Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:26][C@H:25]([CH2:27][O:28]C(=O)C)[C@@H:20]([O:21]C(=O)C)[C@H:15]([O:16]C(=O)C)[C@H:10]2[O:11]C(=O)C)[OH:9])=[CH:4][C:3]=1[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39]C(=O)C)=[CH:35][CH:34]=1.[C-:43]#[N:44].[Na+].O>CN1CCCC1=O.[Ni](Br)Br>[C:43]([C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:26][C@H:25]([CH2:27][OH:28])[C@@H:20]([OH:21])[C@H:15]([OH:16])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:32][C:33]1[CH:34]=[CH:35][C:36]([OH:39])=[CH:37][CH:38]=1)#[N:44]
Reactant: [C-]#N
Reactant: CC(=O)OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(OC(C)=O)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Br[Ni]Br
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1ccc([C@@]2(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc(O)cc1
Temperature: 220 °C
Reaction time: 3 h

Procedure:
A mixture of 200 mg 1-chloro-2-(4-acetoxy-benzyl)-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-benzene, 35 mg sodium cyanide and 75 mg nickel bromide in 0.5 mL N-methyl-2-pyrrolidinone is heated in a microwave oven at 220° C. for 15 min. After cooling to room temperature, water is added and the resultant mixture is extracted with ethyl acetate. After drying over sodium sulfate and evaporation of the solvent, the residue is dissolved in 3 mL methanol. 3 mL of 4 M aqueous potassium hydroxide solution is added and the reaction solution is stirred at ambient temperature for 3 h. The solution is neutralized with 1 M hydrochloric acid and the methanol is evaporated. The residue is extracted with ethylacetate, the combined extracts are dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is purified by HPLC on reversed phase (YMC C18; water/acetonitrile 95:5->1:99).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[CH:12]=[O:13].P(O)(O)([O-])=[O:15].[Na+].Cl([O-])=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[C:12]([OH:15])=[O:13]
Reactant: O=P([O-])(O)O
Reactant: O=Cc1ccnc2c(Br)cccc12
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccnc2c(Br)cccc12
Temperature: 5 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
As shown in step 9-iv of Scheme 9, to a stirred suspension of 8-bromoquinoline-4-carbaldehyde (531.4 g, 2.25 mol) in THF (4.8 L) was added water (4.8 L) and monosodium phosphate (491.1 g, 4.05 mol). The mixture was cooled to 5° C. and, keeping the reaction temperature below 15° C., sodium chlorite (534.4 g, 4.727 mol) was slowly added portionwise as a solid over about 1 hour. After addition was complete the reaction mixture was stirred at 10° C. for 1 hour followed by the portionwise addition of 1N Na2S2O3 (1.18 L) whilst keeping the temperature below 20° C. The reaction mixture was stirred at RT followed by the removal of the THF under reduced pressure. The resulting aqueous solution containing a precipitate was treated with sat'd NaHCO3 (about 1 L) until a pH of 3 to 4 was achieved. This mixture was stirred an additional 15 minutes and the solid was collected by filtration, washed with water (2×1 L), washed with tert butyl methyl ether (2×500 mL), and dried in a convection oven at 60° C. for 48 hours. Additional drying under high vacuum provided 8-bromoquinoline-4-carboxylic acid (compound 2032, 530.7 g, 94% yield from compound 1030) as a yellowish tan solid: LC-MS=252.34 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 14.09 (s, 1H), 9.16 (d, J=4.4 Hz, 1H), 8.71 (dd, J=8.6, 1.2 Hz, 1H), 8.25 (dd, J=7.5, 1.2 Hz, 1H), 8.03 (d, J=4.4 Hz, 1H), 7.64 (dd, J=8.6, 7.5 Hz, 1H).
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])=[CH:7][C:8]=2[CH3:12])[N:3]=1.N([O-])=[O:21].[Na+]>FC(F)(F)C(O)=O>[CH3:12][C:8]1[CH:7]=[C:6]([C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])[N:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2](=[O:21])[NH:3]2
Reactant: Cc1cc(C(F)(F)C(F)(F)F)nc2nc(N)ccc12
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(F)(F)C(F)(F)F)nc2[nH]c(=O)ccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-Amino-5-methyl-7-pentafluoroethyl-1,8-naphthyridine (5.54 g., 20 mmole) is dissolved in trifluoroacetic acid (40 ml.) and to the stirred solution cooled to -5° to 0° C. is added finely powdered sodium nitrite (3.0 g., 43.5 mmole) in small portions. Stirring of the mixture is continued at room temperature for one hour, after which it is poured into ice-water (ca. 500 ml.). The product precipitates and is collected, washed and dried at 60° C. in air. It can be purified by recrystallization from diisopropyl ether.
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH2:3][C:4]#[CH:5].CCN(CC)CC.ClC(OCC)=O.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C(Cl)Cl>[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:1](=[O:7])[CH2:2][CH2:3][C:4]#[CH:5])[CH2:24][CH2:23]1
Reactant: C#CCCC(=O)O
Reactant: CN1CCNCC1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCCC(=O)N1CCN(C)CC1
Reaction time: 0.75 h

