Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[N:7]=1.Cl[C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(C(C)C)C(C)C)C.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[N:9]([C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:10]=2)[N:7]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=c1[nH]nc2ccc(Cl)nn12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=c1n(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc2ccc(Cl)nn12
Temperature: 25 °C
Reaction time: 48 h
Yield: 71.6 %

Procedure:
0.341 g of 6-chloro[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one and 0.669 g of chlorotriphenylmethane were dissolved in 5 ml of N,N-dimethylformamide; 0.414 ml of N-ethyldiisopropylamine was added, followed by stirring at room temperature for 2 days. After water was added, the reaction mixture was extracted with ethyl acetate; the extract was washed with saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (2:1). The desired fraction was collected and concentrated; the crystal obtained was collected by filtration, washed with diethyl ether, and dried, to yield 0.591 g of the title compound.
Reaction SMILES: [F:1][C:2]1[C:12]([F:13])=[C:11]([O:14][CH3:15])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH:6]1[CH2:8][O:7]1.[C:16]1([C:22]2[C:30]3[C:29]([N:31]4[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]4)=[N:28][CH:27]=[N:26][C:25]=3[S:24][CH:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[F:1][C:2]1[C:12]([F:13])=[C:11]([O:14][CH3:15])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH:6]([OH:7])[CH2:8][NH:37][CH:34]1[CH2:35][CH2:36][N:31]([C:29]2[C:30]3[C:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:23][S:24][C:25]=3[N:26]=[CH:27][N:28]=2)[CH2:32][CH2:33]1
Reactant: COc1ccc(OCC2CO2)c(F)c1F
Reactant: NC1CCN(c2ncnc3scc(-c4ccccc4)c23)CC1
Product: COc1ccc(OCC(O)CNC2CCN(c3ncnc4scc(-c5ccccc5)c34)CC2)c(F)c1F
Yield: 49 %

Procedure:
Synthesis followed SP6 (3 h), using 430 μmol 2-((2,3-difluoro-4-methoxyphenoxy)methyl)oxirane and 1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-amine to give O-methylated intermediate 1-(2,3-difluoro-4-methoxyphenoxy)-3-(1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylamino)propan-2-ol upon purification by prep. TLC (1 mm silica gel, PE/CH2Cl2/MeOH 4:6:1) with 49% yield. Product was obtained by O-demethylation according to SP12 (3 h) with 58% yield (LCMS: detected [M+1]=513.2).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl[C:22]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[CH:24][N:23]=1>O1CCCC1>[N+:28]([C:27]1[C:22]([O:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:9]=2)=[N:23][CH:24]=[CH:25][CH:26]=1)([O-:30])=[O:29]
Reactant: Oc1cccc(Oc2ccccc2)c1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccnc1Oc1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-Phenoxyphenol (3 g, 16.1 mmol) was added to a solution of potassium t-butoxide (1.90 g of 90%, 16.6 mmol) in 50 mL of dry tetrahydrofuran at room temperature after which the reaction was stirred at room temperature for 10 min. Then, 2-chloro-3-nitropyridine (2.56 g, 16.1 mmol) was added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water, extracted twice with methylene chloride and dried over magnesium sulfate. The solvent was then removed to yield the title compound of Step A as an oil. 1H NMR (CDCl3 ; 300 MHz): δ 6.85 (m,1H), 6.90 (m,2H), 7.0-7.2 (m,4H), 7.3-7.4 (m,3H), 8.35 (m,2H).
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][CH:10]([OH:12])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23](Cl)[CH:22]=1>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][O:12][CH:10]2[CH2:11][N:8]([CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:9]2)=[CH:22][CH:23]=1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Product: Clc1ccc(COC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Yield: 92 %

Procedure:
This material was prepared from 1-diphenylmethyl-3-azetidinol (6.0 g) and alpha,3,4-trichlorotoluene using the procedure described for compound (1) (yield 92%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2].C1(NC2CCCCC2)CCCCC1.Cl[CH2:27][N:28]1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38]>CN(C=O)C>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([O:8][CH2:27][N:28]1[C:29](=[O:38])[C:30]2=[CH:37][CH:36]=[CH:35][CH:34]=[C:31]2[C:32]1=[O:33])=[O:7])([O-:3])=[O:2]
Reactant: O=C(O)c1ccccc1[N+](=O)[O-]
Reactant: O=C1c2ccccc2C(=O)N1CCl
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: CN(C)C=O
Product: O=C(OCN1C(=O)c2ccccc2C1=O)c1ccccc1[N+](=O)[O-]
Reaction time: 24 h
Yield: 83 %

