Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3](CC)[CH2:4]C)C.[CH:8]1([CH2:14][C:15]([NH:17][CH2:18][CH2:19][S:20][CH2:21][CH:22]([C:27](=[O:34])[C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[CH2:23][C:24]([OH:26])=O)=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.ClC(OCC)=O.CNC>ClCCl.O1CCCC1>[CH:8]1([CH2:14][C:15]([NH:17][CH2:18][CH2:19][S:20][CH2:21][CH:22]([C:27](=[O:34])[C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[CH2:23][C:24]([N:3]([CH3:4])[CH3:1])=[O:26])=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: CCN(CC)CC
Reactant: O=C(O)CC(CSCCNC(=O)CC1CCCCC1)C(=O)c1cccnc1
Agent: CCOC(=O)Cl
Agent: CNC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)C(=O)CC(CSCCNC(=O)CC1CCCCC1)C(=O)c1cccnc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (14.7 tL) was added to a solution of 3-{[2-(N-cyclohexylacetylamino)ethylthio]methyl}-4-oxo-4-(3-pyridyl)butanoic acid (44.6 mg) in dichloromethane (1.1 mL) and stirred for 30 min. The solution was cooled to 0° C. and ethyl chloroformate (10.5 μL) was added and stirred for 10 minutes. Dimethylamine in tetrahydrofuran (2M, 53 μL) was added and stirred at room temperature overnight. The solution was concentrated and purified on preparative HPLC (C-18 prep column, 10% to 90% acetronitrile in water both containing 0.1% TFA) to give 6.8 mg of the title compound; ESMS (M+1)+420.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:10])=[C:5]([C:7]([OH:9])=O)[N:6]=1.[NH2:11][C@H:12]([CH3:28])[CH2:13][N:14]1[CH:18]=[CH:17][C:16]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([Cl:27])[CH:20]=2)=[N:15]1>>[Cl:27][C:21]1[CH:20]=[C:19]([C:16]2[CH:17]=[CH:18][N:14]([CH2:13][C@H:12]([NH:11][C:7]([C:5]3[N:6]=[C:2]([CH3:1])[O:3][C:4]=3[CH3:10])=[O:9])[CH3:28])[N:15]=2)[CH:26]=[CH:25][C:22]=1[C:23]#[N:24]
Reactant: C[C@@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: Cc1nc(C(=O)O)c(C)o1
Product: Cc1nc(C(=O)N[C@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)c(C)o1
Yield: 54.7 %

Procedure:
(R)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2,5-dimethyloxazole-4-carboxamide was prepared using the method of Example 34(d) starting from 2,5-dimethyl-1,3-oxazole-4-carboxylic acid (0.254 g, 1.749 mmol) and (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.4 g, 1.457 mmol). The product was triturated using diethyl ether. Yield 54.7%. 1H-NMR (400 MHz; DMSO-d6): δ 1.08 (d, 3H), 2.43 (d, 6H), 4.28 (dd, 1H), 4.34-4.45 (m, 2H), 6.96 (d, 1H), 7.83 (d, 1H), 7.96-8.01 (m, 2H), 8.10 (dd, 1H), 8.23 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=4)[CH2:16][NH:15][CH2:14]3)[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[Cl:37][C:38](OC(Cl)(Cl)Cl)=[O:39]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:27])[F:28])=[CH:21][CH:20]=4)[CH2:16][N:15]([C:38]([Cl:37])=[O:39])[CH2:14]3)[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(-c2noc(C3CNCC(c4ccc(OC(F)(F)F)cc4)C3)n2)c1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cl)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3cccc(F)c3)no2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
At 0° C., 1.00 g (2.46 mmol) of the compound from Example 178A and 0.34 ml (248 mg, 2.46 mmol) of triethylamine were initially charged in 167 ml of dichloromethane. 0.12 ml (242 mg, 1.23 mmol) of trichloromethyl chloroformate (diphosgene) was added dropwise. The reaction mixture was stirred at RT for 16 h, washed quickly with a little ice-water, dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel. Yield: 944 mg (68% of theory, 83% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[CH3:15])=[O:4].[NH2:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][C:18]=1[O:25][CH:26]([CH2:29][F:30])[CH2:27][F:28].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)(C)C>O>[C:21]([C:20]1[CH:23]=[CH:24][C:17]([NH:16][C:12]2[C:7]3[C:6]([CH3:15])=[C:5]([C:3]([O:2][CH3:1])=[O:4])[S:14][C:8]=3[N:9]=[CH:10][N:11]=2)=[C:18]([O:25][CH:26]([CH2:27][F:28])[CH2:29][F:30])[CH:19]=1)#[N:22]
Reactant: N#Cc1ccc(N)c(OC(CF)CF)c1
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: COC(=O)c1sc2ncnc(Nc3ccc(C#N)cc3OC(CF)CF)c2c1C

