Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N+](C1C=CC([O:11][C:12](=O)[NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]3[C:29]4[C:24](=[C:25]([Cl:31])[CH:26]=[C:27]([Cl:30])[CH:28]=4)[CH2:23][N:22]([CH3:32])[CH2:21]3)[CH:15]=2)=CC=1)([O-])=O.[NH2:34][CH2:35][CH2:36][OH:37]>CN(C=O)C>[Cl:30][C:27]1[CH:28]=[C:29]2[C:24](=[C:25]([Cl:31])[CH:26]=1)[CH2:23][N:22]([CH3:32])[CH2:21][CH:20]2[C:16]1[CH:15]=[C:14]([NH:13][C:12]([NH:34][CH2:35][CH2:36][OH:37])=[O:11])[CH:19]=[CH:18][CH:17]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(NC(=O)Oc3ccc([N+](=O)[O-])cc3)c2)C1
Reactant: NCCO
Agent: Cl
Solvent: CN(C)C=O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(NC(=O)NCCO)c2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.2 %

Procedure:
509 mg (1,0 mmol) [3-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamic-acid 4-nitro-phenyl-ester-Hydrochloride (example 151, intermediate 1) were dissolved in 15 ml DMF and at 0° C. a solution of 67,2 mg (1,1 mmol) of 2-Aminoethanol in 10 ml DMF was added. After stirring for 3 h at room temperature the solvent was removed i. vac. The residue was dissolved in ethylacetate and washed with sat. NaHCO3-solution. The organic layer was separated and the aqueous layer was extracted twice with ethylacetate. The combined organic layers were washed with sat. NaCl-solution, dried (MgSO4) and concentrated. Purification by silica gel chromatography (dichloromethane/methanol) yielded 265 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13](=[O:14])[NH:12][N:11]3[C:15](=[O:26])[N:16]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[N:17]=[C:10]3[C:9]=2[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)=[CH:4][CH:3]=1.[F:34][C:35]([F:45])([F:44])[C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Br)=[CH:38][CH:37]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[F:34][C:35]([F:44])([F:45])[C:36]1[CH:43]=[CH:42][C:39]([CH2:40][N:12]2[C:13](=[O:14])[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[C:9]([C:27]3[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=3)[C:10]3=[N:17][N:16]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:15](=[O:26])[N:11]23)=[CH:38][CH:37]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: C[Si](C)(C)CCOCn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c(=O)[nH]n2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c(=O)n(Cc3ccc(C(F)(F)F)cc3)n2c1=O
Temperature: 80 °C
Yield: 109.9 %

Procedure:
The solution of 7,8-bis(4-chlorophenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazine-3,6(2H,5H)-dione, (112 mg, 0.22 mmol), prepared as described in example 6B, 4-(trifluoromethyl)benzyl bromide (58 mg, 0.24 mmol), K2CO3 (91 mg, 0.66 mmol) in DMF (2 ml), was heated at 80° C. for 0.75 hour. After this time, the solution was cooled to RT and diluted with ethyl acetate. The resulting solution was washed with water. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound, 5-(4-(trifluoromethyl)benzyl)-7,8-bis(4-chlorophenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazine-3,6(2H,5H)-dione, (160 mg).
Reaction SMILES: [BH4-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([N:22]1[C:30]2[C:25](=[CH:26][C:27]([S:31]([CH2:34][N+:35]([O-:37])=[O:36])(=[O:33])=[O:32])=[CH:28][CH:29]=2)[CH2:24][CH2:23]1)(=O)[CH3:20]>ClCCl>[CH2:19]([N:22]1[C:30]2[C:25](=[CH:26][C:27]([S:31]([CH2:34][N+:35]([O-:37])=[O:36])(=[O:32])=[O:33])=[CH:28][CH:29]=2)[CH2:24][CH2:23]1)[CH3:20]
Reactant: CC(=O)N1CCc2cc(S(=O)(=O)C[N+](=O)[O-])ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [BH4-]
Solvent: ClCCl
Product: CCN1CCc2cc(S(=O)(=O)C[N+](=O)[O-])ccc21

