Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH2:10]2)[C:5]([F:16])=[CH:4][N:3]=1.Br[CH2:18][CH:19]=[CH2:20].[NH4+].[Cl-]>CN(C=O)C.[Zn]>[CH2:20]([C:11]1([OH:15])[CH2:12][CH2:13][CH2:14][C@H:9]([NH:8][C:6]2[C:5]([F:16])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:10]1)[CH:19]=[CH2:18]
Reactant: O=C1CCC[C@H](Nc2nc(Cl)ncc2F)C1
Reactant: C=CCBr
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CN(C)C=O
Product: C=CCC1(O)CCC[C@H](Nc2nc(Cl)ncc2F)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of (3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]cyclohexanone, 29b, (0.60 g, 2.46 mmol) and 3-bromoprop-1-ene (0.43 mL, 4.92 mmol) in DMF was added Zn dust (0.32 g, 4.92 mmol). The reaction was stirred at room temperature for 3 days. The mixture was diluted into aqueous saturated NH4Cl solution, extracted twice with EtOAc. The combined organic phases were washed twice with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography using 0-50% EtOAc/hexanes gradient to afford 553 mg of desired product, 58a, as an oil. LC/MS-two peaks corresponding to two diastereomeric products: 286.4 (M+H), RT=3.41 and 3.78.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[N+:18]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1)([O-:20])=[O:19]>>[CH3:16][C:13]1([CH3:17])[N:12]([CH2:25][C:24]2[CH:27]=[CH:28][C:21]([N+:18]([O-:20])=[O:19])=[CH:22][CH:23]=2)[N:11]([CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)[C:14]1=[O:15]
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1ccc([N+](=O)[O-])cc1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 4-nitrobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a yellow crystalline powder.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][CH:3]=1.Cl[CH2:11][CH:12]=O>>[Br:1][C:2]1[N:7]2[CH:11]=[CH:12][N:8]=[C:6]2[C:5]([CH3:9])=[CH:4][CH:3]=1
Reactant: O=CCCl
Reactant: Cc1ccc(Br)nc1N
Product: Cc1ccc(Br)n2ccnc12
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 95 %

Procedure:
A mixture of 6-bromo-3-methylpyridin-2-ylamine (359 mg, 1.92 mmol) and chloroacetaldehyde (1 mL, 50 wt. % in water) in IMS (4 mL) was stirred at 100° C. in a sealed tube for 1.5 hours, then cooled to room temperature and loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was washed with MeOH then eluted with 2 M NH3 in MeOH to give 5-Bromo-8-methylimidazo[1,2-a]pyridine as a beige solid (387 mg, 95%). 1H NMR (400 MHz, CHCl3-d): δ 7.79 (d, J=1.3 Hz, 1 H); 7.69 (d, J=1.3 Hz, 1 H); 6.96 (d, J=7.3 Hz, 1 H); 6.91 (dq, J=7.3, 1.1 Hz, 1 H); 2.61 (d, J=1.1 Hz, 3 H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([OH:20])[CH:11]=2)=[CH:4][N:3]=1.[C:21](O)(=[O:25])/[CH:22]=[CH:23]/[CH3:24].[OH-].[NH4+]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[C:11]3[C:21](=[O:25])[CH2:22][CH:23]([CH3:24])[O:20][C:12]=3[C:13]([O:18][CH3:19])=[C:14]([O:16][CH3:17])[CH:15]=2)=[CH:4][N:3]=1
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(O)c1OC
Reactant: C/C=C/C(=O)O
Agent: [NH4+]
Agent: [OH-]
Product: COc1cc(Cc2cnc(N)nc2N)c2c(c1OC)OC(C)CC2=O
Yield: 29 %