Procedure:
o-Nitrobenzoic acid (10.0 g) and dicyclohexylamine (11.0 g) were added in sequence to 100 ml DMF, more solvent being necessary to dissolve the resulting salt. N-(Chloromethyl)phthalimide was added and the mixture stirred for 24 hours. The product was precipitated out with water. Recrystallization from ethyl acetate/cyclohexane yielded 15.3 g (83%) of the ester, m.p. 159°-160° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:26][CH:27]([CH3:29])[CH3:28])=[C:13]([C:15]2[NH:25][C:18]3=[N:19][CH:20]=[C:21]([CH:23]=O)[CH:22]=[C:17]3[N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][CH:31]([CH3:34])[CH2:32][NH2:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C(O)(=O)C.ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:26][CH:27]([CH3:28])[CH3:29])=[C:13]([C:15]2[NH:25][C:18]3=[N:19][CH:20]=[C:21]([CH2:23][NH:33][CH2:32][CH:31]([CH3:34])[CH3:30])[CH:22]=[C:17]3[N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)Oc1ccc(OCc2ccccc2)cc1-c1nc2cc(C=O)cnc2[nH]1
Reactant: CC(C)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: CC(C)CNCc1cnc2[nH]c(-c3cc(OCc4ccccc4)ccc3OC(C)C)nc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.8 %

Procedure:
A solution of 2-[5-(benzyloxy)-2-isopropoxyphenyl]-3H-imidazo[4,5-b]pyridine-6-carbaldehyde (50 mg) and 2-methylpropan-1-amine (14 mg) in 10% acetic acid-dichloromethane (2 ml) was stirred at room temperature for 20 min. Sodium triacetoxyborohydride (55 mg) was added, and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The extract was washed with water and concentrated. The residue was purified by preparative HPLC. Saturated aqueous sodium hydrogencarbonate solution was added to the obtained fraction to neutralize the mixture, and the mixture was extracted with dichloromethane. The extract was concentrated to give the title compound (32 mg, yield 56%) as colorless crystals. melting point 101-103° C. purity 97%. M+H: 445. 1H NMR (CDCl3) δ: 0.92 (6H, dd, J=6.6, 1.7 Hz), 1.49 (6H, dd, J=5.9, 1.6 Hz), 1.70-1.85 (1H, m), 2.50 (2H, d, J=6.8 Hz), 3.97 (2H, s), 4.71-4.78 (1H, m), 5.15 (2H, s), 6.98-7.08 (2H, m), 7.31-7.50 (5H, m), 8.05 (1H, s), 8.18 (1H, s), 8.33 (1H, s).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:12]([NH2:13])=[CH:11][C:9](=[O:10])[N:8]([CH2:14][CH:15]3[CH2:17][CH2:16]3)[C:6]2=[O:7])[CH2:3][CH2:2]1.N([O-])=O.[Na+].C(O)=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH:33]([NH2:35])=O>>[CH:15]1([CH2:14][N:8]2[C:9](=[O:10])[C:11]3[NH:35][CH:33]=[N:13][C:12]=3[N:5]([CH2:4][CH:1]3[CH2:3][CH2:2]3)[C:6]2=[O:7])[CH2:17][CH2:16]1
Reactant: NC=O
Reactant: Nc1cc(=O)n(CC2CC2)c(=O)n1CC1CC1
Agent: O=N[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O=CO
Product: O=c1c2[nH]cnc2n(CC2CC2)c(=O)n1CC1CC1
Temperature: 100 °C

