Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=1[S:13][C@H:14]1[CH2:23][CH2:22][C@@H:21]2[C@@H:16]([CH2:17][C@@H:18]([C:28]([O:30]CC)=[O:29])[N:19](C(OC)=O)[CH2:20]2)[CH2:15]1)=[O:5])C.[ClH:33]>>[ClH:33].[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=1[S:13][C@H:14]1[CH2:23][CH2:22][C@@H:21]2[C@@H:16]([CH2:17][C@@H:18]([C:28]([OH:30])=[O:29])[NH:19][CH2:20]2)[CH2:15]1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccc(C)cc1S[C@H]1CC[C@H]2CN(C(=O)OC)[C@H](C(=O)OCC)C[C@H]2C1
Agent: Cl
Product: Cc1ccc(C(=O)O)c(S[C@H]2CC[C@H]3CN[C@H](C(=O)O)C[C@H]3C2)c1
Yield: 84 %

Procedure:
Following the procedures for Example 22, Step D, extensive hydrolysis of material from step C (54 mg, 0.12 mmol) with 6M hydrochloric acid (3 mL) gave the title product (39 mg, 84% yield).
Reaction SMILES: [BH4-].[Li+].[CH2:3]([C:5]1[C:6]([O:20][CH3:21])=[N:7][C:8]2[N:9]([CH:12]=[C:13]([C:15](OCC)=[O:16])[N:14]=2)[C:10]=1[CH3:11])[CH3:4].[BH4-]>O1CCCC1>[CH2:3]([C:5]1[C:6]([O:20][CH3:21])=[N:7][C:8]2[N:9]([CH:12]=[C:13]([CH2:15][OH:16])[N:14]=2)[C:10]=1[CH3:11])[CH3:4]
Reactant: CCOC(=O)c1cn2c(C)c(CC)c(OC)nc2n1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1c(OC)nc2nc(CO)cn2c1C
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
11.55 g (0.525 mol) of lithium borohydride were added portionwise over 1 hour to a stirred solution of 19.7 g (75 mmol) of ethyl 6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidine-2-carboxylate in 300 ml of dry tetrahydrofuran and after stirring at room temperature for 18 hours the excess borohydride was destroyed by dropwise addition of 300 ml of saturated sodium chloride solution. Then, the mixture was stirred for 30 minutes before separating the organic layer. The aqueous layer was extracted with chloroform and the combined extracts were dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure to obtain 15.4 g (6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidin-2-yl)methanol (93% yield as a white crystalline solid melting at 186-188° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]([N:9]=[CH:10][N:11](C)C)=O)[S:5][CH:6]=1.[CH3:14][NH:15]N>CC(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:7]2[N:15]([CH3:14])[N:11]=[CH:10][N:9]=2)[S:5][CH:6]=1
Reactant: CNN
Reactant: CN(C)C=NC(=O)c1cc(Cl)cs1
Solvent: CC(=O)O
Product: Cn1ncnc1-c1cc(Cl)cs1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
A 3-L reaction flask equipped with a cooling bath, air stirrer, and thermometer probe is charged with 4-chloro-N-dimethylaminomethylene-2-thiophene carboxamide. (155 g, 0.715 moles) and HOAc (1500 mL) to form a solution. Using an ice-water cooling bath to maintain the temperature at ≦30° C., methylhydrazine (33.2 g, 0.721 moles) is added dropwise via an addition funnel over 15-20 minutes to form a light yellow slurry. Gradually, the reaction is heated to 90° C. and held at 90° C. for 30 minutes. After analysis of the mixture by GC, the reaction is cooled to ˜70° C.; then, concentrated to a thick oil/slurry. De-ionized H2O (1.67 L) is slowly added to precipitate solids; then, the mixture is cooled to <30° C., filtered and washed with de-ionized H2O (1.67 L). The wet solids (125.8 g) are re-dissolved in warm MTBE (1.64 L), dried over Na2SO4, filtered and concentrated to dryness giving the title compound as a pale yellow solid (85.8 g, 60.1% 91.9% area % by GC).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=1>ClCCl.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[N:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=1)=[O:1]
Reactant: COC(=O)c1cccc(CO)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COC(=O)c1cccc(C=O)n1
Temperature: 25 °C
Reaction time: 96 h
Yield: 87 %

