Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:28])[CH2:14][CH2:13][N:12]([CH:15](F)[CH2:16][CH:17]([F:26])[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:19])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:29][NH:30][CH3:31].CS(C)=O>O>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:28])[CH2:14][CH2:13][N:12]([CH:15]([N:30]([CH3:31])[CH3:29])[CH2:16][CH:17]([F:26])[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:19])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: CNC
Reactant: O=C(c1ccccc1)C(F)CC(F)N1CCC(O)(c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: CN(C)C(CC(F)C(=O)c1ccccc1)N1CCC(O)(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of γ-[4-(p-chlorophenyl)-4-hydroxypiperidin-1-yl]-2,4-difluorobutyrophenone hydrochloride (2.0 g), 40 % aqueous solution of dimethylamine (10.0 g) and dimethylsulfoxide (30 ml) was stirred at room temperature for 1 hour. The reaction mixture was poured into cold water (200 ml). The precipitate was filtered and recrystallized from aqueous ethanol to yield γ-[4-(p-chlorophenyl)-4-hydroxypiperidin-1-yl]-4-dimethylamino-2-fluorobutyrophenone. M.P. 160° to 163°C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.Cl[C:15]1[C:16]2[N:17]([CH:21]=[CH:22][N:23]=2)[CH:18]=[CH:19][N:20]=1>C(NC(C)C)(C)C.CN1C(=O)CCC1.C(OCC)(=O)C>[N:23]1[CH:22]=[CH:21][N:17]2[CH:18]=[CH:19][N:20]=[C:15]([N:1]3[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]3)[C:16]=12
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: Clc1nccn2ccnc12
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2nccn3ccnc23)C1
Temperature: 100 °C
Yield: 94.9 %

Procedure:
To a solution of (S)-tert-butyl pyrrolidin-3-ylcarbamate (80.2 g, 0.43 mol, 1.1 eq) in 75 mL of diisopropylamine and 34 mL of NMP was added portionwise 8-chloroimidazo[1,2-a]pyrazine (60 g, 0.39 mol, 1 eq). The reaction mixture was heated at 100° C. for 4 h and was then diluted with 1.2 L of ethyl acetate. The organic layer was washed with H2O and brine, dried with Na2SO4 and concentrated to give (S)-tert-butyl (1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-yl)carbamate (111.7 g, 0.37 mol, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N+:5]([O-])=[C:4]([CH3:9])[CH:3]=1.[Si]([C:14]#[N:15])(C)(C)C.CN(C)C(Cl)=O.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:9])[N:5]=[C:6]([C:14]#[N:15])[CH:7]=1
Reactant: Cc1cc(Cl)cc[n+]1[O-]
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1cc(Cl)cc(C#N)n1
Reaction time: 0.25 h
Yield: 75.5 %

