Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].Cl[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]>[OH-].[K+].O>[CH2:12]([O:11][C:9]([NH:1][C@@H:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4])=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC[C@H](N)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
10 g of 2(S)-aminobutyric acid (97 mmol) are dissolved in aqueous 4M KOH solution (100 ml) and the mixture is cooled to 0° C. 24.7 g of benzyl chloroformate (145 mmol) are added and the mixture is stirred while allowing its temperature to rise to room temperature over 2 hours 30 minutes. The mixture is then diluted with water (100 ml) and extracted with ether (2×200 ml). The aqueous phase is acidified to a pH<1 with concentrated HCl and is extracted with ethyl acetate (3×200 ml). The ethyl acetate fractions are combined and dried (Na2SO4) and the solvent is removed. A white solid is obtained.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Cl:7][C:8]1[N:13]=[C:12](Cl)[CH:11]=[CH:10][N:9]=1.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1.CO.O.C(OC)(C)(C)C>[Cl:7][C:8]1[N:13]=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]=[CH:10][N:9]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Solvent: CO
Product: Clc1nccc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.78 g (20.14 mmol) of K2CO3, 0.21 g (0.18 mmol) of tetrakis(triphenylphosphine)Pd(0) were added to 1.00 g (6.71 mmol) of 2,4-dichloropyrimidine and 0.82 g (6.71 mmol) of benzeneboronic acid in 29 ml of toluene and 7 ml of methanol, and the reaction mixture was stirred at room temperature for 3 hours. The residue after concentration of the reaction mixture was taken up in water/methyl tert-butyl ether. The aqueous phase was then extracted twice with methyl tert-butyl ether. Thereafter the combined organic phase was washed with water and with a saturated aqueous NaCl solution, and the organic phase was dried, filtered to remove the desiccant and concentrated. The solid brown residue was purified by flash chromatography on silica gel (mobile phase: ethyl acetate/cyclohexane: 10:90); yield: 0.90 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.C(N(CC)CC)C.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>ClCCl>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:4]2[C:5]3[O:9][CH2:8][CH2:7][C:6]=3[CH:10]=[C:2]([NH:1][C:25](=[O:26])[O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:3]=2)[CH:12]=1
Reactant: Nc1cc2c(c(-c3cccnc3)c1)OCC2
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cc2c(c(-c3cccnc3)c1)OCC2)Oc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
5-Amino-2,3-dihydro-7-(pyrid-3-yl)benzofuran (D64) (0.13 g, 0.00062 mole) was dissolved in dichloromethane (10 ml) and cooled to 0° C. under argon. Triethylamine (0.09 ml, 0.00068 mole) was added, followed dropwise by phenyl chloroformate (0.08 ml, 0.00065 mole) and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was washed with deionised water, dried (Na2SO4) and evaporated in vacuo to afford the title compound (0.20 g, 97%) as a cream solid.
Reaction SMILES: [CH3:1][O:2][SiH:3]([O:6][CH3:7])[O:4][CH3:5].[CH2:8]([NH:10][CH2:11][C:12](=[CH2:14])[CH3:13])[CH3:9].CO>C1(C)C=CC=CC=1>[CH2:8]([NH:10][CH2:11][CH:12]([CH3:14])[CH2:13][Si:3]([O:6][CH3:7])([O:4][CH3:5])[O:2][CH3:1])[CH3:9]
Reactant: CO[SiH](OC)OC
Reactant: C=C(C)CNCC
Solvent: Cc1ccccc1
Solvent: CO
Product: CCNCC(C)C[Si](OC)(OC)OC
Temperature: 68 °C
Reaction time: 0.75 h
Yield: 81.6 %