Procedure:
A solution of the product from Example 17A (8 g, 48 mmol) in dichloromethane (200 mL) was treated with electrolytic manganese dioxide (41.67 g, 0.48 mol). The mixture was stirred for 4 days at 25° C. and filtered through celite. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on silica gel eluting with 5% methanol in dichloromethane to give the title compound as a white solid (6.9 g, 87% yield).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([O:22][CH3:23])[C:14]([C:24]3[CH2:28][CH:27](O)[O:26][N:25]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([O:22][CH3:23])[C:14]([C:24]3[CH:28]=[CH:27][O:26][N:25]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(C2=NOC(O)C2)c1OC
Solvent: CCO
Product: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccon2)c1OC
Temperature: 140 °C
Reaction time: 1.25 h
Yield: 76.5 %

Procedure:
A solution of ethyl 6-(benzenesulphonylmethyl)-3-(5-hydroxy-4,5-dihydroisoxazol-3-yl)-2-methoxybenzoate (Intermediate 49, 0.041 g) in ethanol (3 ml) was stirred and heated in the microwave at 140° C. for 15 minutes then at 160° C. for 75 minutes. After cooling, the solution was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-50% to give ethyl 6-(benzenesulphonylmethyl)-3-(isoxazol-3-yl)-2-methoxybenzoate (0.03 g) as a gum.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:20])=[C:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:5]=[C:6]([O:8][CH:9]([F:11])[F:10])[CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Cl)=[CH:35][CH:34]=1.CCOC(C)=O>CN(C=O)C>[Br:1][C:2]1[C:3]([Cl:20])=[C:4]([N:12]([CH2:37][C:36]2[CH:39]=[CH:40][C:33]([O:32][CH3:31])=[CH:34][CH:35]=2)[C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])[CH:5]=[C:6]([O:8][CH:9]([F:11])[F:10])[CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(OC(F)F)cc(Br)c1Cl
Reactant: COc1ccc(CCl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2cc(OC(F)F)cc(Br)c2Cl)cc1
Reaction time: 8 h
Yield: 72.9 %

Procedure:
tert-Butyl (3-bromo-2-chloro-5-(difluoromethoxy)phenyl)carbamate (2.78 g, 7.46 mmol) was dissolved in DMF (37.3 ml) at room temperature. NaHMDS (8.95 ml, 8.95 mmol) was added drop wise and the reaction mixture was stirred for 30 min before the addition of 4-methoxybenzyl chloride (1.321 ml, 9.70 mmol). The reaction was allowed to stir overnight. EtOAc (250 mL) was added and the organic layer was washed with 10% LiCl solution (2×, dried over Na2SO4 and concentrated. Column chromatography (120 g SiO2, 0 to 10% EtOAc-hexane gradient elution) afforded tert-butyl (3-bromo-2-chloro-5-(difluoromethoxy)phenyl)(4-methoxybenzyl)carbamate as a clear oil (2.68 g)
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:11](O)=[O:12])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.S(Cl)([Cl:21])=O>>[CH3:1][C:2]1([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:11]([Cl:21])=[O:12])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C(=O)O)cc1C1(C)CCCCC1
Product: COc1ccc(C(=O)Cl)cc1C1(C)CCCCC1
Yield: 100 %

Procedure:
1.24 g (5 mmoles) of 3-(1-methylcyclohexyl)-4-methoxybenzoic acid and 15 ml of thionyl chloride are heated at reflux until the cessation of gas evolution. The reaction mixture is evaporated to dryness. 1.32 g (100% yield) of crude 3-(1-methylcyclohexyl)-4-methoxybenzoic acid chloride which is used as such for the following synthesis are obtained.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][CH:10]([CH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:1]([NH:9][CH:10]([CH:16]1[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(N)C1CCOCC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(NCc1ccccc1)C1CCOCC1