Procedure:
4-Chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (0.2 g), 4-amino-3-(2-fluoro-1-fluoromethyl-ethoxy)-benzonitrile (0.17 g), p-toluenesulfonic acid monohydrate (0.16 g) and isopropanol (3.0 ml) were stirred at 90° C. for 2 hours. Then the mixture was poured in water and filtrated. The solid was washed with water and dried in an oven at 70° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]([CH3:17])[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:10])[CH:5]=[CH:6][CH:7]=1.C[Li].C([Li])(C)(C)C.[B:25](OC)([O:28]C)[O:26]C>O1CCCC1.CCCCC>[CH3:17][N:8]([C:4]1[CH:3]=[C:2]([B:25]([OH:28])[OH:26])[CH:7]=[CH:6][CH:5]=1)[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:10]
Reactant: COB(OC)OC
Reactant: CCCCCNC(=O)N(C)c1cccc(Br)c1
Agent: [Li]C
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCCCCNC(=O)N(C)c1cccc(B(O)O)c1
Yield: 39 %

Procedure:
In a manner similar to that of Example (18a), by reaction of 123 g (0.411 mol, 1 eq) of 1-(3-bromophenyl)-1-methyl-3-pentylurea in 1.23 L of tetrahydrofuran, 150 mL (0.452 mol, 1.1 eq) of methyllithium, 530 mL (0.904 mol, 2.2 eq) of a 1.7 M solution of tert-butyllithium in pentane and 115 mL (0.904 mol, 2.2 eq) of trimethyl borate, and after purification by chromatography on silica gel (50/50 heptane/ethyl acetate) and crystallization from ethyl acetate/heptane, 42.0 g of 3-(1-methyl-3-pentylureido)phenylboronic acid are obtained in the form of a pink-colored powder. Yield=39%
Reaction SMILES: [C:1]([CH:3](C#N)[CH2:4][NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH:16](C#N)[C:17]#[N:18])#[N:2].[ClH:23].[H][H]>O=[Pt]=O>[ClH:23].[ClH:23].[ClH:23].[ClH:23].[NH2:18][CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3][CH2:1][NH2:2]
Reactant: [H][H]
Reactant: N#CC(C#N)CNCCCCCCCCNCC(C#N)C#N
Agent: O=[Pt]=O
Agent: Cl
Product: NCCCNCCCCCCCCNCCCN

Procedure:
Combine 50.0 gm of the product of Example 1, 2.0 gm PtO2, 133 ml of conc. HCl at 45 lbs./sq.in. in a shaker flask until hydrogen is no longer taken up. Filter the resulting mixture, evaporate the solvent and triturate the product with 1 liter of EtOH. Filter and dry the product to obtain 51.6 gm of the title compound, Rf is 0.17 (silica gel plates eluted with 40% conc. NH3 /CH3OH).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[NH:7][S:6]1(=[O:16])=[O:15].[F:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:23]=1[F:24]>>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:21]2[CH:20]=[CH:19][C:18]([F:17])=[C:23]([F:24])[CH:22]=2)[S:6]1(=[O:16])=[O:15]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: O=S1(=O)Nc2ccccc2CN1CCCCl
Product: O=S1(=O)N(CCCCl)Cc2ccccc2N1c1ccc(F)c(F)c1