Procedure:
A solution of 4-pentynoic acid (519 mg, 5.29 mmol) and Et3N (737 μL, 5.29 mmol) in DCM (10 mL) was treated with ethyl chloroformate (504 μL, 5.29 mmol) at rt for 15 min. Then N-methyl-piperazine (588 μL, 5.29 mmol) was added, and stirring was prolonged for 45 min. Work-up (sat. aq. NaHCO3) and concentration gave the title compound as a colorless oil. 1H NMR (CDCl3) δ 3.63 (t, 2H), 3.48 (t, 2H), 2.55 (m, 4H), 2.38 (quint., 4H), 2.30 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C1(S([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20]([C:27]3[CH:32]=[CH:31][N:30]=[C:29](Cl)[N:28]=3)=[CH:19]2)(=O)=O)C=CC=CC=1>>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:29]1[N:28]=[C:27]([C:20]2[C:21]3[C:22](=[N:23][CH:24]=[CH:25][CH:26]=3)[NH:18][CH:19]=2)[CH:32]=[CH:31][N:30]=1
Reactant: Nc1ccccc1F
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Product: Fc1ccccc1Nc1nccc(-c2c[nH]c3ncccc23)n1
Yield: 54.7 %

Procedure:
Using the procedure of example 1, 2-fluoroaniline (90 mg) was reacted with compound 1f (100 mg) to provide compound 31 (45 mg, 55%). 1H NMR (400 MHz, CD3OD) δ 8.73 (d, J=8.0 Hz, 1H), 8.29 (d, J=5.2 Hz, 1H), 8.26 (m, 1H), 8.24 (s, 1H), 8.04 (t, J=8.0 Hz, 1H), 7.25 (d, J=5.6 Hz, 1H), 7.22-7.14 (m, 4H). MS (ESI) m/z: 306 (M+H)+.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[N:13]1[NH:14][N:15]=[C:16]([C:18]([OH:20])=O)[CH:17]=1.[NH2:21][CH2:22][CH2:23][C:24]([N:26]1[CH2:45][CH2:44][C:29]2[N:30]=[C:31]([NH:34][CH:35]3[CH2:43][C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH2:36]3)[N:32]=[CH:33][C:28]=2[CH2:27]1)=[O:25]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:43][CH:35]1[NH:34][C:31]1[N:32]=[CH:33][C:28]2[CH2:27][N:26]([C:24](=[O:25])[CH2:23][CH2:22][NH:21][C:18]([C:16]3[N:15]=[N:14][NH:13][CH:17]=3)=[O:20])[CH2:45][CH2:44][C:29]=2[N:30]=1
Reactant: O=C(O)c1cn[nH]n1
Reactant: NCCC(=O)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(NCCC(=O)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1)c1c[nH]nn1
Yield: 62.3 %