Procedure:
A one-liter three-neck round bottom flask was equipped with a magnetic stir bar, standard heating mantle, thermocouple, addition funnel, condenser and N2 inlet/bubbler. The flask was charged with 220 g (1.80 mols) of trimethoxysilane and heated to 60° C. at which temperature 0.25 ml of platinum tris(divinyltetramethyl disiloxane)diplatinum (0) (5% Pt content in toluene—referred to as Pt catalyst throughout these examples) was added. The solution was further heated to 68° C. and dropwise addition of 150 g (1.52 mols) of N-ethylmethallylamine was then conducted over a period of 45 minutes. After addition, the contents were heated to 90° C. and maintained at this temperature for 1 hr. The temperature was then increased to 105° C. and held for 4.5 hrs. Upon completion of the reaction, the mixture was cooled to room temperature and 16 g (0.5 mols) of methanol were added and gently heated prior to distillation. Final purification via vacuum distillation yielded 273 g (1.24 mols) of N-ethyl-3-trimethoxysilyl-2-methylpropanamine. The product (b.p. 98-100° C. at 12 mm Hg) was characterized via GC/MS. The isolated yield was 82%. Product structure was supported by GC/MS analysis.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][S:8][C:4]=2[CH:3]=1.Br[CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C([O-])([O-])=O.[K+].[K+].[ClH:31]>CCOCC.CCOC(C)=O.O.CC#N>[ClH:31].[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][CH2:14]3)=[N:7][S:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)CCBr
Reactant: Fc1ccc2c(C3CCNCC3)nsc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)CCN1CCC(c2nsc3cc(F)ccc23)CC1
Yield: 64 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisothiazole (6.0 g, 25 mmol), ethyl 3-bromopropionate (4.5 g, 25 mmol), K2CO3 (3.5 g) and CH3CN (100 ml) was stirred and refluxed for 16 hours. The reaction was poured into H2O, and after extractive workup with EtOAc, 6.0 g of an orange oil was realized. The oil was dissolved in Et2O and ethereal HCl was added to precipitate 6.3 g of a white hydrochloride salt. The salt was recrystallized from CH3CN to yield 6.0 g (64%) of the desired compound. An analytical sample was obtained by recrystallization of a 1.0 g sample g from EtOH-Et2O to yield 0.8 g of a white solid, m.p.=197°-199° C.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][C@@H:23]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24]1>>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][C@@H:23]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](ON)C1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Yield: 98.2 %

Procedure:
Following a procedure analogous to Example 27, from the carboxylic acid (6b, 553 mg, 2.00 mmol) of Example 9 or 16 and (R)-tert-butyl 3-(aminooxy)pyrrolidine-1-carboxylate (606 mg) described in Reference Example 13, 904.6 mg of the title compound was afforded (yield 98.3%).
Reaction SMILES: C(OC=CC[S:8]C)(=O)C.CO.[C]=O.[C:14]([O:17][CH:18]([CH2:23][CH2:24][S:25][CH3:26])[C:19]([O:21][CH3:22])=O)(=[O:16])[CH3:15]>O1CCCC1.[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Mn].[Mn].C1(C)C=CC=CC=1>[C:14]([O:17][CH:18]([CH2:23][CH2:24][S:25][CH3:26])[C:19]([O:21][CH3:22])=[S:8])(=[O:16])[CH3:15]
Reactant: CSCC=COC(C)=O
Reactant: COC(=O)C(CCSC)OC(C)=O
Agent: [Mn]
Agent: [C-]#[O+]
Agent: [C]=O
Solvent: C1CCOC1
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=S)C(CCSC)OC(C)=O
Temperature: 120 °C

Procedure:
0.5 mmoles 1-acetoxy-3-methylthiopropene (Z-:E ratio 43:57) and 0.5 mmoles methanol were charged into a 71 cc stainless steel bomb equipped with a glass liner and a Teflon coated stir bar. One mole percent, based on 1-acetoxy-3-methylthiopropene, of a catalyst comprising Mn2 (CO)10 was added. Toluene was included as an internal standard. Five milliliters of tetrahydrofuran as a solvent were also included in the reaction system. The reaction mixture was charged under argon. The bomb was sealed and carbon monoxide at a pressure of 1000 psi (at room temperature) was charged to the bomb, and the bomb was heated to 120° C. and allowed to react for 44 hours with stirring. At the termination of the reaction, the reaction products were analyzed by gas chromatography and it was found that no 2-acetoxy-4-(methylthio)butanoic acid, methyl ester was produced and that no 2-acetoxy-4-(methylthio)thiobutanoic acid, methyl ester was produced.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)([F:4])[F:3].[N+:12]([O-])([OH:14])=[O:13]>C([O-])(=O)C.[Na+]>[N+:12]([C:8]1[CH:9]=[CH:10][C:5]([C:2]([F:3])([F:4])[F:1])=[CH:6][C:7]=1[OH:11])([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(C(F)(F)F)cc1O
Reaction time: 1 h