Procedure:
1,3-Di-cyclopropylmethyl xanthine was prepared using an analogous procedure to that described in Chem. Berichte 88, 1306-1312, 1955: 20.2 g (0.0855 mol) of 1,3-dicyclopropylmethyl-6-amino-uracil was dissolved in 100 ml of formamide, then 5.9 g sodium nitrite was added and at 60° C. 13.4 ml formic acid was added slowly with stirring. After the colour had changed from yellow to violet, the mixture was heated up to 100° C. and 3.1 g of sodium dithionite (Na2S2O4) was added in small portions.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:12](Cl)(=[O:14])=[O:13].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:25][C:24]=2[C:32]([NH2:34])=[O:33])=[CH:19][CH:18]=1>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:12]([NH:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:25][C:24]=2[C:32]([NH2:34])=[O:33])=[CH:21][CH:22]=1)(=[O:14])=[O:13]
Reactant: NC(=O)c1[nH]c2ccccc2c1-c1ccc(N)cc1
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)ccc1F
Solvent: c1ccncc1
Product: NC(=O)c1[nH]c2ccccc2c1-c1ccc(NS(=O)(=O)c2cc(C(F)(F)F)ccc2F)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
162 mg of 2-fluoro-5-trifluoromethylphenylsulfonyl chloride in 6 ml of pyridine are added dropwise to a solution of 100 mg of 3-(4-aminophenyl)-1H-indole-2-carboxamide (example 1) in 12 ml of pyridine at 0° C. The mixture is stirred at ambient temperature for 6 hours and then poured into 50 ml of ice-cold water, and the precipitate formed is filtered off. After purification by flash chromatography on a silica column, elution being carried out with a mixture of cyclohexane and ethyl acetate (20/80 by volume), 50 mg of 3-[4-(2-fluoro-5-trifluoromethylbenzenesulfonylamino)phenyl]-1H-indole-2-carboxamide are obtained, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][C@H:2]([CH:26]([CH3:28])[CH3:27])[CH2:3][C:4]1[CH:9]=[C:8]([S:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH2:19][C@H:20]([CH3:24])[CH:21]([CH3:23])[CH3:22])[CH:13]=2)=[O:11])[CH:7]=[CH:6][C:5]=1[CH3:25].ClC1C=C(C=CC=1)C(OO)=[O:34]>ClCCl>[CH3:1][C@H:2]([CH:26]([CH3:28])[CH3:27])[CH2:3][C:4]1[CH:9]=[C:8]([S:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH2:19][C@H:20]([CH3:24])[CH:21]([CH3:22])[CH3:23])[CH:13]=2)(=[O:34])=[O:11])[CH:7]=[CH:6][C:5]=1[CH3:25]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(S(=O)c2ccc(C)c(C[C@H](C)C(C)C)c2)cc1C[C@H](C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)c2ccc(C)c(C[C@H](C)C(C)C)c2)cc1C[C@H](C)C(C)C