Procedure:
In an analogous manner to Example 1 step 7, 3-(3-chloropropyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (474 mg) was coupled to 3,4-difluorophenylboronic acid to provide 3-(3-chloropropyl)-1-(3,4-difluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (92 mg):
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][NH:7][CH2:8][CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:20][S:21]([N:24]1[CH2:29][CH2:28][CH:27]([O:30][C:31]2[CH:32]=[CH:33][C:34]([S:37](Cl)(=[O:39])=[O:38])=[N:35][CH:36]=2)[CH2:26][CH2:25]1)(=[O:23])=[O:22]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[S:37]([C:34]2[CH:33]=[CH:32][C:31]([O:30][CH:27]3[CH2:28][CH2:29][N:24]([S:21]([CH3:20])(=[O:22])=[O:23])[CH2:25][CH2:26]3)=[CH:36][N:35]=2)(=[O:38])=[O:39])=[CH:12][CH:13]=1
Reactant: CC(C)CNCc1ccc(F)cc1
Reactant: CS(=O)(=O)N1CCC(Oc2ccc(S(=O)(=O)Cl)nc2)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)CN(Cc1ccc(F)cc1)S(=O)(=O)c1ccc(OC2CCN(S(C)(=O)=O)CC2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37 %

Procedure:
A solution of (4-fluorobenzyl)-isobutylamine (53 mg, 0.295 mmol) and pyridine (34 μL, 0.423 mmol) in DCM (3 mL) was treated with 5-(1-methanesulfonyl-piperidin-4-yloxy)-pyridine-2-sulfonyl chloride (75 mg, 0.211 mmol) and stirred at room temperature for 18 hours. The mixture was diluted with DCM, washed with 1 M aqueous citric acid, saturated aqueous NaHCO3, water and brine, dried over Na2SO4 and concentrated under vacuum. Purification by silica gel column chromatography (0-100% EtOAc in cyclohexane) and re-purification by silica gel column chromatography (0-10% EtOAc in DCM) to give the title compound (39 mg, 37%). 1H NMR (400 MHz, DMSO) δ 8.45 (d, J=2.8 Hz, 1H), 7.89 (d, J=8.7 Hz, 1H), 7.66 (dd, J=8.8, 2.9 Hz, 1H), 7.38-7.32 (m, 2H), 7.17-7.09 (m, 2H), 4.84-4.76 (m, 1H), 4.39 (s, 2H), 3.43-3.34 (m, 2H), 3.18-3.10 (m, 2H), 3.00 (d, J=7.5 Hz, 2H), 2.92 (s, 3H), 2.11-2.01 (m, 2H), 1.84-1.73 (m, 2H), 1.63-1.52 (m, 1H), 0.68 (d, J=6.6 Hz, 6H). LCMS (m/z, Method B) ES+ 499.9 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH3:16])[C:12]([C:17]([F:20])([F:19])[F:18])=[CH:11][N:10]=2)=[C:4]([O:21][CH3:22])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:29][N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[N:31]1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][O:21][C:4]1[CH:3]=[C:2]([C:33]2[CH:32]=[N:31][N:30]([CH3:29])[CH:34]=2)[CH:7]=[CH:6][C:5]=1[NH:8][C:9]1[N:14]=[C:13]([NH:15][CH3:16])[C:12]([C:17]([F:20])([F:19])[F:18])=[CH:11][N:10]=1
Reactant: CNc1nc(Nc2ccc(Br)cc2OC)ncc1C(F)(F)F
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CNc1nc(Nc2ccc(-c3cnn(C)c3)cc2OC)ncc1C(F)(F)F
Yield: 24.8 %