Procedure:
Tetrabutylammonium borohydride (3.85 g, 15 mmol) was added to a solution of 1-acetyl-5-(nitromethylsulphonyl)indoline (1.45 g, 5 mmol) in dichloromethane (30 ml), and the mixture was stirred at reflux for 18 hours. The solvent was removed by evaporation, 2 M hydrochloric acid (30 ml) was added, and the mixture was heated at reflux for 20 minutes. The solution was then poured into sufficient of an ice-cold saturated solution of sodium hydrogen carbonate to adjust the mixture to pH 6. The mixture was then extracted with dichloromethane, the combined extracts were dried (MgSO4), and the solvent was removed by evaporation. The resultant yellow oil was purified by flash chromatography on silica (Merck kieselgel Art. 7736), eluting with dichloromethane, to give 1-ethyl-5-(nitromethylsulphonyl)indoline as a solid, m.p. 122° C.; microanalysis, found: C,49.3; H,5.1; N,10.4%; C11H14N2O4S requires: C,48.9; H,5.2; N,10.4%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:10]=[C:11]=[O:12])=[C:4]([F:13])[CH:3]=1.[OH:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][NH:17]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([NH:10][C:11]([N:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]2[CH2:15][OH:14])=[O:12])=[C:4]([F:13])[CH:3]=1
Reactant: COc1cc(N=C=O)c(F)cc1Cl
Reactant: OCC1CCCCN1
Solvent: Cc1ccccc1
Product: COc1cc(NC(=O)N2CCCCC2CO)c(F)cc1Cl
Reaction time: 2 h
Yield: 79.6 %

Procedure:
10.1 g (0.05 mol) of 4-chloro-2-fluoro-5-methoxyphenyl isocyanate are dissolved in 50 ml of toluene, and 5.8 g (0.05 mol) of 2-hydroxymethylpiperidine, dissolved in 20 ml of toluene, are added dropwise at RT(1). The mixture is stirred for 2 hours at 20°-25° C. and cooled in and ice bath, and the precipitate which has been deposited is filtered off with suction. 12.6 g (79% of theory) of 1-[N-(4-chlor-2-fluor-5-methoxyphenyl)-carbamoyl]-2-hydroxymethylpiperidine are obtained after drying in the form of colorless crystals, melting point 176°-179° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:17].[OH-].[Ca+2].[OH-]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[N+:4]([O-:17])[CH:5]=[C:6]([C:8]([OH:11])([CH3:9])[CH3:10])[CH:7]=1
Reactant: CC(C)(O)c1cncc(Br)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC(C)(O)c1cc(Br)c[n+]([O-])c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-bromo-5-(1-hydroxy-1-methylethyl)pyridine from Step 1 (3.1 mmol) in chloroform (10 mL) was added m-chloroperoxybenzoic acid 70% (1.5 eq) and the resulting mixture was stirred at room temperature for 18 hours. An excess of calcium hydroxide was added and after stirring for 5 minutes, the mixture was filtered through celite and the filtrate was evaporated. The crude material was chromatographed on silica gel eluting with 10% ethanol in methylene chloride (saturated with ammonia) to afford the 3-bromo-5-(1-hydroxy-1-methylethyl)pyridine-N-oxide compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:5]([C:15]#[N:16])=[C:4](S(C)=O)[N:3]=1.[OH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:5]([C:15]#[N:16])=[C:4]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:3]=1
Reactant: OCc1ccccn1
Reactant: CS(=O)c1nc(N)c(C#N)c(-c2ccco2)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(N)nc(OCc2ccccn2)c(C#N)c1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyridine-3,5-dicarbonitrile, 2-(hydroxymethyl)pyridine and DBU in DME. EI-MS m/e (%): 317 (M+, 66), 92 (100), 65 (55).
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1)=[O:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>CO>[OH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:18][CH:17]=1)=[O:15]
Reactant: O=C(CCCCCCOC1CCCCO1)c1ccc(C(F)(F)F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(CCCCCCO)c1ccc(C(F)(F)F)cc1
Yield: 99.2 %