Procedure:
(2S)-2,3-Dimethylbutyl-p-tolylsulfoxide (10) (52 mg, 0.2 mmol) was dissolved in 1.0 mL of anhydrous dichloromethane and 60 mg (0.3 mmol) of 3-chloroperoxybenzoic acid (80-85%, Sigma) added with stirring. The reaction mixture was stirred for 2 h and quenched with 10% sodium bicarbonate. More dichloromethane was added and the combined organic extracts were washed with aqueous sodium sulfite and brine and dried with MgSO4. The solvent was removed in vacuo and the crude sulfone was purified by silica gel flash chromatography using hexane ethyl acetate mixtures to afford sulfone (12) as a colorless oil. For analytical purposes this was also purified by HPLC (Zorbax Sil 9.4×25 cm column) using 10% ethyl acetate in hexane to give 42 mg of pure (2S)-sulfone (12): [α]D20 =+17 (c=3.5 in CHCl3); MS m/z (relative intensity) 240 (M+, 3), 197 (5), 157 (100), 92 (19), 91 (27), 85 (25), 84 (31), 43 (72); 1H NMR δ0.77 (3H, d, J=7 Hz), 0.82 (3H, d, J=7.0 Hz), 1.00 (3H, d, J=7.0 Hz), 1.66-1.98 (2H, m), 2.45 (3H, s, CH3 -Aryl), 2.86 (1H, dd, J=8, 11 Hz), 3.06 (1H, dd, j=4, 12 Hz), 7.35 (2H, d, J=7.0 Hz, H-aryl ortho), 7.75 (2H, d, J=8, H-aryl ortho). Anal. Calcd. for C13H20O2S: C, 64.96; H, 8.39; S, 13.34. Found C13H20O2S: C, 65.05; H, 8.37; S, 13.24
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH2:12][CH2:13][OH:14])[CH:4]=[CH:3]1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH2:12][CH2:13][O:14][C:15](=[O:17])[CH3:16])[CH:4]=[CH:3]1
Reactant: CC(=O)OC(C)=O
Reactant: Cn1ccc2cccc(OCCO)c21
Solvent: c1ccncc1
Product: CC(=O)OCCOc1cccc2ccn(C)c12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 2-(1-methyl-1H-indol-7-yloxy)-ethanol (0.78 g, 4 mmol) in pyridine (10 mL) was treated with acetic anhydride (5 mL). The reaction mixture was stirred at rt for 4 h and concentrated. The residue was quenched with ice/water and extracted with ethyl acetate. The organics were washed with 2N sulfuric acid, sat. sodium bicarbonate and brine, dried and concentrated. The residue was chromatographed on silica gel using heptanelethyl acetate as eluent to produce the desired compound (0.90 g) as an off-white solid. MS (ISP): m/e 234.1 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:17](=[O:18])[N:16]([C:19]3[CH:24]=[C:23]([Cl:25])[C:22](=[O:26])[N:21]([CH3:27])[CH:20]=3)[CH:15]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[C:8]=2[N:9]([CH:12]([CH3:14])[CH3:13])[C:10]=1Br)=[O:5])[CH3:2].[CH3:35][O:36][C:37]1[N:42]=[C:41]([O:43][CH3:44])[C:40](B(O)O)=[CH:39][N:38]=1.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.C(C1C=CC(OC)=C(B(O)O)C=1)#N>>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:17](=[O:18])[N:16]([C:19]3[CH:24]=[C:23]([Cl:25])[C:22](=[O:26])[N:21]([CH3:27])[CH:20]=3)[CH:15]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[C:8]=2[N:9]([CH:12]([CH3:14])[CH3:13])[C:10]=1[C:40]1[C:41]([O:43][CH3:44])=[N:42][C:37]([O:36][CH3:35])=[N:38][CH:39]=1)=[O:5])[CH3:2]
Reactant: COc1ncc(B(O)O)c(OC)n1
Reactant: CCOC(=O)c1c2c(n(C(C)C)c1Br)C(c1ccc(Cl)cc1)N(c1cc(Cl)c(=O)n(C)c1)C2=O
Agent: COc1ccc(C#N)cc1B(O)O
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: CCOC(=O)c1c2c(n(C(C)C)c1-c1cnc(OC)nc1OC)C(c1ccc(Cl)cc1)N(c1cc(Cl)c(=O)n(C)c1)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described for Example 17 but 2-bromo-5-(5-chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-b]pyrrole-3-carboxylic acid ethyl ester (Intermediate BM) and 2,4-dimethoxypyrimidine-5-boronic acid were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 5-cyano-2-methoxyphenylboronic acid respectively. The title compound was obtained as a white solid. tR=1.10 min (HPLC 3); ESI-MS: tR=1.05 min, [M+H]+ 626/628 (LC-MS 1); TLC: Rf=0.05 (EtOAc).
Reaction SMILES: [CH:1]1[N:5]=[CH:4][N:3]([CH2:6][C:7]([P:13]([OH:16])([OH:15])=[O:14])([P:9]([OH:12])([OH:11])=[O:10])[OH:8])[CH:2]=1.[OH-:17].[Na+:18].[Na].CC([OH:23])C>O>[CH:1]1[N:5]=[CH:4][N:3]([CH2:6][C:7]([P:9]([O-:12])([OH:11])=[O:10])([P:13]([O-:15])([OH:16])=[O:14])[OH:8])[CH:2]=1.[OH2:23].[OH2:17].[OH2:8].[OH2:8].[Na+:18].[Na+:18]
Reactant: O=P(O)(O)C(O)(Cn1ccnc1)P(=O)(O)O
Reactant: [OH-]
Reactant: CC(C)O
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: O=P([O-])(O)C(O)(Cn1ccnc1)P(=O)([O-])O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A 0.5 liter reactor equipped with a mechanical stirrer, a thermometer and a reflux condenser was loaded with Zoledronic acid form I (10.0 g) and water (260 ml). The suspension was heated to 80° C. to obtain a clear solution. Sodium hydroxide (pearls, 2.84 g) was added. A pH test of the sodium salt showed pH=7.35. The solution was cooled to 60° C. and IPA (10.5 ml) was added. The reaction mixture was cooled to room temperature during 2 hours and was stirred at this temperature for about 16 hours. After cooling to 5° C. and stirring at this temperature for 2 hours, the solution was evaporated to dryness to obtain a white solid. The obtained solid was reslurried in water (50 ml) and cooled to 4° C. The product was then isolated by filtration and dried in a vacuum oven at 50° C. for 24 hours to obtain 3.2 g of Zoledronate disodium crystal form VII (24%) (pH=7.27). Purity by HPLC 100.0%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14](C(OC(C)(C)C)=O)[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[N:24])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:16]=[CH:17][C:18]([O:21][CH2:22][C:23]#[N:24])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(N(C(=O)OC(C)(C)C)c2ccc(OCC#N)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CCOc1ccc(NC2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.8 %