Procedure:
A mixture of 2,4-diamino-5-(3-hydroxy-4,5-dimethoxybenzyl)pyrimidine (2.76 g, 0.01 mole) and crotonic acid (0.87 g, 0.01 mole) in polyphosphoric acid (27 g) was stirred and heated on a steam bath for 4 hr. The reaction mixture was cooled to 50° and poured onto ice (100 g) with stirring. The resulting solution was basified to pH 8.0 with concentrated ammonium hydroxide, giving a suspension which was then extracted with methylene chloride (3×100 mL). The combined extracts were washed with 0.1N sodium hydroxide (2×100 mL), water (100 mL) and then dried over anhydrous magnesium sulfate. Evaporation of solent in vacuo gave the title compound (1.0 g, 29%). This was recrystallised from 95% ethanol to give 2,4-diamino-5-(3,4-dihydro-7,8-dimethoxy-2-methyl-4-oxo-2H-1-benzopyran-5-ylmethyl)pyrimidine as the hemihydrate, mp 128°-132°. Anal. Calcd for C17H20N4O4.1/2H2O: C, 57.78; H, 5.99; N, 15.85. Found: C, 57.79; H, 6.02; N, 15.86.
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[N:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:31][CH2:32][O:33][CH3:34])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:37])[CH:3]=1.[O-:38][C:39]#[N:40].[Na+]>CC(O)=O.O>[F:37][C:4]1[CH:3]=[C:2]([NH:1][C:39]([NH2:40])=[O:38])[CH:36]=[CH:35][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[N:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:31][CH2:32][O:33][CH3:34])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:18][CH:17]=3)[S:15][C:8]=12
Reactant: N#C[O-]
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(N)=O)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 61.5 %

Procedure:
To a solution of compound 126 (3.0 g, 5.72 mmol) in AcOH (13.6 mL) at 0° C. was added a solution of sodium cyanate (0.743 g, 11.44 mmol, 2 eq.) in water (5.2 mL). The mixture was stirred at r.t. for 20 h. Water (100 mL) was added and the reaction mixture turned into a suspension. After 30 min, the solid was collected by filtration and the product cake was washed with water (2×20 mL), dried in vacuum and purified by Biotage SPI Flash Purification System (eluent a gradient EA/MeOH, 100/0 to 90/10) to afford 288 as a white solid (2.0 g, 3.52 mmol, 62% yield). MS (m/z): 568.4 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[N:18]=[C:17]4[C:13]([NH:14][C:15](=[S:30])[N:16]4[C@H:19]4[C:28]5[C:23](=[C:24]([F:29])[CH:25]=[CH:26][CH:27]=5)[O:22][CH2:21][CH2:20]4)=[CH:12][N:11]=3)[C:6]=2[CH:31]=1.[CH3:32]CN(P1(N(C)CCCN1)=NC(C)(C)C)CC.IC>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[N:18]=[C:17]4[C:13]([NH:14][CH:15]([S:30][CH3:32])[N:16]4[C@H:19]4[C:28]5[C:23](=[C:24]([F:29])[CH:25]=[CH:26][CH:27]=5)[O:22][CH2:21][CH2:20]4)=[CH:12][N:11]=3)[C:6]=2[CH:31]=1
Reactant: CCN(CC)P1(=NC(C)(C)C)NCCCN1C
Reactant: Fc1ccc2ncn(-c3ncc4[nH]c(=S)n([C@@H]5CCOc6c(F)cccc65)c4n3)c2c1
Solvent: CC#N
Solvent: CI
Product: CSC1Nc2cnc(-n3cnc4ccc(F)cc43)nc2N1[C@@H]1CCOc2c(F)cccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.6 %