Procedure:
4-chloro-2-methylpyridine-N-oxide (8.97 g, 62.5 mmol, 1.00 eq) was dissolved in CH2Cl2 and dried over MgSO4. The solution was added to a flame-dried round-bottom flask and CH2Cl2 was added to give a total volume of 188 mL. TMS-cyanide (10 mL, 75 mmol, 1.2 eq) was added and the reaction stirred for 15 minutes. Dimethylcarbamyl chloride (6.9 mL, 75 mmol, 1.2 eq) was added dropwise over 20 minutes, and the reaction was stirred for 24 hours. An additional one equivalent each of TMS-cyanide and dimethylcarbamyl chloride were added and the reaction was stirred for another 72 hours. The reaction was made basic with 10% K2CO3 and extraxcted with CH2Cl2 (3×). The combined organics were dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 7.2 g (75%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J=1.6 Hz, 1H), 7.82 (d, J=1.7 Hz, 1H), 2.52 (s, 3H); ES-MS [M+1]+: 153.2.
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].CC(C)([O-])C.[K+].Cl[CH:24]([CH3:27])[C:25]#[N:26].Cl>CS(C)=O.C(OCC)(=O)C>[CH3:10][O:9][C:7]([C:6]1[S:5][C:4]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:3]=2[C:2]=1[O:1][CH:24]([C:25]#[N:26])[CH3:27])=[O:8]
Reactant: COC(=O)c1sc2ccc(OC)cc2c1O
Reactant: CC(Cl)C#N
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1sc2ccc(OC)cc2c1OC(C)C#N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a room temperature solution of methyl 3-hydroxy-5-methoxybenzo[b]thiophene-2-carboxylate (1.00 g, 4.2 mmol) [Connor, et al., J. Med. Chem. 35:958 (1992)] in 20 mL of DMSO is added potassium t-butoxide (494 mg, 4.41 mmol) followed by 2-chloropropionitrile (1.1 mL, 12.6 mmol). The mixture is stirred at room temperature for 1.5 hours then warmed to 82° C. for 3 hours. The reaction mixture is poured into ethyl acetate and 1N HCl. The organic layer is washed with 1N HCl, followed by several portions of brine and dried over MgSO4. Filtration followed by removal of solvent in vacuo and recrystallization of the residue from ethyl acetate:hexane gives 853 mg, mp 127°-129° C.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@H:16]1[CH2:20][O:19][C:18]([CH3:22])([CH3:21])[N:17]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:10]([CH:13]1[CH2:15][CH2:14]1)[CH2:11]O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1C=CC(OP(OC2C=CC=CC=2)([N:72]=[N+:73]=[N-:74])=O)=CC=1>C1COCC1>[N:72]([CH2:11][C@H:10]([CH:13]1[CH2:15][CH2:14]1)[C@H:9]([C@H:16]1[CH2:20][O:19][C:18]([CH3:22])([CH3:21])[N:17]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[N+:73]=[N-:74]
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N1[C@@H]([C@H](O[Si](C)(C)C(C)(C)C)[C@H](CO)C2CC2)COC1(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H]([C@H](O[Si](C)(C)C(C)(C)C)[C@H](CN=[N+]=[N-])C2CC2)COC1(C)C
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
To a solution of tert-butyl (4R)-4-((1R,2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-cyclopropyl-3-hydroxypropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (1.3 g, 3.0 mmol) and triphenylphosphine (1.6 g, 6.1 mmol) in anhydrous THF (20 mL), DIAD (1.2 mL, 5.9 mmol) was added drop-wise under an atmosphere of nitrogen. Upon completion of addition, a precipitate was formed. The reaction mixture was stirred for 30 min. then diphenylphosphonic azide (1.3 mL, 6.2 mmol) in anhydrous THF (1.0 mL) was added. After stirring at ambient temperature for 3 h, the volatile organic solvents were removed under reduced pressure and the crude product was purified by flash column chromatography (120 g of silica gel, eluting with 0-15% EtOAc-hexanes) to afford the sub-title compound as a light yellow oil (1.18 g, 86%). LC/MS (ESI) m/z calc. for C17H35N4O2Si: 355.30 [M-Boc+H]+. found: 355.1.
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C@@H:8]([C:20](=[O:39])[N:21]([CH3:38])[C@@H:22]([C:30](=[O:37])[NH:31][CH2:32][C:33]([F:36])([F:35])[F:34])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].O>ClCCl>[CH3:6][NH:7][C@H:8]([CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)[C:20]([N:21]([CH3:38])[C@@H:22]([C:30](=[O:37])[NH:31][CH2:32][C:33]([F:34])([F:35])[F:36])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:39]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)NCC(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)NCC(F)(F)F
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 101.8 %

Procedure:
N-Methyl-N-((1R)-1-(N-methyl-N-((1R)-2-phenyl-1-((2,2,2-trifluoroethyl)carbamoyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamic acid tert-butyl ester (1.12 g, 1.97 mmol) was dissolved in dichloromethane (6 ml). The solution was cooled to 0° C. Trifluoroacetic acid (6 ml) was added. The reaction mixture was stirred for 45 min at 0° C. A saturated solution of aqueous sodium hydrogen carbonate (30 ml) was added. Solid sodium hydrogen carbonate was added until pH 7. Water (100 ml) was added until a clear solution was obtained. The phases were separated. The aqueous solution was extracted with dichloromethane (2×50 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (90 g), using dichloromethane/methanol/25% aqueous ammonia 100:10:1 as eluent, to give 946 mg of (2R)-2-methylamino-N-methyl-3-(2-naphthyl)-N-((1R)-2-phenyl-1-((2,2,2-trifluoroethyl)carbamoyl)ethyl)propionamide.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][N:6]([S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH:31]=[CH2:32])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)=[CH:10][CH:9]=1)C.O.[OH-].[Li+].Cl>C1COCC1.CO>[CH2:29]([O:28][C:25]1[CH:24]=[CH:23][C:22]([S:19]([N:6]([CH2:5][C:4]([OH:33])=[O:3])[CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:18]=[N:17][CH:16]=[N:15]3)=[CH:10][CH:9]=2)(=[O:21])=[O:20])=[CH:27][CH:26]=1)[CH2:30][CH:31]=[CH2:32]
Reactant: C=CCCOc1ccc(S(=O)(=O)N(CC(=O)OCC)Cc2ccc(-n3cncn3)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C=CCCOc1ccc(S(=O)(=O)N(CC(=O)O)Cc2ccc(-n3cncn3)cc2)cc1
Reaction time: 3.5 h

