Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[CH:11]=[C:12]([C:16](=[O:18])[CH:17]=2)[C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28].O>C(OCC)(=O)C>[C:27]([O:25][C:22]1[CH:21]=[CH:20][C:19]([N:10]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([N:2]([CH3:26])[CH3:1])=[CH:4][CH:5]=3)=[CH:17][C:16](=[O:18])[C:12]([C:13]([OH:15])=[O:14])=[CH:11]2)=[CH:24][CH:23]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)c1ccc(-c2cc(=O)c(C(=O)O)cn2-c2ccc(O)cc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)Oc1ccc(-n2cc(C(=O)O)c(=O)cc2-c2ccc(N(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
With 1 g of 6-(4-dimethylaminophenyl)-1-(4-hydroxyphenyl)-4-oxo-1,4-dihydronicotinic acid was mixed 10 ml of acetic anhydride and the resulting mixture was subjected to reaction at 130° C. for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and introduced into 150 ml of water. After stirring the mixture for 1 hour, 150 ml of ethyl acetate was added to the mixture, and the organic layer was separated, washed with 100 ml of water and then with 50 ml of a saturated aqueous solution of sodium chloride, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the residue was added 20 ml of diethyl ether, and the resulting mixture was filtered to obtain 0.75 g of 1-(4-acetyloxyphenyl)-6-(4-dimethylaminophenyl)-4-oxo-1,4-dihydronicotinic acid having a melting point of 128°-131° C.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][N:7]([CH:11]1[CH2:17][CH2:16][CH2:15][NH:14][C:13]2[CH:18]=[CH:19][C:20]([C:22]([F:25])([F:24])[F:23])=[CH:21][C:12]1=2)[C:8](=[O:10])[CH3:9].[Br:35]Br>CC(O)=O>[F:30][C:29]([F:31])([F:32])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:28]=1)[CH2:6][N:7]([CH:11]1[CH2:17][CH2:16][CH2:15][NH:14][C:13]2[C:18]([Br:35])=[CH:19][C:20]([C:22]([F:23])([F:24])[F:25])=[CH:21][C:12]1=2)[C:8](=[O:10])[CH3:9]
Reactant: BrBr
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCNc2ccc(C(F)(F)F)cc21
Solvent: CC(=O)O
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCNc2c(Br)cc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
To a solution of crude N-(3,5-Bis-trifluoromethyl-benzyl)-N-(7-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-acetamide (0.0980 mg, 0.197 mmol) in HOAc (2.00 ml), was added bromine (0.0106 ml, 0.207 mmol) dropwise. The reaction mixture was stirred at room temperature overnight. Remove the solvent on a rotary evaporator. Purification by silica gel chromatography (eluent, 0-40% ethyl acetate in hexane) provided the titled compound (0.0850 mg, 75%). MS (ES+): 577, 579 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13](S)=[N:12][CH:11]=2)=[CH:4][CH:3]=1.BrCC1C=CC(OC(F)(F)F)=CC=1B(O)O.CCN(C(C)C)C(C)C.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[N:12][CH:11]=2)=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(F)cc1)c1ccc(S)nc1
Agent: OB(O)c1cc(OC(F)(F)F)ccc1CBr
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(F)cc1)c1cccnc1
Reaction time: 0.5 h
Yield: 88 %

Procedure:
As described in Method B, N-(4-fluoro-phenyl)-6-mercapto-nicotinamide IIa (372 mg, 1.5 mmol) and 2-bromomethyl-5-trifluoromethoxy-phenylboronic acid (572 mg, 1.5 mmol) were suspended in DMF (15 ml). To the reaction flask DIPEA (261 μL, 1.5 mmol) was added and the reaction was stirred for 30 minutes. Reaction completion was monitored by LC-MS. Cold water (100 mL) was added and the precipitate was collected by filtration and washed several times with cold water to afford 724.8 mg (88% yield, >90% purity by LC-MS) of the off-white solid product, 6-(2-boronic pinacol ester-5-trifluoromethoxy-benzylsulfanyl)-N-(4-fluoro-phenyl)-nicotinamide. ESI-MS m/z=549.1 [M+H+].
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([NH2:12])[CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=1.C(N(CC)CC)C.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C1COCC1>[N:20]1([CH2:2][C:3]2[CH:4]=[C:5]([NH2:12])[CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: Nc1cc(CBr)cc([N+](=O)[O-])c1
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1cc(CN2CCOCC2)cc([N+](=O)[O-])c1