Procedure:
2-(6-Fluoro-1H-benzo[d]imidazol-1-yl)-9-((R)-8-fluorochroman-4-yl)-7H-purine-8(9H)-thione (4 mg, 0.009 mmol) was dissolved in 1 mL anhydrous acetonitrile, add 25 mg (0.054 mmol) 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine on polystyrene (Fluka), then 3 microliter iodomethane. The mixture was stirred at room temperature for 30 minutes. After concentration in vacuo, the residue was purified by silica gel column chromatography eluting with 2% MeOH in DCM and EtOAc to yield 2.1 mg (52%) the titled compound as a pale yellow solid.
Reaction SMILES: C(N(CC)CC)C.[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH2:13][C:14]([NH:16][C@@H:17]1[C:29](=[O:30])[N:19]2[C:20]([C:26]([OH:28])=[O:27])=[C:21]([CH2:24][OH:25])[CH2:22][S:23][C@H:18]12)=[O:15].[C:31]1(=[O:37])[O:36][C:34](=[O:35])[CH2:33][CH2:32]1>ClCCl>[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH2:13][C:14]([NH:16][C@@H:17]1[C:29](=[O:30])[N:19]2[C:20]([C:26]([OH:28])=[O:27])=[C:21]([CH2:24][O:25][C:31](=[O:37])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])[CH2:22][S:23][C@H:18]12)=[O:15]
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12
Reactant: O=C1CCC(=O)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)CCC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
In dichloromethane (30 ml) was dissolved 7β-(2-thienylacetamido)-3-hydroxymethyl-3-cephem-4-carboxylic acid triethylamine salt (4.55 g), followed by the addition of succinic anhydride (1.50 g). The mixture was stirred at room temperature for 2 hours. The dichloromethane was distilled off and, following the addition of 3% aqueous phosphoric acid solution (100 ml), the residue was extracted with ethyl acetate (150 ml). The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride (100 ml×2), dried (over magnesium sulfate) and concentrated under reduced pressure. The residue was treated with ether and the resultant powder was recovered by filtration, washed with ether and dried under reduced pressure over phosphorus pentoxide. The procedure provided 7β-(2-thienylacetamido)-3-(3-carboxypropionyloxy)methyl-3-cephem-4-carboxylic acid (4.00 g).
Reaction SMILES: [C:1]([N:4](CC1C=CC(OC)=CC=1)[CH2:5][C:6]([C:9]1[CH:13]=[C:12]([NH:14][C:15](=[O:28])[C:16]([CH3:27])([S:18]([CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH3:17])[O:11][N:10]=1)([CH3:8])[CH3:7])(=[O:3])[CH3:2].C(#N)C>O>[C:1]([NH:4][CH2:5][C:6]([C:9]1[CH:13]=[C:12]([NH:14][C:15](=[O:28])[C:16]([CH3:17])([S:18]([CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH3:27])[O:11][N:10]=1)([CH3:8])[CH3:7])(=[O:3])[CH3:2]
Reactant: COc1ccc(CN(CC(C)(C)c2cc(NC(=O)C(C)(C)S(=O)(=O)C3CCOCC3)on2)C(C)=O)cc1
Solvent: CC#N
Solvent: O
Product: CC(=O)NCC(C)(C)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 4 %

Procedure:
To a solution of N-(3-{2-[acetyl-(4-methoxy-benzyl)-amino]-1,1-dimethyl-ethyl}-isoxazol-5-yl)-2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionamide (116 mg, 0.22 mmol) in the mixture of acetonitrile (2 mL) and water (0.7 mL) is added ceric ammonium nitrate (476 mg, 0.87 mmol). The reaction mixture is stirred at room temperature for 40 minutes. After this time, the reaction mixture is quenched with saturated aqueous NaHCO3 solution and extracted with ethyl acetate 3 times. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by preparative HPLC provides the title compound. Yield: 4%; m/z 416 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4]Br.[OH:7][C:8]1[CH:17]=[C:16]2[C:11]([N:12]=[CH:13][C:14]([O:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([NH:27][C:28]([C:30]4[CH:31]=[CH:32][C:33]5[S:38][CH2:37][C:36](=[O:39])[NH:35][C:34]=5[CH:40]=4)=[O:29])[CH2:23][CH2:22]3)=[N:15]2)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:6])[CH2:4][O:7][C:8]1[CH:17]=[C:16]2[C:11](=[CH:10][CH:9]=1)[N:12]=[CH:13][C:14]([O:18][CH2:19][CH2:20][N:21]1[CH2:22][CH2:23][CH:24]([NH:27][C:28]([C:30]3[CH:31]=[CH:32][C:33]4[S:38][CH2:37][C:36](=[O:39])[NH:35][C:34]=4[CH:40]=3)=[O:29])[CH2:25][CH2:26]1)=[N:15]2
Reactant: O=C1CSc2ccc(C(=O)NC3CCN(CCOc4cnc5ccc(O)cc5n4)CC3)cc2N1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc2ncc(OCCN3CCC(NC(=O)c4ccc5c(c4)NC(=O)CS5)CC3)nc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 6.9 %