Procedure:
To a magnetically stirred solution of 7-(tetrahydropyran-2-yloxy)-1-[4-(trifluoromethyl)phenyl]heptan-1-one (7.70 g, 0.0215 mol) in methanol (50 ml) was added para-toluenesulfonic acid hydrate (4.18 g, 0.022 mol). The resulting acidic mixture (pH˜2, pH paper) was reacted at room temperature for 20 hours. NaOH (1N) was added until the solution was neutral (pH˜7, pH paper) and the resulting mixture was concentrated in vacuo. NaOH (1N, 50 ml) was added and the mixture was extracted with dichloromethane (3×). The combined organic layers were successively washed with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give crude 7-hydroxy-1-[4-(trifluoromethyl)phenyl]heptan-1-one (5.85 g, 99% yield) as a white solid. This obtained solid was treated with pyridine (29.6 ml) and a solution of tosyl chloride (17.72 g, 0.093 mol) in pyridine (89 ml) was added at 0° C. The mixture was allowed to attain room temperature and reacted for 1 hour. The mixture was cooled at −10° C. and quenched with excess water. Extraction with diethyl ether (3×), followed by drying over Na2SO4, filtering and concentration in vacuo gave crude product which was purified by column chromatography (dichloromethane/heptane=2/1 (v/v)) to give pure toluene-4-sulfonic acid 7-oxo-7-[4-(trifluoromethyl)phenyl]heptyl ester (7.91 g, 87% yield). 1H-NMR (400 MHz, CDCl3) δ 1.35-1.38 (m, 4H), 1.57-1.73 (m, 4H), 2.44 (s, 3H), 2.97 (t, J=7, 2H), 4.03 (t, J=7, 2H), 7.35 (d, J˜8, 2H), 7.73 (d, J˜8, 2H), 7.79 (d, J˜8, 2H), 8.04 (d, J˜8, 2H).
Reaction SMILES: [CH:1]([NH:4][OH:5])([CH3:3])[CH3:2].[C:6]([C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1)([O:8][CH3:9])=[O:7].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[CH:1]([N:4]([CH2:14][C:13]1[CH:12]=[CH:11][C:10]([C:6]([O:8][CH3:9])=[O:7])=[CH:17][CH:16]=1)[OH:5])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(CCl)cc1
Reactant: CC(C)NO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN(O)C(C)C)cc1
Temperature: 60 °C
Reaction time: 20 h
Yield: 41.3 %

Procedure:
N-isopropylhydroxylamine (13.74 g, 90%, 165 mmol), 4-carbomethoxybenzyl chloride (30.4 g, 165 mmol) and Na2CO3 (18.0 g, 170 mmol) were dissolved in DMF (150 mL) and stirred at 60° C. under Argon for 20 h. The reaction mixture was filtered, concentrated, diluted with CHCl3 (300 mL), washed with water (3×200 mL), dried with MgSO4, concentrated, dissolved in EtOAC (10 mL) and chromatographed on an Si gel eluting with 4:1 hexanes/EtOAc to give 15.2 g (41%) N-isopropyl-N-(4-carbomethoxybenzyl)-hydroxylamine. 1H NMR (DMSO-d6) δ 7.85 (d, J=8.2 Hz, 2), 7.43 (d, J=8.2 Hz, 2), 7.44 (s, 1), 3.80 (s, 3), 3.73 (s, 1), 2.85 (sept, J=6.3 Hz, 1), 1.02 (d, J=6.3 Hz, 6). 13C{1H} NMR (DMSO-d6) δ 166.2, 145.6, 129.0, 128.8, 127.8, 59.3, 56.8, 52.0, 18.4.
Reaction SMILES: F[C:2]1[CH:16]=CC(F)=C[C:3]=1[CH2:4][P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[Br:18][C:19]1[N:24]=C(CBr)C=C[N:20]=1>>[CH2:7]([O:6][P:5]([CH2:4][C:3]1[CH:2]=[CH:16][N:24]=[C:19]([Br:18])[N:20]=1)(=[O:12])[O:9][CH2:10][CH3:11])[CH3:8]
Reactant: CCOP(=O)(Cc1cc(F)ccc1F)OCC
Reactant: BrCc1ccnc(Br)n1
Product: CCOP(=O)(Cc1ccnc(Br)n1)OCC