Procedure:
Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.111 g; 1.5 equiv; 0.58 mmoles) to a solution of 2H-triazole-4-carboxylic acid (0.048 g; 1.1 equiv; 0.42 mmoles), 3-amino-1-[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]propan-1-one (0.13 g; 1.0 equiv; 0.39 mmoles), and N,N-dimethyl-4-pyridinamine, (0.0094 g; 0.2 equiv; 0.077 mmoles) in dichloromethane (1.28 mL). Stir the reaction at ambient temperature for 16 hours. Load the mixture directly onto a silica gel column and purify by column chromatography (0 to 10% methanol in ethyl acetate) to afford N-{3-[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]-3-oxopropyl}-1H-1,2,3-triazole-4-carboxamide (0.105 g; 63%) as a white solid: MS (m/z): 433(M+1).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[C:16]1([NH:22][C:23]([NH2:25])=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[O:24]=[C:23]1[N:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:4](=[O:6])[C:3]2[C:2](=[CH:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=2)[NH:25]1
Reactant: COC(=O)c1ccc(C(=O)OC)c(Br)c1
Reactant: NC(=O)Nc1ccccc1
Product: COC(=O)c1ccc2c(=O)n(-c3ccccc3)c(=O)[nH]c2c1

Procedure:
The title compound was prepared from dimethyl 2-bromoterephthalate (1.50 g, 5.5 mmol) and phenylurea (0.97 g, 7.1 mmol) following the procedure outlined in Example 14, step 1 (1.3 g, 79%). LC-MS: (FA) ES+ 297.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][C:16](=O)[CH2:15]2)[CH2:9][CH2:8]1.[C:21]1([Li])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[C:21]1([C:16]2[CH2:15][CH:14]([CH2:13][N:10]3[CH2:11][CH2:12][N:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:8][CH2:9]3)[CH2:19][CH2:18][CH:17]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: [Li]c1ccccc1
Reactant: O=C1CCCC(CN2CCN(c3ccccn3)CC2)C1
Solvent: C1CCOC1
Product: C1=C(c2ccccc2)CC(CN2CCN(c3ccccn3)CC2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 5.14 g of 3-[[4-(2-pyridinyl)piperazinyl]methyl]cyclohexanone (Example B) in 250 mL of tetrahydrofuran at 0° C. under nitrogen is added dropwise a solution of phenyllithium (23.5 mL, 2.0M in cyclohexane/diethyl ether, 70/30). The solution is stirred at 0° C. for 1 hour, quenched with dropwise addition of 250 mL of saturated potassium phosphate monobasic solution. The solvent is evaporated in vacuo, the residue is basified with concentrated ammonium hydroxide to a pH of 9 and extracted into chloroform. The chloroform extract is dried over magnesium sulfate and filtered. A solution of the filtrate in 250 mL of chloroform containing 14.5 mL of trifluoroacetic acid is stirred at room temperature under nitrogen for 12 hours. The solvent is evaporated in vacuo, the residue is dissolved into ethyl acetate (250 mL) and washed with 1N sodium hydroxide solution and brine (250 mL of each). The ethyl acetate extract is dried over magnesium sulfate, filtered, and concentrated. The crude product is purified by medium pressure chromatography (silica gel, 90% hexanes - 10% ethyl acetate) to give (±)-1-[(3-phenyl-3-cyclohexen-1-yl)methyl]-4-(2-pyridinyl)piperazine (Example 4) as an off-white solid; mp 96°-98° C. and (±)-1-[(3-phenyl-2-cyclohexen-1-yl)methyl]-4-(2-pyridinyl)piperazine (Example 4a) as an off-white solid; mp 78°-82° C.
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[Br:9]Br>C(Cl)(Cl)Cl.Br.CC(O)=O>[Br:9][CH2:2][C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)=[O:3]
Reactant: CC(=O)c1cccs1
Reactant: BrBr
Agent: Br
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: O=C(CBr)c1cccs1
Reaction time: 1 h
Yield: 36.9 %