Procedure:
Bromo-acetic acid methyl ester (20.0 μL, 0.22 mmol, 1.05 eq) is added at room temperature to a stirred solution of 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid {1-[2-(7-hydroxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amide (100 mg, 0.21 mmol, 1.0 eq) in N,N-dimethylformamide (2 mL), followed by potassium carbonate (57.6 mg, 0.42 mmol, 2.0 eq). After 5 hours stirring at room temperature, solvent is evaporated and the residue is extracted with dichloromethane (3×5 mL) and water (5 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by preparative HPLC to afford [3-(2-{4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-piperidin-1-yl}-ethoxy)-quinoxalin-6-yloxy]-acetic acid methyl ester as a white powder (8 mg, 6% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([NH:13][CH2:14][CH3:15])=[O:12])[C:5]([Cl:20])=[CH:4][N:3]=1.[N:21]1([CH:27]2[CH2:33][CH2:32][C:31]3[CH:34]=[C:35]([NH2:38])[CH:36]=[CH:37][C:30]=3[CH2:29][CH2:28]2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([NH:13][CH2:14][CH3:15])=[O:12])=[N:7][C:2]([NH:38][C:35]2[CH:36]=[CH:37][C:30]3[CH2:29][CH2:28][CH:27]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH2:33][CH2:32][C:31]=3[CH:34]=2)=[N:3][CH:4]=1
Reactant: Nc1ccc2c(c1)CCC(N1CCOCC1)CC2
Reactant: CCNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CCNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCC(N2CCOCC2)CC3)ncc1Cl

Procedure:
The title compound was prepared from 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-ethyl-benzamide and 7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine in an analogous manner to Example 179. Product was isolated as a tan solid (30 mg, 40%). LCMS (m/e) 521 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.65 (d, 1H, J=8.3 Hz), 8.04 (s, 1H), 7.52 (broad s, 1H), 7.50 (d, 1H, J=7.6 Hz), 7.43 (dd, 1H, J=8.1, 7.6 Hz), 7.37 (s, 1H), 7.29 (s, 1H), 7.09 (t, 1H, J=7.6), 7.04 (d, 1H, J=8.1 Hz), 6.16 (broad s, 1H), 3.71 (s, 4H), 3.52 (m, 3H), 2.63-2.85 (m, 4H), 2.58 (s, 4H), 2.8 (m, 2H), 1.42 (m, 2H), 1.27 (t, 3H, J=7.3 Hz).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[C:6]([NH:8][CH2:9][C:10]([NH:12][CH2:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[O:11])=[O:7].[OH:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH:29]=O.[BH3-]C#N.[Na+]>C(O)(=O)C.CO>[OH:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:29][N:17]1[CH2:18][CH2:19][CH:14]([CH2:13][NH:12][C:10](=[O:11])[CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:20]=[CH:21][CH:22]=[C:3]([C:2]([F:1])([F:23])[F:24])[CH:4]=2)[CH2:15][CH2:16]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC1CCNCC1
Reactant: COc1ccc(C=O)cc1O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(CN2CCC(CNC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)CC2)cc1O
Temperature: 60 °C
Reaction time: 15 h

Procedure:
A 5% acetic acid/methanol (1.0 mL) solution of 4-[[N-(3-(trifluoromethyl)benzoyl)glycyl]aminomethyl]piperidine (20.0 mg, 0.058 mm ol) and 3-hydroxy-4-methoxybenzaldehyde (33 mg) was added to a 5% acetic acid/methanol (1.0 mL) solution of NaBH3CN (16.5 mg), and the mixture was stirred at 60° C. for 15 hours. The resulting reaction mixture wa's then loaded onto a Varian™ SCX column and washed with methanol (15 mL). The obtained crude product was eluted with a 2 M NH3-methanol (5 mL) and concentrated to thereby afford 1-[3-hydroxy-4-methoxybenzyl]4-[[N-(3-(trifluoromethyl)benzoyl)glycyl]aminomethyl]piperidine (Comp d. No. 1452) (25.8 mg, 92%). The purity was determined by RPLC/MS (91%). ESI/MS m/e 480 (M++H, C24H28F3N3O4).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:22]=[CH:21][C:16]([O:17][CH2:18][C:19]#[N:20])=[C:15]([CH:23]=O)[CH:14]=1.N1CCCC1>CO>[Cl:12][C:13]1[CH:22]=[CH:21][C:16]([O:17][CH2:18][C:19]#[N:20])=[C:15](/[CH:23]=[C:6]2\[C:7](=[O:11])[NH:8][C:9]3[C:5]\2=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=3)[CH:14]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: N#CCOc1ccc(Cl)cc1C=O
Solvent: C1CCNC1
Solvent: CO
Product: N#CCOc1ccc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Temperature: 70 °C
Yield: 22.4 %