Procedure:
A solution of 3-bromomethyl-5-nitrophenylamine (398 mg, 1.72 mmol), triethylamine (0.3 mL) and morpholine (0.2 mL) in 15 mL of THF was heated at 60° C. for 30 minutes. The solvent was evaporated in vacuo. The residue was mixed with water (20 mL) and extracted with ether. Organic layer was separated, dried over MgSO4 and concentrated in vacuo to afford a yellow solid (411 mg), which was purified by column chromatography. The title compound was isolated as yellow crystals in an amount of 302 mg (1.274 mmol, 74%); MS (m/z, ES+): 238 (M+1, 100%).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][C@H:4]1[OH:16].[NH2:17][C:18]1[C:23]2[CH2:24][CH2:25][O:26][C:22]=2[C:21]([C:27](N2C=CN=C2)=[O:28])=[CH:20][C:19]=1[Cl:34]>C(#N)C>[NH2:17][C:18]1[C:23]2[CH2:24][CH2:25][O:26][C:22]=2[C:21]([C:27]([NH:1][CH2:2][C@H:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:5][C@H:4]2[OH:16])=[O:28])=[CH:20][C:19]=1[Cl:34]
Reactant: Nc1c(Cl)cc(C(=O)n2ccnc2)c2c1CCO2
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN)[C@H](O)C1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC[C@H](CNC(=O)c2cc(Cl)c(N)c3c2OCC3)[C@H](O)C1
Temperature: 0 °C
Yield: 77.5 %

Procedure:
A mixture of intermediate (1-f) (0.09 mol) and intermediate (3-c) (0.087 mol) in ACN (600 ml) was stirred and refluxed for 1 hour. The reaction mixture was cooled to 0° C., and the solvent was evaporated. The residue was partitioned between DCM and water. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/(CH3OH/NH3) 97/3). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from ACN. The precipitate was filtered off and dried), yielding 28.7 g (78%) of (±)-1,1-dimethylethyl cis-4-[[[(4-amino-5-chloro-2,3-dihydro-7-benzofuranyl)carbonyl]amino]methyl]-3-hydroxy-1-piperidinecarboxylate (interm. 4. mp. 218° C.).
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2[N:17]([CH2:18][C:19]([OH:21])=O)[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)[CH:6]=[CH:7][CH:8]=1.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C(N(CC)CC)C>CN(C)C=O>[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2[N:17]([CH2:18][C:19]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[O:21])[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21
Reactant: Nc1ccccn1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Cn1c(-c2cccc(Cl)c2)nc2cccnc21)Nc1ccccn1
Temperature: 0 °C
Yield: 15.8 %

Procedure:
Under a nitrogen atmosphere, oxayl chloride (2.38 g, 0.019 mole) was added slowly dropwise to a stirred and chilled (15°-20° C.) solution of 2-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.70 g, 0.016 mole) in 50 ml of dimethylformamide. The reaction mixture was stirred at ambient temperature for 1/2 hr., then warmed to 60°-65° C. for 5 hrs. This acylchloride solution was added dropwise under nitrogen to a stirred and chilled (15°-20° C.) solution of 2-aminopyridine (1.76 g, 0.019 mole), triethylamine (1.89 g, 0.019 mole), and 30 ml of dimethylformamide. The reaction mixture was stirred at room temperature over the weekend. The reaction mixture was poured into 400 ml of ice water and extracted with ehtyl acetate (3×). The ethyl acetate layers were washed with 5% potassium hydroxide (2×50 ml), water (2×50 ml), dried, and filtered. The residue was treated with isopropyl alcohol and excess ethereal hydrogen chloride to give solid which was recrystallized twice from isopropyl alcohol-isopropyl ether and once from isopropyl alcohol. The solid was collected by filtration, washed with cold isopropyl alcohol, then isopropyl alcohol-water, and dried under high vacuum for 2 days to give 0.92 g (15.8%) of title compound, mp 165°-66° C.
Reaction SMILES: [C:1]1([CH:7]2[NH:13][CH2:12][CH2:11][NH:10][C:9](=[O:14])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([CH3:32])[CH:31]=1)[C:26](Cl)=[O:27]>ClCCl>[CH3:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([CH3:32])[CH:31]=1)[C:26]([N:13]1[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][C:9](=[O:14])[NH:10][CH2:11][CH2:12]1)=[O:27]
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Reactant: O=C1CC(c2ccccc2)NCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)cc(C(=O)N2CCNC(=O)CC2c2ccccc2)c1
Yield: 98.5 %