Procedure:
To a solution of 500 mg (3.96 mmol) of 2-acetyl thiophene (Aldrich Chemical Co.) dissolved in 20 mL of CHCl3, was added 1 drop of 30% HBr/CH3COOH (Aldrich Chemical Co.) followed by 3.96 mmol (633 mg; 204 μL) of bromine (Aldrich Chemical Co.) added dropwise over 30 min. The reaction was allowed to stir for 1 h. The solution was concentrated to an oil and dried in vacuo. The crude product was purified on 1 mm silica prep plates eluting with neat CH2Cl2 to obtain 300 mg (37% yield) of 2-bromo-1-(2-thienyl)ethan-1-one. 1H-NMR (CDCl3; 300 MHz) δ 7.8 (m, 2H), 7.18 (m, 1H), 4.37 (s, 2H).
Reaction SMILES: F[C:2](F)(F)[C:3]([NH:5][C:6]1[CH:10]([CH3:11])[CH2:9][N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=1)=[O:4].C(OC(=O)C)(=O)C.O>CN(C)C1C=CN=CC=1.ClCCl>[CH3:11][CH:10]1[CH2:9][N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=[C:6]1[NH:5][C:3](=[O:4])[CH3:2]
Reactant: CC1CN(c2ccccc2)N=C1NC(=O)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: O
Product: CC(=O)NC1=NN(c2ccccc2)CC1C
Reaction time: 18 h

Procedure:
A 10.0 g. amount of 3-amino-4-methyl-1-phenyl-2-pyrazoline (prepared as described in Example 6) is dissolved in 50 ml. of acetic anhydride, then 500 mg. of 4-dimethylaminopyridine is added and the reaction mixture is allowed to stand at room temperature for 18 hours. The mixture is poured into water to separate a gum which solidifies and is collected by filtration. The solid is added with stirring to 150 ml. of methanol containing 10.0 g. of sodium hydroxide. After 30 minutes, the solvent is removed in vacuo and water is added to provide a gum which becomes solid. This solid is dissolved in dichloromethane, dried over anhydrous magnesium sulfate and passed through a short column of a hydrous magnesium silicate. The effluent is concentrated while adding hexane to yield crystals. The material is collected and dried to give 3.3 g. of the desired product as a white solid, m.p. 149°-150° C.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:34]([N:36](CC)CC)C.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.Cl.CN>C(OCC)(=O)C.CN(C)C=O>[CH:1]1([N:7]2[CH2:13][C:12]([F:14])([F:15])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:36][CH3:34])=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reactant: CCN(CC)CC
Agent: CN
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCCCC2)CC(F)(F)C(=O)N3C)c(OC)c1
Reaction time: 0.25 h
Yield: 44.1 %

Procedure:
A mixture of 0.100 g (0.22 mmole) of 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-246), 0.089 g (0.88 mmole) of triethylamine, 0.125 g (0.33 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate and 5 mL of dimethylformamide was stirred for 15 minutes and then 0.023 g (0.35 mmole) of methylamine hydrochloride was added. The mixture was stirred for 3 hours, then taken up in 100 mL of ethyl acetate and washed twice with 100 mL of water and then 100 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol-ammonium hydroxide (gradient 100:0:0-92:8:0.3) to give 0.046 g of 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-methyl-benzamide (I-249).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1)=[O:4].[CH3:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>>[CH3:24][C:25]1[CH:26]=[C:27]([NH:31][C:32](=[O:33])[NH:1][CH2:2][C:3]([N:5]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=2)=[O:4])[CH:28]=[CH:29][CH:30]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: CC(C)(C)OC(=O)CN(C(=O)CN)c1cccc(C(F)(F)F)c1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OC(C)(C)C)c2cccc(C(F)(F)F)c2)c1
Yield: 22.7 %