Procedure:
Prepared according to the same procedure as diethyl 2,5-difluorobenzylphosphonate, starting with 2-bromo-4-(bromomethyl)pyrimidine. 1H NMR (500 MHz, DMSO-d6) δ 8.69-8.58 (m, 1H), 7.67-7.44 (m, 1H), 4.14-3.91 (m, 4H), 3.62-3.43 (m, 2H), 1.42-1.09 (m, 6H), Mass spec.: 310.1 (MH)+.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:9][CH2:10][C@H:11]1[O:15][C@@H:14]([N:16]2[CH:24]=[N:23][C:22]3[C:17]2=[N:18][C:19](I)=[N:20][C:21]=3[NH:25][O:26][CH3:27])[C@H:13]([OH:29])[C@@H:12]1[OH:30].C(N(CC)CC)C>CN(C)C=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:9][CH2:10][C@H:11]1[O:15][C@@H:14]([N:16]2[CH:24]=[N:23][C:22]3[C:17]2=[N:18][C:19]([C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:20][C:21]=3[NH:25][O:26][CH3:27])[C@H:13]([OH:29])[C@@H:12]1[OH:30]
Reactant: CONc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CONc1nc(C#Cc2ccccc2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
CuI (0.35 mg, 0.002 mmol) and phenylacetylene (2.1 mmol) were added to a solution of (4S,2R,3R,5R)-5-(hydroxymethyl)-2-[2-iodo-6-(methoxyamino)purin-9-yl]oxolane-3,4-diol (0.35 mmol), a compound of formula (5), in dry N,N-dimethylformamide (6 mL) and triethylamine (1.4 mL) under an atmosphere of nitrogen in the presence of bis(triphenylphosphine)palladium dichloride (5 mg, 0.007 mmol). The reaction mixture was stirred at room temperature for 5 hours. After evaporation under reduced pressure the residual oil was purified by silica gel column chromatography, eluting with chloroform/methanol 90/10. After evaporation in vacuo, the residual oil was purified by silica gel column chromatography, eluting with the suitable mixture of solvents, to provide (4S,2R,3R,5R)-5-(hydroxymethyl)-2-[6-(methoxyamino)-2-(2-phenylethynyl)purin-9-yl]oxolane-3,4-diol, a compound of Formula I (mp 175-177° C.).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=2)[NH2:19])[CH:5]=[CH:4][N:3]=1.[CH:23]1([S:26](Cl)(=[O:28])=[O:27])[CH2:25][CH2:24]1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:19][S:26]([CH:23]3[CH2:25][CH2:24]3)(=[O:28])=[O:27])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)c1nc(-c2cccc(N)c2)c(-c2ccnc(Cl)n2)s1
Reactant: O=S(=O)(Cl)C1CC1
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)C3CC3)c2)c(-c2ccnc(Cl)n2)s1
Yield: 94.4 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]aniline (1.0 g, 3.03 mmol) and cyclopropanesulfonyl chloride (465 mg, 3.32 mmol) the title compound of Step A was obtained (1.24 g, 94.4% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.30 (d, J=5.3 Hz, 1H), 7.36-7.42 (m, 2H), 7.29-7.36 (m, 2H), 7.01 (d, J=5.3 Hz, 1H), 6.91-6.93 (br, 1H), 3.29-3.40 (m, 1H), 2.46-2.53 (m, 1H), 1.44 (d, J=7.0 Hz, 6H), 1.12-1.18 (m, 2H), 0.93-1.01 (m, 2H). MS (ES+): 435 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:10](=[O:17])[C@@H:9]([CH2:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[N:29])[CH:23]=3)=[O:20])[O:8][C@H:7]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])[C:6]=2[CH:37]=1.[N-:38]=[N+:39]=[N-:40].[Na+].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]([CH3:14])([CH3:15])[CH3:16])[C:10](=[O:17])[C@@H:9]([CH2:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]4[NH:40][N:39]=[N:38][N:29]=4)[CH:23]=3)=[O:20])[O:8][C@H:7]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])[C:6]=2[CH:37]=1
Reactant: CC(C)(C)CN1C(=O)[C@@H](CC(=O)Nc2cccc(C#N)c2)O[C@H](c2ccccc2Cl)c2cc(Cl)ccc21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)CN1C(=O)[C@@H](CC(=O)Nc2cccc(-c3nnn[nH]3)c2)O[C@H](c2ccccc2Cl)c2cc(Cl)ccc21
Yield: 50.9 %