Procedure:
0.53 ml (4.5 mmol) benzylbromide, 0.85 g (4.5 mmol) ethyl (rac)-amino-(tetrahydropyran-4-yl)-acetate and 1.9 g (13.7 mmol) potassium carbonate in 10 mL DMF were stirred for 2 h at 100° C. After cooling the mixture was mixed with water and extracted three times with ethyl acetate. The combined organic phases were extracted with saturated, aqueous saline solution, three times with 0.5 M hydrochloric acid and once more with saturated saline solution. The combined aqueous phases were adjusted to pH 9 with conc. aqueous ammonia solution and extracted three times with dichloromethane. The combined organic phases were washed with saturated saline solution, dried and concentrated by rotary evaporation.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[C:4]#[C:5][CH2:6][OH:7].Br[CH2:10][C:11]#[N:12]>C1COCC1>[OH:7][CH2:6][C:5]#[C:4][CH2:3][O:8][CH2:10][C:11]#[N:12]
Reactant: OCC#CCO
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCOCC#CCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
Sodium hydride (60% dispersion in oil, 7.5 g, 188 mmol) was added to a solution of 2-butyne-1,4-diol (16.1 g, 187 mmol) in THF (150 mL) at 0° C. under nitrogen. After 1 h at 0° C., bromoacetonitrile (8.33 mL, 120 mmol) was added slowly and the reaction was allowed to warm to rt. After 22 h at rt, the reaction was quenched with 1 N HCl (150 mL) and extracted with EtOAc (3×150 mL). The combined extracts were washed with brine (150 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→2% MeOH/CH2Cl2, gradient) afforded 4.35 g (29%) of (4-hydroxy-but-2-ynyloxy)-acetonitrile.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)[C:10]([NH:12][CH2:13][CH2:14][C:15]#[N:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C[Si]([N:65]=[N+:66]=[N-:67])(C)C>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:10]1[N:12]([CH2:13][CH2:14][C:15]#[N:16])[N:67]=[N:66][N:65]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)NCCC#N
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)c1nnnn1CCC#N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (S)-2-t-butoxycarbonylamino-3-biphenyl-4-yl-N-(2-cyanoethyl)-propionamide (18 g, 45.7 mmol) in THF (375 mL) under nitrogen is added triphenylphosphine (12 g, 45.7 mmol). The solution is cooled to 0° and treated with diethyl azodicarboxylate (DEAD, 7.2 mL, 24.3 mmol) followed by trimethylsilyl azide (3.2 mL, 24.3 mmol). The solution is warmed up to room temperature and stirred for 18 hours. One additional equivalent of triphenyl phosphine (12 g, 45.7 mmol), DEAD (7.2 mL, 24.3 mmol) and trimethylsilyl azide (3.2 mL, 24.3 mmol) are added and stirring is continued for 3 days. The solution is cooled to 0°. Ceric ammonium nitrate (2.2 L; 10% aqueous solution) is added dropwise. After 20 minutes of stirring, extraction is carried out with methylene chloride (3×200 mL). The combined organic layers are dried over anhydrous sodium sulfate, then filtered and concentrated in vacuo. The residue is taken up in ethyl acetate (500 mL) and hexane (50 mL). A small amount of (S)-3-[5-(1-t-butoxycarbonylamino-2-biphenyl-4-yl-ethyl)-tetrazol-1-yl]-propionitrile crystallizes out. The filtrate is concentrated and the residue purified by flash-chromatography eluting with a gradient of ethyl acetate in hexane (30% to 50%). The pure fractions of product (Rf=0.6 in 1/1 ethyl acetate/hexane) are combined and concentrated under reduced pressure to give (S)-3-[5-(1-t-butoxycarbonylamino-2-biphenyl-4-yl-ethyl)tetrazol-1-yl]-propionitrile as a colorless crystalline solid, m.p. 184°-185°, [α]D =-2.90° (c 0.89, CHCl3).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1O)=[CH:13][CH:12]=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=2)=[O:5])[CH3:2].C(Cl)(=O)C([Cl:23])=O.[OH-].[Na+]>C(Cl)(Cl)Cl.CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:23])=[CH:13][CH:12]=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=2)=[O:5])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)c1cnc2cc([N+](=O)[O-])ccc2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cnc2cc([N+](=O)[O-])ccc2c1Cl
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
4-Hydroxy-7-nitro-quinoline-3-carboxylic acid ethyl ester (15.6 g, 59.5 mmol) was suspended in chloroform (250 ml) and oxalyl chloride (20.7 ml, 30.2 g, 238 mmol) was added, followed by dimethyl formamide (0.4 ml, 0.38 g, 5.2 mmol). After heating at reflux for 2.5 h, the mixture was added to 300 ml of a 2N aqueous sodium hydroxide solution cooled in an ice/water bath. After stirring vigorously for 30 minutes, the aqueous layer was extracted with chloroform (200 ml). The combined organic phases were washed with water, brine and then dried over anhydrous magnesium sulfate. After vacuum filtration, the solution was concentrated under vacuum to provide 15.6 g of a fluffy brown solid. This solid was transferred to a Soxleht thimble and extracted with dichloromethane for 4 h employing a Soxleht extractor. Concentration of the dichloromethane solution under vacuum yielded 14.68 g of a tan solid. This solid was crystallized by dissolving in 400 ml of hot acetone and cooling to 0° C. overnight. The solid was collected by filtration, rinsing with ice-cold acetone, to yield 9.91 g of the title product as light yellow needles.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][C:25]1=[O:29]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[N:6]=[N:7][C:2]([N:24]4[CH2:28][CH2:27][CH2:26][C:25]4=[O:29])=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: O=C1CCCN1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)nn3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)nn3)CC2)c(C)c1
Yield: 9.3 %