Procedure:
To a solution of 3.61 g (7.67 mmol) of [(4-but-3-enyloxy-benzensulfonyl)-(4-[1,2,4] triazol-1-yl-benzyl)-amino]-acetic acid ethyl ester in 38 ml of THF and 38 ml of MeOH, 0.966 g (23 mmol) of lithum hydroxide monohydrate and 4 ml of H 20 are added at 0–5° C. After being stirred for 3.5 h, the reaction mixture is acidified with 2 N aqueous hydrochloride at 0–5° C. and concentrated under reduced pressure to give [(4-but-3-enyloxy-benzensulfonyl)-(4-[1,2,4]triazol-1-yl-benzyl)-amino]-acetic acid as a colorless powder. To a solution of 3.76 g of the above prepared acid and 1.87 g (13.81 mmol) of 1-hydroxybenztriazole (HOBT) in 35 ml of DMF, 1.61 g (15.34 mmol) of O-(1-methyoxy-1-methyl-ethyl)-hydroxylamine and 1.91 g (12.275 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide are added successively at 0° C. After being stirred for 3.5 h at r.t., the reaction mixture is poured into ice water and the mixture is extracted with AcOEt. The combined extracts are washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: n-Hexane: AcOEt=1:3˜1:4) to give the title compound. 1H-NMR (400 MHz, CDCl3): 1.34 (s, 6H), 2.55–2.65 (m, 2H), 3.29 (s, 3H), 3.73 (s, 2H), 4.09 (t, J=6.60 Hz, 2H), 4.44 (s, 2H), 5.10–5.25 (m, 2H), 5.85–5.95 (m, 1H), 7.01 (d, 2H, J=8.52 Hz), 7.44 (d, 2H, J=8.0 Hz), 7.64 (d, 2H, J=8.52 Hz), 7.81 (d, 2H, J=8.0 Hz), 8.10 (s, 1H), 8.54 (s, 1H), 8.62 (brs, 1H).
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][Cl:26]>C(#N)C>[Cl:26][CH2:25][CH2:24][N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2][CH2:3]1
Reactant: ClCCBr
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(OCc1ccccc1)N1CCN(CCCl)CC1
Reaction time: 96 h
Yield: 49.9 %

Procedure:
Benzyl piperazine-1-carboxylate (1.00 g, 4.54 mmol) and K2CO3 (1.255 g, 9.08 mmol) were dissolved in acetonitrile (12.87 ml) to form a suspension. 1-bromo-2-chloroethane (2.3 ml, 27.24 mmol) was added to the reaction mixture at r.t and the resulting mixture was stirred at this temperature for 96 hours. The reaction mixture was filtered, and the filtrate concentrated under reduced pressure. Purification by column chromatography (ISCO, silica gel column, eluting with 0→100% EtOAc in hexanes) gave the title compound (0.64 g, yield: 50%).
Reaction SMILES: [Li]CCCC.[CH3:6][O:7][CH2:8][O:9][CH2:10][Sn](CCCC)(CCCC)CCCC.[CH:24]([C:26]1[S:27][CH:28]=[CH:29][N:30]=1)=[O:25]>C1COCC1.O>[OH:25][CH:24]([C:26]1[S:27][CH:28]=[CH:29][N:30]=1)[CH2:10][O:9][CH2:8][O:7][CH3:6]
Reactant: CCCC[Sn](CCCC)(CCCC)COCOC
Reactant: O=Cc1nccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COCOCC(O)c1nccs1
Reaction time: 8 h
Yield: 34.8 %