Procedure:
A solution of 0.2 g of trans-7-chloro-5-(2-chlorophenyl)-3-(3-cyanophenylaminocarbonylmethyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine and 80 mg of sodium azide in 5 ml of dimethylformamide was stirred at 90° C. for 60 hours. After water was added, the mixture was washed with water, after which the solvent was removed and the residue was subjected to silica gel column-chromatography to yield 0.11 g of a crystal.
Reaction SMILES: [CH2:1]1[C:6]2[C:7]3[N:8]([CH:19]=[N:20][N:21]=3)[C:9]3[CH:17]=[CH:16][C:15](=[O:18])[CH2:14][C:10]=3[N:11]3[CH:12]=[CH:13][C:4]([C:5]=23)=[CH:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C)C=O>[C:31]1([CH2:30][CH2:29][CH:14]2[C:10]3[N:11]4[CH:12]=[CH:13][C:4]5[C:5]4=[C:6]([CH2:1][CH2:2][CH:3]=5)[C:7]4[N:8]([CH:19]=[N:20][N:21]=4)[C:9]=3[CH:17]=[CH:16][C:15]2=[O:18])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C1C=CC2=C(C1)n1ccc3c1=C(CCC=3)c1nncn12
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1C=CC2=C(C1CCc1ccccc1)n1ccc3c1=C(CCC=3)c1nncn12
Temperature: 95 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
1,2-Dihydrobenzo[b]pyrrolo[3,2,1-jk][1,2,4]triazolo[4,3-d][1,4]benzodiazepin-8(7H)-one (2 g) was dissolved in dimethylformamide (50 ml). Potassium carbonate (0.5 g) was added followed by (2-bromoethyl)benzene (2.7 g). The mixture was stirred at 95° C. overnight, filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by high performance liquid chromatography (2% methanol/dichloromethane) to yield 2.3 g, (84%) of product. Recrystallization from methanol gave the analytical sample, mp 157°-158° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([CH:9]1[CH:11]([C:12]([NH2:14])=O)[C:10]1([CH3:16])[CH3:15])(=[O:8])[CH3:7]>C1C=CC=CC=1>[C:6]([C@H:9]1[C@H:11]([C:12]#[N:14])[C:10]1([CH3:16])[CH3:15])(=[O:8])[CH3:7]
Reactant: CC(=O)C1C(C(N)=O)C1(C)C
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)[C@H]1[C@H](C#N)C1(C)C

Procedure:
Phosphorus oxychloride (202.4 g, 1.32 m) was added dropwise to a solution of 3-acetyl-2,2-dimethyl-cyclopropane-1-carboxamide. (34.6 g, 0.22 m) in benzene (140 ml) and the resultant mixture refluxed for 3 hours. Excess reagents were removed in vacuo and the residue dissolved in ether (100 ml). The ether was washed with water (3×60 ml), dried over anhydrous magnesium sulphate and evaporated in vacuo to give a dark oil b.p. 72°-5° C./1.0 mm.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].[Cu][C:15]#[N:16]>CN1C(=O)CCC1.O>[C:15]([C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6])#[N:16]
Reactant: N#C[Cu]
Reactant: CCc1ccc(C(=O)OC)cc1Br
Solvent: CN1CCCC1=O
Solvent: O
Product: CCc1ccc(C(=O)OC)cc1C#N
Temperature: 20 °C
Yield: 48.8 %

Procedure:
Methyl 3-bromo-4-ethyl-benzoate (D44) (5 g) in NMP (180 mL) was treated with copper (I) cyanide (3.69 g). The mixture was then heated at reflux for 5 h, under argon. After cooling to 20° C. the reaction mixture was diluted with water, then filtered through kieselguhr, washing well with water and EtOAc. The organic layer was washed with water, brine and dried over MgSO4. The solvent was evaporated to dryness in vacuo and the residue was purified by chromatography on silica eluting with EtOAc-Hexane (1:9) to give the title compound (1.9 g) 1H NMR (CDCl3) δ 1.33 (3H, t), 2.94 (2H, q), 3.94 (3H, s), 7.43 (1H, d), 8.17 (1H, dd), 8.28 (1H, d).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([OH:14])=[O:13])[C:6]([CH3:15])=[CH:5]2.[C:16]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1.II.Cl>CN(C=O)C.O>[C:16]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=[CH:18][C:19]([S:22][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[N:7]([CH2:11][C:12]([OH:14])=[O:13])[C:6]=2[CH3:15])=[CH:20][CH:21]=1
Reactant: Cc1cc2cc(F)ccc2n1CC(=O)O
Reactant: Sc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: II
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(Sc2ccc(-c3ccccc3)cc2)c2cc(F)ccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 0 %