Procedure:
The subtitle compound was prepared by using 3-(1,1,1-trifluoromethyl)phenol (5.0 g) which was cooled to 0 C and 65% nitric acid (6 ml) was added dropwise. After the addition, the mixture was kept at 0 C for 1 hour. This was diluted with saturated sodium acetate solution, extracted with ethyl acetate, dried and concentrated under reduced pressure to give an oil. Yield 3.67 g
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[N:4]1[CH2:10][C:11]([OH:13])=[O:12].O[N:15]1[C:19](=[O:20])[CH2:18][CH2:17][C:16]1=[O:21].C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[O:21]=[C:16]1[CH2:17][CH2:18][C:19](=[O:20])[N:15]1[O:12][C:11](=[O:13])[CH2:10][N:4]1[CH:3]([CH3:2])[CH2:8][CH2:7][CH2:6][CH:5]1[CH3:9]
Reactant: CC1CCCC(C)N1CC(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Product: CC1CCCC(C)N1CC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4.15 g (20 mMol) (2,6-dimethyl-piperidin-1-yl)-acetic acid hydrochloride (6), in 50 ml DMF, was added to 2.3 g (20 mMol) N-hydroxysuccinimide and 8.1 g (40 mMol) dicyclohexylcarbodiimide. The reaction mixture was stirred for 16 h at RT. The residue was filtered and the filtrate was evaporated under vacuum to dryness. After dissolving the residue in CH2Cl2, the solution was washed with NaHCO3, dried (sodium sulphate) and the solvent evaporated. The compound was then recrystallised from diisopropylether (A-Kohle).
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]1[CH2:8][CH2:7][N:6]([C:9]([C:11]2[S:19][C:18]3[C:13](=[N:14][CH:15]=[CH:16][C:17]=3[Cl:20])[CH:12]=2)=[O:10])[CH2:5]1.[CH3:21]I.[C-]#N.[K+]>C1COCC1>[Cl:20][C:17]1[CH:16]=[CH:15][N:14]=[C:13]2[CH:12]=[C:11]([C:9]([N:6]3[CH2:7][CH2:8][C@@H:4]([O:3][CH3:21])[CH2:5]3)=[O:10])[S:19][C:18]=12
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CC[C@@H](O)C1
Reactant: CI
Agent: [C-]#N
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CO[C@@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Reaction time: 0.33 h
Yield: 60.9 %

Procedure:
NaH (2.1 g, 53.1 mmol) was added to a solution of (3R)-(3-hydroxy-pyrrolidin-1-yl)-[7-chloro-thieno[3,2-b]pyridin-2-yl]-methanone (5.0 g, 17.7 mmol) in THF (100 mL), at 0° C. The reaction mixture was allowed to stir for 20 min., and MeI (3.26 g, 22.9 mmol) was added dropwise. After 3 h the reaction was treated with saturated aqueous KCN. The aqueous layer was extracted with CH2Cl2. The combined organic layers were dried (Na2SO4), and the solvent was removed under reduced pressure. Purification by flash chromatography on silica gel, eluting with CH2Cl2/MeOH (94:6) afforded the title compound as a white solid (3.2 g, 61%). MS: 297.2/299.2 (MH+); HPLC Rf: 4.25 min.; HPLC purity: 95%.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].Cl.[C:8]1([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCCC1>[C:8]1([C@H:14]2[CH2:15][CH2:16][C@H:17]([OH:20])[CH2:18][CH2:19]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1CCC(c2ccccc2)CC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: O[C@H]1CC[C@H](c2ccccc2)CC1

Procedure:
First, 2 g of lithium aluminium hydride and 20 ml of tetrahydrofuran were placed in a 300 ml flask. Then, a solution in which 25 g of 4-phenylcyclohexanone was dissolved in 200 ml of tetrahydrofuran was added dropwise to the mixture at room temperature. The mixture was stirred under reflux for 1 hour. Diluted hydrochloric acid was added to the reaction mixture, and an organic layer was extracted with ether. The ether layer was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was recrystallized from acetone to obtain 18 g of trans-4-phenylcyclohexanol (Y: 71.5%). The compound thus obtained had a purity of 98.4% by GC and an m.p. of 117° C. to 119° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[N:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH:28]([CH2:31][NH2:32])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C(N(CC)CC)C>C(O)C>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:8]([C:7]2[C:2]([NH:32][CH2:31][CH:28]3[CH2:27][CH2:26][N:25]([C:22]4[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=4)[CH2:30][CH2:29]3)=[N:3][CH:4]=[CH:5][CH:6]=2)=[O:9])=[CH:12][CH:13]=1
Reactant: NCC1CCN(c2ccncc2)CC1
Reactant: COc1ccc(NC(=O)c2cccnc2Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(NC(=O)c2cccnc2NCC2CCN(c3ccncc3)CC2)cc1
Yield: 23.8 %