Procedure:
n-BuLi (2.87 mmol, 1.8 mL, 1.6M) was added dropwise to a -78° C. solution of (methoxymethoxymethyl)tributyl tin (1.05 g, 2.87 mmol) in dry THF (10 mL). After stirring for 30 minutes a solution of 2-formylthiazole (2.73 mmol, 0.31 g) in THF (2 mL) was added and the solution stirred overnight. The reaction was diluted with water and extracted with ethyl acetate, dried (MgSO4), filtered and concentrated. The residue was subjected to flash chromatography (45% ethyl acetate/hexane) to afford 0.18 g (34%) of 2-(1-hydroxy-2-(methoxymethoxy)ethyl)thiazole.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:9](=[O:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]2[S:28][C:29]([C:32]#[N:33])=[CH:30][N:31]=2)[CH:21]=1>CS(C)=O>[CH3:2][N:3]1[C:9](=[O:10])[CH2:8][CH2:7][N:6]([CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]3[S:28][C:29]([C:32]#[N:33])=[CH:30][N:31]=3)[CH:21]=2)[CH2:5][CH2:4]1
Reactant: CN1CCNCCC1=O
Reactant: N#Cc1cnc(Nc2cc(CCl)ccn2)s1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN1CCN(Cc2ccnc(Nc3ncc(C#N)s3)c2)CCC1=O
Reaction time: 20 h

Procedure:
4-Methyl-[1,4]diazepan-5-one hydrochloride (0.394 g, 2.39 mmol) was dissolved in 3 mL DMSO. Triethylamine (0.33 mL, 2.4 mmol) was added followed by the addition of 2-(4-chloromethyl-pyridin-2-ylamino)-thiazole-5-carbonitrile (0.200 g, 0.798 mmol). The solution as stirred for 20 h. The reaction mixture was purified directly by loading the solution onto a reverse phase preparative column. The fractions containing pure product were concentrated and the white solid that resulted was characterized as the TFA salt. 1H NMR (CD3OD) δ 8.47 (d, 1H, J=5.1 Hz), 8.02 (s, 1H), 7.09 (s, 1H), 7.07 (d, 1H, J=5.0 Hz), 3.78 (bs, 2H), 3.61 (bs, 2H), 2.98 (s, 3H), 2.83-2.67 (bs, 6H). [M+H]+=343.2.
Reaction SMILES: [CH2:1]([C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([CH2:13][CH3:14])[C:4]=1[CH:5]=O)[CH3:2].[C:15](Br)(Br)([Br:17])[Br:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[Br:16][C:15]([Br:17])=[CH:5][C:4]1[C:3]([CH2:1][CH3:2])=[C:10]([O:11][CH3:12])[CH:9]=[CH:8][C:7]=1[CH2:13][CH3:14]
Reactant: CCc1ccc(OC)c(CC)c1C=O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCc1ccc(OC)c(CC)c1C=C(Br)Br

Procedure:
2-(2,2-Dibromo-vinyl)-1,3-diethyl-4-methoxy-benzene was prepared from 2,6-diethyl-3-methoxy-benzaldehyde, carbon tetrabromide and triphenylphosphine in analogy to Example 1d): colourless oil; 1H-NMR (CDCl3): 1.08 (3H, t, CH3), 1.17 (3H, t, CH3), 2.55 (4H, m, 2×CH2), 3.81 (3H, s, OMe), 6.82 (1H, d, ArH), 7.05 (1H, d, ArH), 7.44 (1H, s, CH═CBr2).
Reaction SMILES: [PH:1](=[O:4])([OH:3])[OH:2].[CH2:5]([C:7]([CH2:35][CH3:36])([CH:9]([OH:34])[C:10]1[N:14]=[CH:13][N:12]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]=1)[CH3:8])[CH3:6].C(N(CC)CC)C.[C:44](OC(=O)C)(=[O:46])[CH3:45]>CN(C)C1C=CN=CC=1.ClCCl>[PH:1](=[O:2])([OH:4])[OH:3].[CH2:35]([C:7]([CH2:5][CH3:6])([CH:9]([O:34][C:44](=[O:46])[CH3:45])[C:10]1[N:14]=[CH:13][N:12]([C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]=1)[CH3:8])[CH3:36]
Reactant: CCC(C)(CC)C(O)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: O=[PH](O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(C)(CC)C(OC(C)=O)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
A stirred solution of diethyl 3-hydroxy-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (1.0 g, prepared as described in Example 24), triethylamine (0.22 g) and 4-dimethylaminopyridine (0.03 g) in dry dichloromethane (10 ml) was treated dropwise with acetic anhydride (0.28 g), whilst maintaining the temperature below 5° C. The mixture was allowed to warm to room temperature, stirred for a further two hours, diluted with dichloromethane, washed with water, dried over magnesium sulphate and evaporated under reduced pressure. The residue was chromatographed on silica, using dichloromethane-ethanol (19:1) as eluant, to give diethyl 3-acetoxy-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (0.86 g, m.p. 100-102° C.). NMR (CDCl3): δ 1.3(6H,t), 1.65-1.9(2H,m), 2.1(3H,s), 2.2-2.35(2H,m), 4.05(4H,m), 5.9(1H,t), 7.1(6H,m), 7.3(9H,m), 7.9(1H,s). M/S: M+ 547.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=O)[C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:46]([C:50]1[CH:69]=[CH:68][C:53]([CH2:54][NH:55][CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([O:64][CH:65]([F:67])[F:66])[CH:59]=2)=[CH:52][CH:51]=1)([CH3:49])([CH3:48])[CH3:47]>CN(C=O)C.O>[C:46]([C:50]1[CH:69]=[CH:68][C:53]([CH2:54][N:55]([CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([O:64][CH:65]([F:67])[F:66])[CH:59]=2)[C:12]([C:9]2[C:10]([F:11])=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:14])=[CH:52][CH:51]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)c1ccc(CNCCc2cccc(OC(F)F)c2)cc1
Reactant: O=C(O)c1c(F)c(Cl)cc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(CN(CCc2cccc(OC(F)F)c2)C(=O)c2c(F)c(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 36.6 %