Procedure:
Using (6-chloropyridazin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 230 and pyrrolidin-2-one (46 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (16 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:26][CH3:27])=[CH:4][C:5]([O:21][CH2:22][CH:23]([F:25])[F:24])=[C:6]([CH:20]=1)[C:7]([NH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([F:19])([F:18])[F:17])[CH2:12][CH2:11]1)=[O:8].[N:28]([C:31]1[CH:32]=[C:33]([CH:42]=[CH:43][C:44]=1[C:45]([F:48])([F:47])[F:46])[CH2:34][N-:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])=[C:29]=S>>[F:17][C:16]([F:18])([F:19])[C@H:13]1[CH2:14][CH2:15][C@H:10]([NH:9][C:7]([C:6]2[C:5]([O:21][CH2:22][CH:23]([F:24])[F:25])=[CH:4][C:3]3[N:26]([CH3:27])[C:29]([NH:28][C:31]4[CH:32]=[C:33]([CH2:34][NH:35][C:36]([C:37]([CH3:40])([CH3:39])[CH3:38])=[O:41])[CH:42]=[CH:43][C:44]=4[C:45]([F:48])([F:47])[F:46])=[N:1][C:2]=3[CH:20]=2)=[O:8])[CH2:11][CH2:12]1
Reactant: CC(C)(C)C(=O)[N-]Cc1ccc(C(F)(F)F)c(N=C=S)c1
Reactant: CNc1cc(OCC(F)F)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1N
Product: Cn1c(Nc2cc(CNC(=O)C(C)(C)C)ccc2C(F)(F)F)nc2cc(C(=O)N[C@H]3CC[C@H](C(F)(F)F)CC3)c(OCC(F)F)cc21

Procedure:
The sub-title compound was prepared from 5-amino-2-(2,2-difluoroethoxy)-4-(methylamino)-N-(trans-4-trifluoromethyl-cyclohex-1-yl)-benzamide and N-(3-isothiocyanato-4-trifluoromethyl-benzyl)-pivaloylamide in analogy to example 72a.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][CH:19]=[C:20]([CH2:22][N:23]3[C@H:27]([CH2:28][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[CH2:26][CH2:25][C:24]3=O)[N:21]=2)=[CH:13][CH:12]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[O:18][CH:19]=[C:20]([CH2:22][N:23]3[CH2:24][CH2:25][CH2:26][C@H:27]3[CH2:28][N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)[N:21]=2)=[CH:15][CH:16]=1
Reactant: CC1CCCN1CCCOc1ccc(-c2nc(CN3C(=O)CC[C@H]3CN3CCOCC3)co2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC1CCCN1CCCOc1ccc(-c2nc(CN3CCC[C@H]3CN3CCOCC3)co2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 28.8 %