Procedure:
To a stirred solution of 4-[tert-butoxycarbonyl-(5-cyanomethoxy-pyridin-2-yl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (0.90 g, 2.1 mmol, 1.0 equiv) in dichloromethane (15 mL) was added 90% trifluoroacetic acid (1.69 mL, 2.37 g, 19 mmol, 9.0 equiv) drop by drop and the reaction mixture stirred at rt for 16 h. It was then poured into ice water and the pH adjusted to 9-10 by addition of a sat. solution of potassium carbonate. The solution was extracted three times with a mixture of dichloromethane/isopropanol (4:1). The combined organic layers were concentrated by evaporation under reduced pressure to give 0.15 g (30%) of the title compound as yellow oil. MS (ISP): 233.0 [M+H]+.
Reaction SMILES: [Cl:1]Cl.[N+]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=1)([O-])=O>>[Cl:1][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(OC(F)(F)F)cc1
Reactant: ClCl
Product: FC(F)(F)Oc1ccc(Cl)cc1
Yield: 83 %

Procedure:
Chlorine and p-nitrotrifluoromethoxybenzene (10.7 parts) were fed simultaneously at a molar ratio of 3:1, Cl2 :organic reactant, into a vapor phase reactor maintained at 300° to 320° C. over a 30 minute period to yield 8.2 parts of p-chlorotrifluoromethoxybenzene (83% yield). The structure of the product was confirmed by gas chromatographic-mass spectrum and F19 nuclear magnetic resonance analysis.
Reaction SMILES: C(Br)C.FC1C=CC=CC=1C1C2C=C([N+]([O-])=O)C=CC=2N(C)C(=O)C(C)(C)N=1.[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]1[C:42]2[CH:43]=[C:44]([N+:47]([O-:49])=[O:48])[CH:45]=[CH:46][C:41]=2[N:40](CC)[C:39](=[O:52])[C:38]([CH3:54])([CH3:53])[N:37]=1>CCOCC>[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]1[C:42]2[CH:43]=[C:44]([N+:47]([O-:49])=[O:48])[CH:45]=[CH:46][C:41]=2[NH:40][C:39](=[O:52])[C:38]([CH3:54])([CH3:53])[N:37]=1
Reactant: CCN1C(=O)C(C)(C)N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc21
Agent: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc21
Solvent: CCOCC
Solvent: CCBr
Product: CC1(C)N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2NC1=O

Procedure:
From 1.7 g (0.005 mol) of 5-(o-chlorophenyl)-1,3-dihydro-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one and ethyl bromide there is obtained, in analogy to the details in paragraph (c) of Example 1, with a reaction period of 36 hours, 5-(o-chlorophenyl)-1-ethyl-1,3-dihydro-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one of melting point 174° (ether).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(N(CC)CC)C.I[C:28]1[C:29](=[O:43])[NH:30][C:31](=[O:42])[N:32]([CH:41]=1)[C@@H:33]1[O:40][C@H:37]([CH2:38][OH:39])[C@@H:35]([OH:36])[CH2:34]1.[CH3:44][O:45][C:46](=[O:49])[CH:47]=[CH2:48]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:46](/[CH:47]=[CH:48]/[C:28]1[C:29](=[O:43])[NH:30][C:31](=[O:42])[N:32]([CH:41]=1)[C@@H:33]1[O:40][C@H:37]([CH2:38][OH:39])[C@@H:35]([OH:36])[CH2:34]1)([O:45][CH3:44])=[O:49]
Reactant: C=CC(=O)OC
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)/C=C/c1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Temperature: 70 °C
Yield: 70.3 %