Procedure:
To a solution of (5-fluoro-2-methyl-indol-1-yl)-acetic acid (0.5 g) and biphenyl-4-thiol (0.19 g) in DMF (5 ml) was added iodine (0.25 g). After stirring at RT overnight the mixture was poured into water, the pH adjusted to 3 using 1M HCl and the organics extracted with EtOAc. The EtOAc extractions were combined, washed with brine, dried (MgSO4) and evaporated under reduced pressure to give crude material. Purification using RPHPLC gave the title compound as a pink solid (0.1 μg).
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:13]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH3:22])[N:16]=1)=[O:14]>C1COCC1>[CH3:22][S:21][C:17]1[N:16]=[C:15]([C:13](=[O:14])[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:20]=[CH:19][N:18]=1
Reactant: CON(C)C(=O)c1ccnc(SC)n1
Reactant: Cl[Mg]Cc1ccccc1
Solvent: C1CCOC1
Product: CSc1nccc(C(=O)Cc2ccccc2)n1
Temperature: -78 °C

Procedure:
A solution of benzylmagnesium chloride (4.7 mL, 9.38 mmol, 2 equiv) was added to a solution of N-methoxy-N-methyl-2-(methylthio)pyrimidine-4-carboxamide (1–2, 1.0 g, 4.7 mmol, 1 equiv) in THF (25 mL) cooled to −78° C. The reaction solution was allowed to warm to 0° C. and partitioned between ethyl acetate (2×100 mL) and brine. The organic extracts were combined, dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography. Elution with CH2Cl2 to 15% EtOAc/CH2Cl2 provided 1-[2-(methylthio)pyrimidin-4-yl]-2-phenylethanone (3-1) as a pale yellow solid. 1H NMR (500 MHz, CDCl3) δ 8.73 (d, 1H, J=5 Hz), 7.52 (d, 1H, J=5 Hz), 7.25–7.37 (m, 5H), 4.48 (s, 2H), 2.66 (s, 3H).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([OH:13])=O)[CH2:4][CH2:3][CH2:2]1.[NH2:14][CH2:15][CH2:16][CH2:17][C@H:18]1[O:22][C:21](=[O:23])[N:20]([C:24]2[CH:25]=[CH:26][C:27]3[S:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=3[CH:34]=2)[CH2:19]1>>[O:23]=[C:21]1[N:20]([C:24]2[CH:25]=[CH:26][C:27]3[S:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=3[CH:34]=2)[CH2:19][C@@H:18]([CH2:17][CH2:16][CH2:15][NH:14][C:11]([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[NH:1][CH2:2][CH2:3][CH2:4]3)=[O:13])[O:22]1
Reactant: O=C(O)c1cccc2c1NCCC2
Reactant: NCCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Product: O=C1CSc2ccc(N3C[C@@H](CCCNC(=O)c4cccc5c4NCCC5)OC3=O)cc2N1
Yield: 85 %

Procedure:
Starting from 1,2,3,4-tetrahydroquinoline-8-carboxylic acid and 6-[(R)-5-(3-amino-propyl)-2-oxo-oxazolidin-3-yl]-4H-benzo[1,4]thiazin-3-one (described in WO 2010/041219) and using Procedure D, the title compound was obtained as a beige solid (114 mg; 85% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[NH:10][C:9]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:41](O)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:41]([N:10]1[C:11]([C:13]([F:15])([F:16])[F:14])=[CH:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[C:9]1[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CCOC(=O)c1[nH]c(C(F)(F)F)cc1-c1ccc(Cl)cc1
Reactant: OCc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1c(-c2ccc(Cl)cc2)cc(C(F)(F)F)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.2 %

Procedure:
To a solution of ethyl 3-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxylate (2.0 g, 6.30 mmol) in dry THF (20 mL) was added triphenylphosphine (1.899 g, 7.24 mmol) and benzyl alcohol (0.720 mL, 6.92 mmol). DIAD (1.373 mL, 6.92 mmol) in dry THF (5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1 h. THF was removed in vacuo. The crude product was dissolved in EtOAc (20 mL) and saturated NaHCO3 (40 mL) was added. The layers were separated and the aqueous layer was extracted with EtOAc (20 mL). The combined organic layer was washed with brine (50 mL) and dried over Na2SO4 and the solvent was evaporated. The residue was co-evaporated with DCM (10 mL) and then stirred in Et2O (20 mL) and the solids were filtered off. The filtrate was purified by column chromatography (silica, heptane/EtOAc, 3:1) to give 2.6 g (97%) the desired product as a yellow oil.