Procedure:
(5S)-1-[(2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-1,3-oxazol-4-yl)methyl]-5-(morpholin-4-ylmethyl)pyrrolidin-2-one 137 (0.21 g, 1 eq, 0.43 mmol) is dissolved in tetrahydrofuran (5 ml), then the mixture is cooled to 0° C. and lithium aluminium hydride (0.03 g, 2 eq, 0.87 mmol) is added. The mixture is stirred 1 h at 0° C. and then overnight at room temperature. Water (0.05 ml), a solution of sodium hydroxide 2N (0.05 ml) and again water (0.15 ml) are added. Then, the mixture is filtered through celite and concentrated under vacuum. Purification by chromatography on silicagel (eluent: dichloromethane/methanol/ammonia 951510.5) affords 0.058 g of 4-({(2S)-1-[(2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-1,3-oxazol-4-yl)methyl]pyrrolidin-2-yl}methyl)morpholine 144.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].CCOCC>CO.O>[C:18]([O:17][C:15]([NH:14][CH2:13][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:4]=1[C:3]([OH:22])=[O:2])=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)c1c(CNC(=O)OC(C)(C)C)cccc1[N+](=O)[O-]
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1cccc([N+](=O)[O-])c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
A mixture of 2-(tert-butoxycarbonylamino-methyl)-6-nitro-benzoic acid methyl ester (38.96 g, 126 mmol) lithium hydroxide (3.61 g, 151 mmol) in methanol (450 mL) and water (225 mL) was stirred with a mechanical stirrer at room temp overnight. The methanol was evaporated and to the aqueous solution, was added 1 N HCl (200 mL) to form the precipitate. Ether (300 mL) was added, and the mixture was stirred at 0° C. for 2 hours. The suspension was filtered, washed with water (100 mL) and ether (100 mL), and suction dried in hood overnight to give 2-(tert-butoxycarbonylamino-methyl)-6-nitro-benzoic acid as a yellow solid (22.4 g, 60% yield). The product was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[N+:9]([O-])([O-:11])=[O:10].[Na+].O>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[C:4]([OH:8])[CH:3]=1
Reactant: Oc1cccc(Br)c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc(Br)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.6 %

Procedure:
3-Bromophenol (32.9 g, 0.19 mol) was added slowly to a cold (10° C.) solution of sodium nitrate (29.0 g, 0.34 mol) in conc. sulfuric acid; (40.0 g) and water (70.0 mL) and the resulting mixture was allowed to stir at room temperature for 2 h. Water (200 mL) was added and the resulting mixture was extracted with diethyl ether and the extract was dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (silica gel, 10% ethyl acetate/hexanes) to afford first the title compound (8.1 g, 20%), mp 40-42° C., then the undesired isomer, 3-bromo-4-nitrophenol, as a yellow solid (12.7 g, 31%). mp 125-127° C.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:26][CH2:27][CH:28]([NH:31][S:32]([C:35]1[S:39][C:38]([NH2:40])=[N:37][C:36]=1[CH3:41])(=[O:34])=[O:33])[CH2:29][OH:30]>>[OH:26][CH2:27][CH:28]([NH:31][S:32]([C:35]1[S:39][C:38]([NH:40][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=4)=[N:6][C:7]=23)=[O:14])=[N:37][C:36]=1[CH3:41])(=[O:34])=[O:33])[CH2:29][OH:30]
Reactant: Cc1nc(N)sc1S(=O)(=O)NC(CO)CO
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Cc1nc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)sc1S(=O)(=O)NC(CO)CO