Procedure:
Using a procedure similar to that described in Example 1, but starting with tert-butyl 2-[2-amino-N-(3-trifluoromethylphenyl)acetamido]acetate (4.9 g) and 3-methylphenyl isocyanate (2 g), and after recrystallisation in diisopropyl ether, tert-butyl 2-{2-[3-(3-methylphenyl)ureido]-N-(3-trifluoromethylphenyl)acetamido}acetate (1.56 g), m.p. 140° C., is obtained.
Reaction SMILES: CN(C=O)C.[CH:6]1([C:9]([NH:11][C:12]2[N:29]=[C:15]3[CH:16]=[CH:17][CH:18]=[C:19]([C:20]4[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=4)[N:14]3[N:13]=2)=[O:10])[CH2:8][CH2:7]1.C(Cl)(=O)C([Cl:33])=O>C(Cl)Cl>[CH:6]1([C:9]([NH:11][C:12]2[N:29]=[C:15]3[CH:16]=[CH:17][CH:18]=[C:19]([C:20]4[CH:28]=[CH:27][C:23]([C:24]([Cl:33])=[O:25])=[CH:22][CH:21]=4)[N:14]3[N:13]=2)=[O:10])[CH2:8][CH2:7]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(-c2cccc3nc(NC(=O)C4CC4)nn23)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(-c2cccc3nc(NC(=O)C4CC4)nn23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2 Drops of DMF were added to a solution of 4-[2-(cyclopropanecarbonyl-amino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl]-benzoic acid (1 eq) obtained by Method A in DCM under N2 atmosphere. Then oxalyl chloride (2 eq) was added dropwise to this resulting solution (gas release). The mixture was stirred at room temperature for 2 hours. After completion of the reaction by LCMS, the solvent was removed. The crude acid chloride was used without further purification in next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-])=O)=[C:6]([CH:15]=1)[C:7]([NH:9][CH:10]([CH:12]1[CH2:14][CH2:13]1)[CH3:11])=[O:8].Cl.O>C(O)C>[NH2:16][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:15][C:6]=1[C:7]([NH:9][CH:10]([CH:12]1[CH2:14][CH2:13]1)[CH3:11])=[O:8]
Reactant: CC(NC(=O)c1cc(Cl)ccc1[N+](=O)[O-])C1CC1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(NC(=O)c1cc(Cl)ccc1N)C1CC1
Reaction time: 0.5 h
Yield: 67.9 %

Procedure:
5.8 g of 5-chloro-N-(1-cyclopropylethyl)-2-nitrobenzamide was dissolved in 88 ml of ethanol, and 12.6 ml of concentrated hydrochloric acid was dropwise added under cooling with ice. After stirring at the same temperature for 0.5 hour, 4.0 g of reduced iron was added dividedly in several addition. After stirring at room temperature for 3 hours, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate, and ethyl acetate was distilled off under reduced pressure. Hexane/ethyl acetate were added to the residue, followed by stirring, and the mixture was subjected to filtration to obtain 3.5 g of the pale yellow desired product (melting point: 135° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:26]([C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1)#[N:27]>>[C:26]([C:28]1[CH:29]=[CH:30][C:31]([S:34]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:16]=[C:15]4[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]4=[O:17])=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)(=[O:36])=[O:35])=[CH:32][CH:33]=1)#[N:27]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NS(=O)(=O)c4ccc(C#N)cc4)cc3)cc2C1=O