Procedure:
A pressure tube (Aldrich) was charged with 2-chloro-N-(4-methoxyphenyl)pyridine-3-carboxamide (139 mg, 0.524 mmol), 1-(4-pyridyl)piperidine-4-methylamine (100 mg, 0.524 mmol), triethylamine (0.22 mL), and ethanol (3 mL). The mixture was placed in a 110° C. bath for 5 days. The mixture was concentrated and the residue purified by RPHPLC, yielding 52 mg (24%) of the title compound as a hydrochloride salt.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][N:15]=2)[N:10]=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18]>>[Cl:3][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][N:15]=2)[N:10]=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnc2cccnc2c1O
Product: O=[N+]([O-])c1cnc2cccnc2c1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.9 %

Procedure:
Phosphorus oxychloride (38 mL, 408 mmol) was added dropwise over a period of 70 minutes to a stirred suspension of 4-hydroxy-3-nitro[1,5]naphthyridine (60 g, 313.9 mmol). The orange suspension was stirred at ambient temperature for 5 hours and then poured into ice water (1.9 L) and stirred for 30 minutes. The solid was isolated by filtration, washed with water (3×200 mL), and then dissolved in dichloromethane (1.2 L). The solution was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 61.1 g of 4-chloro-3-nitro[1,5]naphthyridine as an orange solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.[Si:9](Cl)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].N1C=CN=C1>CN(C=O)C>[Si:9]([O:8][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
A mixture of pyridin-4-ylmethanol (8.0 g, 73 mmol), tert-butyldimethylsilyl chloride (14.3 g, 95 mmol) and imidazole (12.9 g, 0.19 mol) in DMF (40 mL) was stirred overnight at room temperature. The reaction was poured onto water and extracted twice with ethyl acetate. The combined organic phases were dried (MgSO4) and evaporated under reduced pressure to yield the title compound as yellow oil (7.5 g, 46%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.C(N(CC)CC)C.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>C(Cl)Cl>[Si:16]([O:8][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCc1ccncc1
Temperature: 34 °C
Reaction time: 8 h