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 2-amino-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-1-hydroxymethyl-ethyl)-amide (example B.16) according to general procedure II. Light yellow solid. MS (ISP) 604.8 [(M−H)−]; mp 217° C.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][CH:7]([P:18](=[O:27])([O:23][CH2:24][CH:25]=[CH2:26])[O:19][CH2:20][CH:21]=[CH2:22])[P:8](=[O:17])([O:13][CH2:14][CH:15]=[CH2:16])[O:9][CH2:10][CH:11]=[CH2:12])=[CH:4][CH:3]=1.N1C=CC=CC=1.[Br:36][CH2:37][C:38](Br)=[O:39]>C(Cl)Cl>[Br:36][CH2:37][C:38]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]([P:18](=[O:27])([O:23][CH2:24][CH:25]=[CH2:26])[O:19][CH2:20][CH:21]=[CH2:22])[P:8](=[O:17])([O:13][CH2:14][CH:15]=[CH2:16])[O:9][CH2:10][CH:11]=[CH2:12])=[CH:28][CH:29]=1)=[O:39]
Reactant: O=C(Br)CBr
Reactant: C=CCOP(=O)(OCC=C)C(Cc1ccc(N)cc1)P(=O)(OCC=C)OCC=C
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCOP(=O)(OCC=C)C(Cc1ccc(NC(=O)CBr)cc1)P(=O)(OCC=C)OCC=C
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 75.9 %

Procedure:
To a solution of aminobenzyl bisphosphonate 27 (180 mg, 0.41 mmol) in CH2Cl2 (5 mL) at 0° C. was added pyridine (49 μL, 0.61 mmol) followed by bromoacetylbromide (35 μL, 0.41 mmol). The reaction mixture was stirred at 0° C. for 30 min and at room temperature for another 2.5 h. The reaction mixture was diluted with CH2Cl2, washed with aqueous 1N HCl solution, saturated NaHCO3 solution, and saturated NaCl solution, then dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel using a gradient of 0-10% MeOH in CH2Cl2 as eluant to provide bromide 28 as a clear yellow oil (175 mg, 3.11×10−4 mol, 76%). 1H NMR (400 MHz, CDCl3) δ 2.72 (tt, J=23.9, 6.2 Hz, 1H), 3.26 (dt, J=16.3, 6.1 Hz, 2H), 4.02 (s, 2H), 4.48-4.62 (m, 8H), 5.20-5.24 (m, 4H), 5.29-5.35 (m, 4H), 5.83-5.94 (m, 4H), 7.25-7.28 (m, 2H), 7.42-7.46 (m, 2H), 8.11 (bs, 1H).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([CH2:14][NH:15][CH2:16][CH3:17])([OH:13])[CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[CH2:16]([NH:15][CH2:14][C:10]1([OH:13])[CH2:11][CH2:12][NH:8][CH2:9]1)[CH3:17]
Reactant: CCNCC1(O)CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CCNCC1(O)CCNC1

Procedure:
10 g (42.7 mmol) of 1-benzyl-3-ethylaminomethyl-3-hydroxypyrrolidine in 60 ml of methanol are hydrogenated using 2 g of palladium/active carbon (10%) at 92° C. and 107 bar. The catalyst is filtered off, the filtrate is concentrated and the residue is distilled.
Reaction SMILES: C1OCCOCCOCCOCCOCC[O:3]C1.[CH3:19][O:20][C:21]1[CH:31]=[CH:30][C:29]2[C:32]3[C:22]=1[C:23](=[O:34])[C:24](=[O:33])[C:25]=3[CH:26]=[CH:27][CH:28]=2.O.Cl>CS(C)=O>[CH3:19][O:20][C:21]1[CH:22]=[C:32]2[C:29]([CH:28]=[CH:27][CH:26]=[C:25]2[C:24](=[O:33])[C:23]([OH:34])=[O:3])=[CH:30][CH:31]=1
Reactant: COc1ccc2cccc3c2c1C(=O)C3=O
Reactant: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc2cccc(C(=O)C(=O)O)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
In a reactor, 4 mg of 18-crown-6 ether and then 230 mg of NaNH2 are successively introduced into a suspension of 100 mg of 3-methoxyacenaphthoquinone in 1 ml of DMSO. The mixture is stirred for 30 minutes at ambient temperature. Water (2 ml) is then added, followed by 2N HCl solution (3 ml). After two extractions with ethyl acetate, the solvents are dried over Na2SO4 and then evaporated off to yield the title product in the form of a yellow solid in a yield of 88% and with a chemical purity of more than 94%.