Procedure:
To a solution of 100 mg (0.47 mmol) of 5-chloro-6-fluoro-1H-indole-7-carboxylic acid and 150 mg of TBTU (0.47 mmol) in 10 ml DMF, were added 0.4 ml (2.34 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 156 mg (0.47 mmol) of (4-tert-butyl-benzyl)-[2-(3-difluoromethoxy-phenyl)-ethyl]-amine were added. After stirring for 22 h at rt, the reaction mixture was diluted with 10 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by two successive column chromatographies (8 g silica gel; EtOAc/heptane 1:3; then again 8 g silica gel; and DCM/heptane 70:30 to 90:10) to give 91 mg white solid (27%). MS(ISP) 528.3 (M+H)+.
Reaction SMILES: Cl.[Br:2][C:3]1[N:7]([CH2:8][CH3:9])[C:6]([CH2:10]Cl)=[N:5][C:4]=1[CH3:12].C([O-])([O-])=O.[K+].[K+].[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[NH:27][CH:28]=[CH:29][N:30]=2)[N:21]=1.O>CN(C=O)C>[Br:2][C:3]1[N:7]([CH2:8][CH3:9])[C:6]([CH2:10][N:30]2[CH:29]=[CH:28][N:27]=[C:26]2[C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([F:19])[N:21]=2)=[N:5][C:4]=1[CH3:12]
Reactant: Fc1cccc(-c2ncc[nH]2)n1
Reactant: CCn1c(CCl)nc(C)c1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(Cn2ccnc2-c2cccc(F)n2)nc(C)c1Br
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 74 mg (0.27 mmol) of 5-bromo-2-chloromethyl-1-ethyl-4-methyl-1H-imidazole hydrochloride in 1.5 ml of DMF is added 224 mg (1.62 mmol) of K2CO3 and 45 mg (0.27 mmol) of 2-fluoro-6-(1H-imidazol-2-yl)-pyridine. The mixture is stirred at room temperature for 24 hours. 5 ml water is added and the mixture was extracted with EtOAc (3×15 ml). The combined extracts are washed with 15 ml brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue is purified by preparative TLC, developing with 10:0.4:0.05 CH2Cl2—MeOH—NH4OH solution. The purified compound is then dissolved in 3 ml of EtOAc and to it is added 2 ml of 2N HCl in ether. The resulting suspension is stirred at room temperature for 15 minutes. Evaporation of the solvent provided the title compound as a white powder. LC-MS (M+1) 364.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([OH:28])[CH:26]=2)[N:21]=[CH:20][N:19]=1>>[CH3:16][N:13]1[CH:14]=[CH:15][C:11]([NH:10][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:28][C:2]4[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=4)[CH:26]=3)[N:21]=[CH:20][N:19]=2)=[N:12]1
Reactant: OCc1cccnc1Cl
Reactant: Cn1ccc(N)n1
Reactant: Oc1ccc2ncnc(Cl)c2c1
Product: Cn1ccc(Nc2ncnc3ccc(Oc4ncccc4CO)cc23)n1