Procedure:
A mixture of Pd(OAc)2 (0.316 g, 1.41 mmol), PPh3 (0.741 g, 2.82 mmol), and triethylamine (4.9 mL) in 1,4-dioxane (50 mL) was stirred at 70° C. until an intense red colour had developed. To this 5-iodo-2′-deoxyuridine (10 g, 28.24 mmol) and methylacrilate (4.862 g, 56.48 mmol, 5.1 mL) in 1,4-dioxane (20 mL) were added and the mixture stiffed at refluxed for 30 mins. The reaction was filtered while still hot and the 20 filtrate cooled over night at 4° C. The resulting pale yellow precipitate was filtered, washed with DCM and dried in vacuo to give the product as white solid (6.2 g, yield 70.7%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5](N)=[C:4]([C:9]2[CH2:13][CH2:12][O:11][N:10]=2)[C:3]=1[CH3:14].[ClH:15].N([O-])=O.[Na+].[S:20](=[O:22])=[O:21]>C(O)(=O)C.O.[Cu](Cl)Cl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([S:20]([Cl:15])(=[O:22])=[O:21])=[C:4]([C:9]2[CH2:13][CH2:12][O:11][N:10]=2)[C:3]=1[CH3:14]
Reactant: Cl
Reactant: Cc1c(Br)ccc(N)c1C1=NOCC1
Reactant: O=S=O
Agent: Cl[Cu]Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(Br)ccc(S(=O)(=O)Cl)c1C1=NOCC1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
At 15° C., a solution of 9 g (35 mmol) of 4-bromo-2-(4,5-dihydro-isoxazol-3-yl)-3-methylaniline in 50 ml of glacial acetic acid is added to 15 ml of conc. hydrochloric acid. At 5-10° C., a solution of 2.44 g (35 mmol) of sodium nitrite in 10 ml of water is then added dropwise, and the mixture is stirred at 5° C. for 1 hour. This solution is then added dropwise at room temperature to a mixture of a solution of 47 g (0.74 mol) of sulfur dioxide in 100 ml of glacial acetic acid and a solution of 2.23 g (13 mmol) of copper(II) chloride in 5 ml of water. The mixture is stirred at room temperature for 1 hour and then poured onto 300 ml of ice-water and extracted with methylene chloride. The organic phase is washed with water, dried with magnesium sulfate and concentrated.
Reaction SMILES: N#N.[F:3][C:4]([F:18])([CH3:17])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[O:10][CH:11]=[C:12]([C:14](Cl)=[O:15])[N:13]=1.[N-:19]=[N+:20]=[N-:21].[Na+]>CC(C)=O.O>[F:3][C:4]([F:18])([CH3:17])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[O:10][CH:11]=[C:12]([C:14]([N:19]=[N+:20]=[N-:21])=[O:15])[N:13]=1
Reactant: CC(F)(F)CCCCc1nc(C(=O)Cl)co1
Reactant: [N-]=[N+]=[N-]
Agent: N#N
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(F)(F)CCCCc1nc(C(=O)N=[N+]=[N-])co1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of this crude 2-(5,5-difluoro-hexyl)-oxazole-4-carbonyl chloride was dissolved in dry acetone (12.0 mL). The solution was cooled to 0° C. and a solution of sodium azide (196 mg, 2.98 mmol) in H2O (1.4 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 45 min. The mixture was concentrated under reduced pressure, and the residue was dissolved in CH2Cl2 and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a brown solid. LC-MS-conditions 02: tR=0.98 min, [M+H]+=259.09.
Reaction SMILES: [C:1](=[O:21])([O:7][C:8]1[C:12]2[CH:13]=[C:14]([CH:19]=O)[C:15](F)=[C:16]([F:17])[C:11]=2[O:10][N:9]=1)[O:2][C:3]([CH3:6])([CH3:5])[CH3:4].[NH:22]1[C:29](=[O:30])[CH2:28][C:26](=[O:27])[NH:25][C:23]1=[O:24].[CH3:31][CH:32]([OH:34])[CH3:33]>>[C:1](=[O:21])([O:7][C:8]1[C:12]2[CH:13]=[C:14]3[C:15](=[C:16]([F:17])[C:11]=2[O:10][N:9]=1)[N:9]1[CH2:31][C@@H:32]([CH3:33])[O:34][C@@H:12]([CH3:11])[C@@H:8]1[C:28]1([C:26](=[O:27])[NH:25][C:23](=[O:24])[NH:22][C:29]1=[O:30])[CH2:19]3)[O:2][C:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)Oc1noc2c(F)c(F)c(C=O)cc12
Reactant: O=C1CC(=O)NC(=O)N1
Reactant: CC(C)O
Product: C[C@@H]1CN2c3c(cc4c(OC(=O)OC(C)(C)C)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Temperature: 80 °C

Procedure:
To a stirred solution of tert-butyl 6,7-difluoro-5-formyl-1,2-benzisoxazol-3-yl carbonate Intermediate 531 (175 mg, 0.44 mmol) in dry IPA (10 mL) was added barbituric acid (8 mg, 0.062 mmol), and the solution heated around 80° C. for 12 h. Solvents were evaporated and the residue was purified over a silica gel column to give product as a white solid. Yield: 40 mg (18%).