Procedure:
A mixture of N2-(4-bromo-2-methoxyphenyl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (0.365 g, 1 mmol), Pd(PPh3)4 (115 mg, 0.1 mmol), K2CO3 (0.415 g, 3 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.415 g, 2 mmol) in dioxane (10 mL) and water (1.25 mL) was degassed under a stream of nitrogen for 10 min. The reaction tube was sealed and the mixture irradiated in the microwave at 100° C. for 20 min. The mixture was cooled and concentrated under reduced pressure. The residue was partitioned between ethyl acetate (20 mL) and water (20 mL) and the product extracted into ethyl acetate (2×20 mL). The combined organics were passed through a phase separation cartridge and the solvent removed under reduced pressure. Purification of the residue via silica gel column chromatography (0-100% ethyl acetate/isohexane) afforded a residue that was triturated with diethyl ether yielding N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine as an off-white solid (94 mg, 25%). LCMS (10 cm_ESCI_Formic_MeCN): [MH+]=379 at 3.11 min. 1H NMR (400 MHz, CDCl): δ 8.49 (d, J=8.4, 1H); 8.17 (s, 1H); 7.76-7.68 (m, 2H); 7.58 (s, 1H); 7.10 (dd, J=8.4, 1.9, 1H); 6.98 (d, J=1.9, 1H); 5.20 (s, 1H); 3.95 (s, 6H); 3.12 (d, J=4.7, 3H).
Reaction SMILES: [C:1](O)(=O)/[C:2](=[C:4](\[CH:6]=[O:7])/[Cl:5])/[Cl:3].Cl.[C:11]([NH:15][NH2:16])([CH3:14])([CH3:13])[CH3:12]>CO>[C:11]([N:15]1[C:6](=[O:7])[C:4]([Cl:5])=[C:2]([Cl:3])[CH:1]=[N:16]1)([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C/C(Cl)=C(/Cl)C(=O)O
Reactant: CC(C)(C)NN
Agent: Cl
Solvent: CO
Product: CC(C)(C)n1ncc(Cl)c(Cl)c1=O

Procedure:
A solution of mucochloric acid (33.8 g, 200 mmol) and tert.-butylhydrazine hydrochloride (24.9 g, 200 mmol) in methanol (400 mL) was stirred at reflux overnight. Methanol was removed in vacuo and the residue was partitioned between ether and water. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (silica gel, 100% hexanes). Product-containing fractions were combined and the title compound was crystallized from ether/hexanes (yield: 10.0 g, 22.6%). mp 63-64° C. 1H NMR (300 MHz, CDCl3) δ 1.65 (s, 9H), 7.73 (s, 1H). MS (DCI/NH3) m/z 221 (M+H)+, 238 (M+NH4)+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([NH:11][C:12](=O)[CH:13]([CH3:15])[CH3:14])[CH:3]=1.[NH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.C(C#N)(C)=O.P(Cl)(Cl)Cl.[OH-].[Na+]>O>[OH:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6](=[O:8])[N:17]([C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=3)[C:12]([CH:13]([CH3:15])[CH3:14])=[N:11]2)=[CH:9][CH:10]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: CC(C)C(=O)Nc1cc(O)ccc1C(=O)O
Agent: CC(=O)C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClP(Cl)Cl
Product: CC(C)c1nc2cc(O)ccc2c(=O)n1-c1ccc(C#N)cc1
Temperature: 22 °C
Reaction time: 20 h
Yield: 75.2 %

Procedure:
A 2-L Argonaut reactor, equipped with pitched-blade impeller, RTD sensor, reflux condenser, addition funnel, and nitrogen inlet-outlet, was charged with 54.90 g (246.0 mmol) of 4-hydroxy-2-isobutyrylamino-benzoic acid (5), 31.96 g (270.6 mmol) of 4-aminobenzonitrile (6) and 919.2 g (1.177 L) of AcCN. The suspension was stirred at 22±3° C. for 30 min with an efficient mixing, and 70.97 g (45.09 mL, 516.7 mmol) of PCl3 were added while maintaining an internal temperature of 22±10° C. The suspension was then warmed to an internal temperature of 60±3° C. over 1 h, and the mixture was stirred at 60±3° C. for 20 h with an efficient mixing. The suspension was cooled to an internal temperature of 15±3° C. over 30 min, and then 54.275 g (1356.87 mmol) of NaOH in 220 g of water were added while maintaining an internal temperature of 15±10° C. The suspension was warmed to an internal temperature of 75±5° C. over 1 h, then the mixture was stirred at this temperature for 30 min. Then the mixture was cooled to an internal temperature of 30±5° C. over 45 min, and the organic layer was separated off. The organic layer was then line-filtered by pressure (300 to 500 mbar) and the solvent was concentrated under vacuum (100-50 torr) at an internal temperature of 20-30° C. to collect ˜950 mL of solvent (batch volume ˜200 mL). 875 mL of water were added to the concentrate. Again the solvent was concentrated under vacuum (200-150 torr) at an internal temperature of 20-30° C. to collect ˜200 mL of solvent (batch volume ˜820 mL). The remaining suspension was stirred at 20±3° C. for 2 h, and the solid was removed by filtration over a polypropylene filter paper in a Büchner funnel with suction. The filter cake was washed with 2×100 mL of H2O. The solid was dried under vacuum (100-150 mbar) at 50±5° C. with nitrogen bleeding until ≦1% LOD (15 h) to obtain 56.5 g of 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline-3-yl)-benzonitrile (7) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[O:6][C@:5]([C:8]2[CH:9]=[C:10]([S:13][C:14]3[CH:19]=[CH:18][C:17]([C:20](=O)[CH3:21])=[CH:16][CH:15]=3)[S:11][CH:12]=2)([CH3:7])[CH2:4][O:3]1.Cl.[NH2:25][OH:26]>>[CH3:1][C:2]1([CH3:23])[O:6][C@:5]([C:8]2[CH:9]=[C:10]([S:13][C:14]3[CH:19]=[CH:18][C:17](/[C:20](=[N:25]/[OH:26])/[CH3:21])=[CH:16][CH:15]=3)[S:11][CH:12]=2)([CH3:7])[CH2:4][O:3]1
Reactant: NO
Reactant: CC(=O)c1ccc(Sc2cc([C@@]3(C)COC(C)(C)O3)cs2)cc1
Agent: Cl
Product: C/C(=N\O)c1ccc(Sc2cc([C@@]3(C)COC(C)(C)O3)cs2)cc1
Yield: 95 %