Procedure:
The compound of Example 124 was manufactured by the same method as in Example 95, by a similar method thereto or by a combination of such a method with a conventional method using 2-chloro-3-hydroxymethylpyridine, 3-amino-1-methyl-1H-pyrazole and 4-chloro-6-hydroxy-quinazoline.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([C:13]([F:16])([F:15])[F:14])=[CH:7][CH:8]=2)[N:3]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>COCCCOCCCO>[CH3:1][C:2]1[CH:11]=[C:10]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[C:9]2[C:4](=[CH:5][C:6]([C:13]([F:16])([F:15])[F:14])=[CH:7][CH:8]=2)[N:3]=1
Reactant: C1CNCCN1
Reactant: Cc1cc(Cl)c2ccc(C(F)(F)F)cc2n1
Agent: COCCCOCCCO
Product: Cc1cc(N2CCNCC2)c2ccc(C(F)(F)F)cc2n1
Temperature: 140 °C
Reaction time: 8 h

Procedure:
2-Methyl-4-chloro-7-(trifluoromethyl)quinoline (1.1 g, 4.4 mmol) was dissolved in dipropyleneglycolmonomethylether, piperazine was added (12 g, 14 mmol) and the mixture was stirred at 140° C. overnight. The solvent was removed under reduced pressure and the residue purified by column chromatography (prepacked silica column, gradient ethyl acetate/methanol with the addition of 1% ammonia) to yield 1.07 g of a solid. (3.6 mmol, 82%) MS (APCI): m/z=295.8 [M+1]+.
Reaction SMILES: [CH:1]1([C:4]2[C:10]([F:11])=[CH:9][C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:5]=2[NH2:6])[CH2:3][CH2:2]1.C[Si]([N:19]=[N+:20]=[N-:21])(C)C.[CH3:22]OC(OC)OC.[OH-].[Na+]>CC(O)=O.CCOC(C)=O>[CH:1]1([C:4]2[C:10]([F:11])=[CH:9][C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:5]=2[N:6]2[CH:22]=[N:19][N:20]=[N:21]2)[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COC(OC)OC
Reactant: Nc1cc([N+](=O)[O-])cc(F)c1C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(F)c(C2CC2)c(-n2cnnn2)c1
Temperature: 70 °C
Reaction time: 7 h
Yield: 90 %

Procedure:
A mixture of 2-cyclopropyl-3-fluoro-5-nitroaniline (300 mg, 1.53 mmol, 1 equiv), trimethylsilyl azide (1.0 mL, 7.65 mmol, 5 equiv), trimethylorthoformate (1.67 mL, 15.29 mmol, 10 equiv) in AcOH (3 mL) was heated to 70° C. and stirred for 7 hours behind a blast shield. After allowing to cool to room temperature, the mixture was further cooled in ice-water and basified to ca. pH 12-14 with 1N NaOH and diluted with EtOAc. The aqueous and organic layers were partitioned and the aqueous extracted with EtOAc (2×150 mL). The combined organic extracts were washed with 1N NaOH (1×100 mL), dried (Na2SO4), filtered, and the solvent removed under vacuum—silica gel was added at this stage so that the crude product was absorbed directly on to silica gel. The crude product was purified by column chromatography on silica gel using EtOAc/hexanes (30-50% EtOAc in increments of 10% EtOAc) to give the product 1-(2-cyclopropyl-3-fluoro-5-nitrophenyl)-1H-tetrazole (343 mg, 90%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[CH:14]=[C:13]([CH2:15]O)[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].P(Br)(Br)[Br:18].O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:18][CH2:15][C:13]1[N:12]=[N:11][N:10]([CH2:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH:14]=1
Reactant: OCc1cn(Cc2ccc(Cl)c(Cl)c2)nn1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Clc1ccc(Cn2cc(CBr)nn2)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of {1-[(3,4-dichlorophenyl)methyl]-1H-1,2,3-triazol-4-yl}methanol (Intermediate 16) (0.17 g, 0.66 mmol) in DCM was added PBr3 (125 μL, 2 eq) and the reaction was stirred at room temperature for 3 hours. Water was added, followed by solid NaHCO3. The organic phase was dried over sodium sulphate and evaporated. The title compound was obtained as a colorless oil (0.21 g, 99%) and used in the next step without purification. LC/MS: m/z 320 (M−H)+. Rt: 2.13 min.