Procedure:
To a solution of 4-pyridylcarbinol (50.3 g, 0.46 mol) in methylene chloride (250 mL) under a dry nitrogen atmosphere was added triethylamine (97 mL, 0.69 mol). To this mixture was added dropwise tert-butyl-dimethylsilyl chloride (83.7 g, 0.555 mol) with cooling (T 34° C.). The reaction mixture was stirred overnight at room temperature. The slurry was then filtered and the solvent removed by rotoevaporation. The residue was suspended in toluene and filtered and the solvent removed by rotoevaporation. The residue was suspended in diethyl ether and filtered and the solvent removed by rotoevaporation. The same process was repeated with hexanes to yield 4-t-butydimethylsilyloxymethylpyridine as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH2:11][OH:12])=[N:9][N:8]([C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:5]2=[N:6][CH:7]=1.[K+].[Br-].[O-]Cl.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl.O.CC1(C)N([O])C(C)(C)CCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:11]=[O:12])=[N:9][N:8]([C:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:5]2=[N:6][CH:7]=1
Reactant: OCc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(Br)cc12
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=S([O-])([O-])=S
Agent: [Br-]
Solvent: ClCCl
Solvent: O
Product: O=Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(Br)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
To a solution of (5-bromo-1-trityl-1H-pyrazolo[3,4-b]pyridin-3-yl)methanol (XXIII) (4.05 Kg, 8.6 mol) in DCM (97 L) was added a solution of KBr (205 g, 1.72 mol) in water (4 L). The solution was cooled to 0° C. before adding TEMPO (107.5 g, 688 mmol) and stirring for 30 min To this solution was added a solution of KHCO3 (10.8 Kg, 107.4 mol) and aqueous 7% NaClO (13.4 L) in water (40 L). The reaction was stirred at 0° C. for 18 hours. A solution of Na2S2O3*5H2O (1.4 Kg, 5.7 mol) in water (9.1 L) was added dropwise to the reaction at 0° C. and stirred for 30 min. The aqueous layer was then separated and washed with DCM (48 L). The combined organic phases were washed with aqueous 25% NaCl (48 L), dried over Na2SO4, filtered and concentrated under vacuum. The residue was co-evaporated with 3×MeOH (20 L) and the solid was washed with 2×n-heptane (8 L). The solid was dried under vacuum at 45° C. to give 5-bromo-1-trityl-1H-pyrazolo[3,4-b]pyridine-3-carbaldehyde (XXIV) (3.25 Kg, 6.94 mol, 92.3% purity, 80.6% assay yield). 1H NMR (CDCl3, 400 MHz) δ ppm 7.19 (d, J=6 Hz, 5H), 7.22-7.34 (m, 10H), 8.28 (d, J=2.4 Hz, 1H), 8.70 (d, J=2.4 Hz, 1H), 10.07 (s, 1H); ESIMS found C26H18BrN3O m/z 490.0 (M+Na).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:16](Cl)([Cl:18])=[O:17].C>C1(C)C=CC=CC=1.C1C=CC=CC=1>[Cl:18][C:16]([N:6]1[C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[CH:9]=[CH:10][C:11]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2)=[O:17]
Reactant: C1=Cc2ccccc2Nc2ccccc21
Reactant: O=C(Cl)Cl
Agent: C
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: O=C(Cl)N1c2ccccc2C=Cc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a slurry of 14.10g (0.073 mole) of dibenz[b,f]azepine in 60ml of dry toluene at room temperature was added dropwise a 120ml solution of 12.5% phosgene (excess) in benzene over 45 minutes. The resulting yellow slurry was stirred for 2 hours at room temperature, heated to reflux an additional 2 hours, and then stirred at room temperature overnight. Concentration of the reaction mixture by rotary evaporator in the hood gave a pale yellow solid which was taken up in 200ml benzene and treated with Norit-AR at boiling. The hot solution was filtered through celite, concentrated to one half of its original volume, cooled to room temperature and petroleum ether added to turbidity; white crystals of the named product precipitated. Yield, 14.4g, m.p. 145°-150°. Recrystallization from benzene-hexane afforded needles m.p. 150°-156.5°.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:7]([C:18](=[O:20])[NH2:19])[C:8]1[C:9]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:10]=2[S:11][CH:12]=1)([CH3:6])=[O:5])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].CNCCNC.Br[CH:34]=[CH:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[C:38]([F:43])[CH:37]=1>CN(C)C(=O)C.[Cu]I>[CH2:1]([O:3][P:4]([CH:7]([C:8]1[C:9]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:10]=2[S:11][CH:12]=1)[C:18](=[O:20])[NH:19][CH:34]=[CH:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[C:38]([F:43])[CH:37]=1)([CH3:6])=[O:5])[CH3:2]
Reactant: CCOP(C)(=O)C(C(N)=O)c1csc2ccc(Cl)cc12
Reactant: Fc1ccc(C=CBr)cc1F
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Product: CCOP(C)(=O)C(C(=O)NC=Cc1ccc(F)c(F)c1)c1csc2ccc(Cl)cc12
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
A 3 L 4-necked round-bottomed flask equipped with addition funnel, mechanical stirrer, nitrogen inlet, heating mantle and thermocouple was charged with [carbamoyl-(5-chloro-benzo[b]thiophen-3-yl)-methyl]-methyl-phosphinic acid ethyl ester (100 g, 0.3 mol), Cs2CO3 (58.6 g, 0.18 mol), N,N-dimethylacetamide (DMA) (300 mL, anhydrous 99.8%), N,N′-dimethyl-ethylenediamine (10.6 g, 0.12 mol) and copper (I) iodide (11.4 g, 0.06 mol) and the resulting mixture heated to about 80° C., under nitrogen. To the resulting mixture was then added a solution of 4-(2-bromo-vinyl)-1,2-difluoro-benzene (78.8 g, 0.36 mol) in DMA (30 mL), slowly over a period of about 20 min and the resulting mixture stirred at this temperature for 5 hours. The resulting mixture was then quenched while hot with H2O (600 mL), and diluted with EtOAc (700 mL), added slowly through an addition funnel. The resulting biphasic mixture was cooled to 50-55° C. and at this temperature the layers were separated. The organic layer was washed with H2O (500 mL), 0.5N HCl aqueous solution (500 mL) and brine (500 mL), then filtered and concentrated under reduced pressure to approximately half the original volume (350-400 mL). The concentrated solution was heated to slow reflux. Heptane (250 mL) was then added slowly at this temperature. The resulting suspension was cooled to 5-10° C. over a period of 1 hr, diluted with additional heptane (100 mL) and aged at this temperature for a period of about 2 hrs. The resulting solid precipitate was filtered, rinsed with cold heptane/EtOAc (4/1) solvent mixture (100 ml), and dried at 55° C. in a vacuum oven overnight, to yield the title compound as a white solid.