Procedure:
The compound of example 79 was prepared analogous to compound of example 77 by reaction of compound of example 6 with 4-cyanobenzene sulfonyl chloride. The compound of example 79 was used directly without isolation for the preparation of compound of example 80.
Reaction SMILES: P([O-])([O-])([O-])=O.[Ca+2].P([O-])([O-])([O-])=O.[Ca+2].[Ca+2].[CH2:14]([CH2:26][NH2:27])[CH2:15][C:16]([P:22]([O-:25])([OH:24])=[O:23])([P:18]([OH:21])([OH:20])=[O:19])[OH:17].[Na+]>O>[CH2:14]([CH2:26][NH2:27])[CH2:15][C:16]([P:18]([OH:20])([OH:21])=[O:19])([P:22]([OH:25])([OH:24])=[O:23])[OH:17]
Reactant: NCCCC(O)(P(=O)([O-])O)P(=O)(O)O
Agent: O=P([O-])([O-])[O-]
Agent: [Ca+2]
Agent: [Na+]
Solvent: O
Product: NCCCC(O)(P(=O)(O)O)P(=O)(O)O
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A suspension of calcium phosphate was prepared by introducing 100 mg of CDA into 8.75 ml of ultrapure water mixed with 1.25 ml of a 0.02 mol.l−1 sodium alendronate aqueous solution. The suspension was placed in a tube maintained at room temperature, and was stirred with a rotary stirrer at 16 rpm for 5 days. The suspension was then centrifuged and the most part of the supernatant was removed. The solid residue was filtered off, washed several times with small portions of ultrapure water, and then dried at room temperature. The resulting solid contained 7.4 wt % alendronate.
Reaction SMILES: [Cl-].[NH4+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:5]=1[C@:13]12[CH2:22][C@@H:21]([O:23][CH3:24])[CH2:20][CH2:19][C@H:18]1[CH2:17][S:16][C:15]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[N:14]2>[Fe].C(O)C>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([F:3])=[C:5]([C@:13]23[CH2:22][C@@H:21]([O:23][CH3:24])[CH2:20][CH2:19][C@H:18]2[CH2:17][S:16][C:15]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[N:14]3)[CH:6]=1
Reactant: CO[C@H]1CC[C@H]2CSC(NC(=O)OC(C)(C)C)=N[C@@]2(c2cc([N+](=O)[O-])ccc2F)C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CO[C@H]1CC[C@H]2CSC(NC(=O)OC(C)(C)C)=N[C@@]2(c2cc(N)ccc2F)C1
Temperature: 25 °C

Procedure:
Ethanol (5 mL), a saturated ammonium chloride solution (0.5 mL) and iron powder (175 mg) were added to tert-butyl(±)-[(4aR*,7S*,8aS*)-8a-(2-fluoro-5-nitrophenyl)-7-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate obtained in Preparation Example 57-(9) (138 mg), and the mixture was stirred with heating under reflux for 30 minutes. The reaction solution was cooled to room temperature, and then the solid was removed by filtration through celite. The filtrate was concentrated under reduced pressure. Then, the residue was suspended in dichloromethane, and the solid was removed by filtration. The filtrate was concentrated under reduced pressure and then purified by silica gel column chromatography to obtain the title compound (98 mg).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([C:20](=[NH:23])[NH:21]O)=[C:18]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][C:26]=3[F:35])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]>CC([O-])=O.[Zn]>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([C:20](=[NH:21])[NH2:23])=[C:18]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][C:26]=3[F:35])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3F)c2C(=N)NO)CC1
Agent: CC(=O)[O-]
Agent: [Zn]
Product: CC(C)OC(=O)N1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3F)c2C(=N)N)CC1
Temperature: 70 °C

Procedure:
4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-5-(N-hydroxycarbamimidoyl)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (0.510 g, 0816 mmol) was dissolved in acetic acid glacial (20 mL) and zinc dust (1 g, 16.32 mmol) was added. The reaction mixture was heated at 70° C. for 40 min. The crude was filtered, the filtrate was concentrated under reduced pressure and the residue was purified by HPLC to afford Compound A100 (43 mg, 8.65%). Exact mass calculated for C21H27FN6O5S 494.17, found 495.5 (MH+).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[NH:3]1.I[CH:30]([CH3:32])[CH3:31].C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>C(OCC)(=O)C>[CH3:31][CH:30]([N:3]1[C:2](=[O:1])[C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]12)[CH3:32]
Reactant: CC(C)I
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C(C)C)c2ncnn12
Temperature: 100 °C
Reaction time: 16 h
Yield: 53 %

Procedure:
A mixture of 4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.8 g), 2-iodopropane (0.43 mL), potassium carbonate (0.6 g) and N,N-dimethylacetamide (10 mL) was stirred at 100° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.48 g, 53%).