Procedure:
To the mixture of 6-chlorooxindole (18.4 g, 0.110 mol) and (4-chloro-2-formyl-phenoxy)-acetonitrile (21.5 g, 0.110 mol) in methanol (200 mL) was added pyrrolidine (8.60 g, 0.121 mol) dropwise. Then the mixture was heated at 70° C. for 2 h. After cooled to room temperature, the mixture was filtered. The precipitate was collected and dried to give the title compound as a yellow solid (8.5 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]=2)[CH:5]=[CH:6][N:7]=1.C1C(=O)N([Br:22])C(=O)C1.O>C(#N)C.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:22][C:8]1[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]2=[N:10][C:9]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cn2ccnc(Cl)c2n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: CC#N
Product: COC(=O)c1nc2c(Cl)nccn2c1Br
Temperature: 25 °C
Yield: 80.9 %

Procedure:
To a solution of methyl 8-chloroimidazo[1,2-a]pyrazine-2-carboxylate (9.9 g, 46.8 mmol) in acetonitrile (600 mL) was added NBS (8.9 g, 50.1 mmol), and benzoyl peroxide (90 mg, 0.37 mmol). The mixture was then heated to reflux for 1 h, cooled to r.t., and water (1800 mL) was added. The resulting solids were filtered, washed with water, and air dried to give the title compound (11 g). LRMS (ESI) calc (M+H)+=289.9/291.9. found 290.0/292.0
Reaction SMILES: CC1(C)[O:6][C@H:5]([C:7]2[N:11]=[C:10]([NH:12][C:13]3[C:18]([O:19][C:20]4[C:21]([CH3:26])=[N:22][CH:23]=[CH:24][CH:25]=4)=[CH:17][C:16]([S:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[CH:15][N:14]=3)[S:9][N:8]=2)[CH2:4][O:3]1.Cl>C(O)C>[CH3:26][C:21]1[C:20]([O:19][C:18]2[C:13]([NH:12][C:10]3[S:9][N:8]=[C:7]([C@@H:5]([OH:6])[CH2:4][OH:3])[N:11]=3)=[N:14][CH:15]=[C:16]([S:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[CH:17]=2)=[CH:25][CH:24]=[CH:23][N:22]=1
Reactant: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@@H]2COC(C)(C)O2)ns1
Agent: Cl
Solvent: CCO
Product: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@@H](O)CO)ns1
Temperature: 70 °C
Yield: 82.4 %

Procedure:
A flask was charged with (R)-3-(2,2-dimethyl-1,3-dioxolan-4-yl)-N-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-1,2,4-thiadiazol-5-amine (3.8 g, 7.683 mmol) and added ethanol (40 mL). 3M HCl (5.122 ml, 15.37 mmol) was added, and the reaction was heated to 70° C. for 1 hour, then cooled to ambient temperature. The ethanol removed in vacuo and saturated sodium bicarbonate solution was added. The aqueous layer was extracted with ethyl acetate. The majority of product crashed out of the aqueous layer and collected by filtration. The solids and residue from organic layer were purified over silica gel (10-15% methanol in ethyl acetate) to afford (R)-1-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol (2.877 g, 6.330 mmol, 82.38% yield) as yellow solid. Mass Spectrum (apci) m/z=455.1 (M+H).
Reaction SMILES: [N:1]([C:4](=[CH:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+]=[N-]>CC1C=CC=CC=1C>[CH2:8]([O:7][C:5]([C:4]1[NH:1][C:12]2=[N:13][CH:14]=[CH:15][C:16]([O:17][CH3:18])=[C:11]2[CH:10]=1)=[O:6])[CH3:9]
Reactant: CCOC(=O)C(=Cc1cnccc1OC)N=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1cc2c(OC)ccnc2[nH]1

Procedure:
A stirred solution of ethyl-α-azido-β-(4-methoxypyrid-3-yl)-acrylate 2 (3.7 g, 14.9 mmol) in dry o-xylene (35 mL) was heated in an oil bath at 170° C. for 25 min. During this time the contents of the flask gained brick red color. After cooling, the mixture was concentrated under high vacuum. The resultant brown residue was purified on silica gel column using 5% methanol in CH2Cl2 to give 3 as brick red solid. Mp 195-197° C.; Yield: 3.3 g, 82%; ESI MS: m/z 220.9 (M+1).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([Cl:13])[C:3]=1[NH2:4].[CH3:14]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.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>[Cl:13][C:5]1[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=[C:2]([CH3:14])[C:3]=1[NH2:4]
Reactant: CB1OB(C)OB(C)O1
Reactant: Nc1c(Cl)cc(C(F)(F)F)cc1Br
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: CN(C)C=O
Product: Cc1cc(C(F)(F)F)cc(Cl)c1N
Temperature: 90 °C