Procedure:
Using an analogous procedure to that described in Example 68, 4'-{4-[(4S)-2,2,4-trimethyl-1,3-dioxolan-4-yl]thien-2-ylthio}acetophenone was reacted with hydroxylamine hydrochloride to give (E)-4'-{4-[(4S)-2,2,4-trimethyl-1,3-dioxolan-4-yl]thien-2-ylthio}acetophenone oxime in 95% yield as a gum.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25])[CH:19]=O.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>C1COCC1>[CH3:27][O:26][C:22]1[CH:21]=[C:18]([CH:17]=[C:16]([O:15][CH3:14])[C:23]=1[O:24][CH3:25])[CH2:19][N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: COC(=O)c1ccc2c(c1)CCN2
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)CCN2Cc1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
To a solution of 20 (300 mg, 1.69 mmol), 3,4,5-trimethoxybenzaldehyde (365 mg, 1.86 mmol) and dibutyltin dichloride (51 mg, 0.17 mmol) in THF (8 mL) was added phenylsilane (229 μl, 1.86 mmol). The mixture was stirred overnight at room temperature under nitrogen. Additional aldehyde and phenylsilane were added and the stirring continued until starting material was consumed. THF was evaporated in vacuum and the residue was purified by flash chromatography (eluent 20% EtOAc in hexane). The compound was further purified by re-crystallization in a mixture EtOAc/hexane and finally by a second flash chromatography (eluent 20% EtOAc in hexane) to give the title compound 21 (428 mg, 71%) as a white solid. 1H-NMR (DMSO) δ: 2.96 (t, J=8.4 Hz, 2H); 3.45 (t, J=8.7 Hz, 2H); 3.61 (s, 3H); 3.71 (s, 6H); 3.72 (s, 3H); 4.30 (s, 2H); 6.59 (s, 2H); 6.61 (d, J=8.4 Hz, 1H), 7.54 (d, J=1.6 Hz, 1H); 7.63 (dd, J=1.8, 8.4 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[N:15]=[C:14]([OH:16])[CH:13]=[C:12]([OH:17])[N:11]=1.[N+:18]([O-])([OH:20])=[O:19]>C(O)(=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[N:11]=[C:12]([OH:17])[C:13]([N+:18]([O-:20])=[O:19])=[C:14]([OH:16])[N:15]=1
Reactant: COc1ccc(F)c(-c2nc(O)cc(O)n2)c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(F)c(-c2nc(O)c([N+](=O)[O-])c(O)n2)c1
Temperature: 50 °C

