3500, 1545, 1595 (amine salt); PMR (DMSO-d6) γ8.5 (br, S, 2H), 7.8 (m, 3H), 7.2 (br, S, 2H), 3.7 (S, 2H). Anal. Calcd. for C7H9NI.2HCl: C, 26.17; H, 3.43; N, 8.72. Found: C, 26.21; H, 3.42; N, 8.75.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:13]2[C:12]([CH3:15])([CH3:14])[O:11][C:10]([CH3:17])([CH3:16])[C:9]=2[S:8][C:7]=1[NH2:18])=[O:5])[CH3:2].[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:29]([F:32])([F:31])[F:30])=[C:24]([CH:28]=1)[C:25](Cl)=[O:26]>>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:29]([F:30])([F:31])[F:32])=[C:24]([CH:28]=1)[C:25]([NH:18][C:7]1[S:8][C:9]2[C:10]([CH3:17])([CH3:16])[O:11][C:12]([CH3:15])([CH3:14])[C:13]=2[C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:26]
Reactant: CCOC(=O)c1c(N)sc2c1C(C)(C)OC2(C)C
Reactant: O=C(Cl)c1cc(F)ccc1C(F)(F)F
Product: CCOC(=O)c1c(NC(=O)c2cc(F)ccc2C(F)(F)F)sc2c1C(C)(C)OC2(C)C

Procedure:
The title compound was prepared from the product of Example 18A and commercially available 5-fluoro-2-(trifluoromethyl)benzoyl chloride using the procedure described for Example 1B. 1H NMR (DMSO-d6, 300 MHz) δ 1.30 (t, J=7.1 Hz, 3H), 1.54 (s, 6H), 1.49 (s, 6H), 4.30 (q, J=7.1 Hz, 2H), 7.63-7.70 (m, 1H), 7.82 (dd, J=8.6, 2.5 Hz, 1H), 8.01 (dd, J=8.8, 5.1 Hz, 1H), 11.48 (br s, 1H). MS (ESI+) m/z 460 (M+H)+. Anal. calcd. for C21H21F4NO4S: C, 54.90; H, 4.61; N, 3.05. Found: C, 54.72; H, 4.68; N, 2.98.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([N:5]1[CH:9]=[CH:8][C:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([Cl:18])[CH:11]=2)=[N:6]1)[CH3:4].[C:19]([C:22]1[CH:26]=[C:25]([C:27](O)=[O:28])[NH:24][N:23]=1)(=[O:21])[CH3:20]>>[C:19]([C:22]1[CH:26]=[C:25]([C:27]([NH:1][CH2:2][C@H:3]([N:5]2[CH:9]=[CH:8][C:7]([C:10]3[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([Cl:18])[CH:11]=3)=[N:6]2)[CH3:4])=[O:28])[NH:24][N:23]=1)(=[O:21])[CH3:20]
Reactant: C[C@H](CN)n1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Product: CC(=O)c1cc(C(=O)NC[C@@H](C)n2ccc(-c3ccc(C#N)c(Cl)c3)n2)[nH]n1
Yield: 56.3 %

Procedure:
(R)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (1.29 mmol) was coupled with 3-acetyl-1H-pyrazole-5-carboxylic acid (259 mg, 1.68 mmol) using the method of Example 34(d). Crude product was purified twice by CombiFlash (1st column: C-18, eluent: 0-100% MeCN in water; 2nd column: silica, eluent: 0-7% MeOH in DCM) to yield 288 mg (56%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.49 (d, 3H), 2.48 (s, 3H), 3.56-3.73 (m, 2H), 4.60-4.75 (m, 1H), 6.94 (d, 1H), 7.27 (bs, 1H), 7.87 (d, 1H), 7.91-8.01 (m, 2H), 8.08 (dd, 1H), 8.58 (bs, 1H), 14.2 (bs, 1H).