Procedure:
A mixture of 2-bromo-6-chloro-4-trifluoromethyl aniline (1.00 g, 3.64 mmol), trimethylboroxine (0.66 ml, 0.59 g, 4.47 mmol), potassium carbonate (1.00 g, 7.30 mmol) and catalytic amount (10%) Pd(PPh3)4 in DMF (5 ml) was heated to 90° C. for 14 h. Water (20 ml) was added. The mixture was extracted with ethyl acetate (3×50 ml). The combined EtOAc layers were washed with brine and dried over sodium sulfate. The titled compound was obtained as a colorless oil after a flash column using EtOAc:hexane (1:9) as the elute. 1H NMR (CDCl3, 500 MHz): δ 7.43 (s, 1H), 7.24 (s, 1H), 4.38 (br s, 2H), 2.22 (s, 3H).
Reaction SMILES: C1C(=O)N([I:8])C(=O)C1.[CH3:9][Si:10]([CH3:48])([CH3:47])[CH2:11][CH2:12][O:13][CH2:14][N:15]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:16]1[N:21]2[N:22]=[CH:23][CH:24]=[C:20]2[N:19]=[C:18]([CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)[CH:17]=1>CC#N>[CH3:46][Si:43]([CH3:44])([CH3:45])[CH2:42][CH2:41][O:40][CH2:39][N:15]([CH2:14][O:13][CH2:12][CH2:11][Si:10]([CH3:9])([CH3:47])[CH3:48])[C:16]1[N:21]2[N:22]=[CH:23][C:24]([I:8])=[C:20]2[N:19]=[C:18]([CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)[CH:17]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Cc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NIS (288 mg, 1.28 mmoL) was added to a solution of tert-butyl 4-((7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)methyl)piperidine-1-carboxylate (Int-12d, 741.6 mg, 1.25 mmoL) in CH3CN (10 mL). The mixture was stirred at room temperature for 1 h. Purification by column chromatography afforded tert-butyl 4-((7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)methyl)piperidine-1-carboxylate (Int-12e): LCMS tR=3.02 Min (5 min run, UV254nm). Mass calculated for, M+717.2, observed m/z 718.3 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH:9]=[C:8]([C:17](O)=[O:18])[C:7]=2[CH:20]=1>C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH:9]=[C:8]([CH2:17][OH:18])[C:7]=2[CH:20]=1
Reactant: COc1ccc2c(c1)C(C(=O)O)=Cc1ccccc1O2
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)C(CO)=Cc1ccccc1O2
Yield: 96 %

Procedure:
Preparation analogous to Example 12f) from 8-methoxy-dibenz[b,f]oxepine-10-carboxylic acid. Yield: 96% in the form of a brown oil; TLC (silica gel; ethyl acetate/hexane=1:1; UV): Rf =0.31; 1H-NMR (CDCl3, 300 MHz): 1.80 (sbr, 1H); 3.78 (s, 3H); 4.69 (s, 2H); 6.82-7.33 (m, 8H) MS: 254 (M+), 211, 182, 181, 168, 165, 153, 152.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2[C:14](OC(C)(C)C)=O)[CH:5]=[N:6][CH:7]=1>C=O.C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2[CH3:14])[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(Cl)c1
Agent: C=O
Solvent: O=CO
Product: CN1CC[C@H]1COc1cncc(Cl)c1

Procedure:
A 500 mg sample of 5-chloro-3-(N-t-butoxycarbonyl-2-(S)-azetidinylmethoxy)pyridine, prepared as in Example 39a above, was dissolved in 3 mL of 37% HCHO and 1.5 mL of HCOOH, and the reaction mixture was stirred at 100° C. for 40 minutes. The reaction was quenched by addition of H2O. The mixture was adjusted to pH 7 with NaHCO3 and extracted with methylene chloride, the extract was dried over MgSO4, and the solvent was removed to give the title compound (181 mg). MS (DCI/NH3) m/e: 213/215 (M+H)+. 1H NMR (CDCl3, 300MHz) δ: 8.22 (d, J=2.5 Hz, 1H), 8.17 (d, J=1.9 Hz, 1H), 7.23 (dd, J=2.5, 1.9 Hz, 1H), 4.01 (d, J=5.1 Hz, 2H), 3.52-3.44 (m, 1H), 3.45-3.35 (m, 1H), 2.94-2.83 (m, 1H), 2.41 (s, 3H), 2.15-2.04 (m, 2H).