Procedure:
To a suspension of 2-(2-Fluoro-5-methoxyphenyl)-4,6-dihydroxypyrimidine (12 g) in 35 mL of acetic acid is added 12 mL of 90% nitric acid and the mixture is heated at 50° C. for 45 min. The reaction mixture is diluted with 150 mL of water and the product is collected, washed with water and ethanol and oven dried to afford 2-(2-Fluoro-5-methoxyphenyl)-5 -nitro-4,6-dihydroxy-pyrimidine as a pink solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[Br:11]Br>C(O)(=O)C>[Br:11][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1)=[O:10]
Reactant: CC(=O)c1ccc(I)cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(CBr)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To the solution of 1-(4-Iodo-phenyl)-ethanone (Aldrich, 125 g, 508 mmol) in glacial acetic acid (600 mL) was added the bromine (Aldrich, 79.3 g, 508 mmol, in 50 mL of acetic acid) and stirred at room temperature for 10 hours. It was concentrated under reduced pressure. The residue was then diluted with ethyl acetate (100 mL) and washed with brine (3×50 mL). The organic solution was concentrated. The title compound was obtained as yellow solid by recrystallization from diethyl ether (150 g, 91%). 1H NMR (300 MHz, CDCl3) δ 4.39 (s, 2H), 7.69 (d, J=8.5 Hz, 2H), 7.87 (d, J=8.5 Hz, 2 H) ppm; MS (DCl/NH3) m/z 246 (M−Br)+, 264 (M−Br+NH4)+.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH2:10][CH2:9][O:8][C:7]1=[O:11])C.O.[NH2:14][NH2:15]>C(O)C>[O:11]=[C:7]1[N:6]([CH2:5][C:4]([NH:14][NH2:15])=[O:3])[CH2:10][CH2:9][O:8]1
Reactant: CCOC(=O)CN1CCOC1=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)CN1CCOC1=O

Procedure:
As described for example 112a, (2-oxo-oxazolidin-3-yl)-acetic acid ethyl ester (Potts, Kevin T.; Bhattacharjee, Debkumar; Kanemasa, Shuji. Journal of Organic Chemistry (1980), 45(24), 4985-8) in ethanol was reacted with hydrazine hydrate (1.0 equivalent) at rt for 72 h. All volatiles were evaporated, the residue was chromatographed (SiO2, dichloromethane:methanol:aq.ammonia (25%)=90:10:1) and the title compound was obtained as a white solid (yield: 77%). MS: m/e=160.4 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.C(N(CC)CC)C.[C:14](Cl)(=[O:18])[C:15]([CH3:17])=[CH2:16]>CC(C)=O>[CH3:16][CH:15]1[CH2:17][N:3]2[N:4]=[CH:5][N:6]=[C:2]2[NH:1][C:14]1=[O:18]
Reactant: Nc1nc[nH]n1
Reactant: C=C(C)C(=O)Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC1Cn2ncnc2NC1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
33.63 g (0.4 mol) 3-amino-1H-1,2,4-triazole was suspended in 300 ml acetone. 44.44 g (0.44 mol) triethyl amine was added and the mixture was cooled to 0° C. 33.63 g (0.44 mol) methacryloyl chloride was added dropwise over 45 minutes, while the temperature was kept at 0° C. The reaction was allowed to continue at 0° C. for one hour. The precipitated salts were removed by filtration and an additional 10 ml triethyl amine was added to the filtrate. The mixture was refluxed for 18 hours. The precipitated compounds were removed by filtration and the solvent was evaporated under reduced pressure. 6-methyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidin-5-on was isolated by preparative column chromatography on a Prochrom LC 80 system, using Kromasil C18 100 Å 10 μm silica and MeOH and an aqueous solution of 0.2% (v/v) triethyl amine and 0.5% (v/v) acetic acid in a 42/58 ratio as eluent, at a flow rate of 150 ml/min. 770 mg of 6-methyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidin-5-on was isolated.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:38])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([OH:31])[N:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:45]([O:47][C:48](=[O:51])[CH2:49]Br)[CH3:46]>CN(C=O)C.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:38])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:49][C:48]([O:47][CH2:45][CH3:46])=[O:51])[N:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)n(-c3ccccc3)n2)CC1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1cc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N2CCN(C(=O)OCC)CC2)nn1-c1ccccc1
Temperature: 100 °C

Procedure:
To a solution of 60 mg of 4-{(S)-4-tert-Butoxycarbonyl-2-[(5-hydroxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester in 20 ml of DMF, 73 mg of cesium carbonate and 38 mg of Bromo-acetic acid ethyl ester was added and heated to 100° C. for 4 h. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was used in the subsequent reaction.