Procedure:
3.0 g hexahydro-7-phenyl-1,4-diazepin-5-one (for preparation see Example 1C)) in 40 ml dichloromethane were reacted with 4.0 g triethylamine and 2.9 g 3,5-dimethylbenzoyl chloride according to the method given above in Example 1F). 5.01 g amorphous 1-(3,5-dimethylbenzoyl)-hexahydro-7-phenyl-1,4-diazepin-5-one were obtained, which was reacted without further purification.
Reaction SMILES: [C:1]1([CH:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COC1C=CC(C(C)C([NH2:26])=O)=CC=1>>[C:1]1([CH:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:8]([NH2:26])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(C(C)C(N)=O)cc1
Reactant: CC(C)CC(C(=O)O)c1ccccc1
Product: CC(C)CC(C(N)=O)c1ccccc1
Yield: 94 %

Procedure:
The titled compound was prepared from 2-phenyl-4-methylpentanoic acid in 94% yield in the same manner as the preparation of 2-(4-Methoxyphenyl)propionamide in Example 188b. MS (ESI) 192 (MH+)
Reaction SMILES: N12CCCN=C1CCCCC2.C(O[C:15](=[O:31])[CH:16]([C:22]1[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][C:23]=1[F:30])[C:17]([O:19]CC)=O)C.Cl.[N:33]1[CH:38]=[CH:37][N:36]=[CH:35][C:34]=1[C:39]([NH2:41])=[NH:40].Cl>CN1CCCC1=O.O>[N:33]1[CH:38]=[CH:37][N:36]=[CH:35][C:34]=1[C:39]1[N:41]=[C:15]([OH:31])[C:16]([C:22]2[C:23]([F:30])=[CH:24][C:25]([F:29])=[CH:26][C:27]=2[F:28])=[C:17]([OH:19])[N:40]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1c(F)cc(F)cc1F
Reactant: N=C(N)c1cnccn1
Agent: Cl
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN1CCCC1=O
Product: Oc1nc(-c2cnccn2)nc(O)c1-c1c(F)cc(F)cc1F
Temperature: 95 °C
Reaction time: 7 h
Yield: 76 %

Procedure:
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU; 14.4 g, 0.0944 mol) is added to a mixture of 2-(2,4,6-triflorophenyl)malonic acid diethyl ester (14.3 g, 0.0472 mol) and pyrazine-2-carboxamidine hydrochloride (9.00 g, 0.0566 mol) in 1-methyl-2-pyrrolidinone (NMP; 50 mL) solvent. The resulting mixture is heated to 95° C. while stirring for 7 hours. The mixture is cooled to about 50° C. and then HCl solution (37%, 5.6 mL) is added dropwise, keeping the temperature below 50° C. The mixture is then allowed to cool to about 20° C. Water (50 mL) is added dropwise over 20 minutes, causing the product to precipitate as a solid from the mixture (20–25° C.). The solid is collected by filtration, and the product cake is washed with water (300 mL). The solid is allowed to dry at 23° C. under atmospheric pressure for 24 hours, giving a yellow solid (11.5 g, 97% HPLC area, 76% yield. 1H NMR (DMSO-d6): d 12.45 (bs, 2H), 9.41 (s,1H), 8.91(s,1H), 8.46(m, 1H), 7.23(m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]2[C:20](=[O:32])[N:21]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=[CH:23][CH:24]=2)=[O:18])=[C:11]([F:33])[CH:10]=1.CC1(C)C(C)(C)OB([C:42]2[CH:43]=[N:44][N:45]([CH2:47][C:48]#[N:49])[CH:46]=2)O1.C(=O)([O-])[O-].[K+].[K+].C([O-])(O)=O.[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:48]([CH2:47][N:45]1[CH:46]=[C:42]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3[C:20](=[O:32])[N:21]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[CH:22]=[CH:23][CH:24]=3)=[O:18])=[C:11]([F:33])[CH:10]=2)[CH:43]=[N:44]1)#[N:49]
Reactant: CC1(C)OB(c2cnn(CC#N)c2)OC1(C)C
Reactant: O=C(Nc1cc(F)c(Oc2ccncc2Br)cc1F)c1cccn(-c2ccc(F)cc2)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: N#CCn1cc(-c2cnccc2Oc2cc(F)c(NC(=O)c3cccn(-c4ccc(F)cc4)c3=O)cc2F)cn1
Temperature: 85 °C
Yield: 23.9 %

Procedure:
N-(4-(3-Bromopyridin-4-yloxy)-2,5-difluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (0.119 g, 0.231 mmol) was combined with 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetonitrile (0.054 g, 0.231 mmol) and potassium carbonate (0.096 g, 0.692 mmol) in dioxane (4 mL) and water (0.667 mL), sparged with argon for several minutes, treated with tetrakis(triphenylphosphine)palladium(0) (0.013 g, 0.012 mmol) and heated to 85° C. overnight. The mixture was cooled to room temperature, treated with saturated NaHCO3 and extracted with EtOAc (2×). The combined organics were washed with brine, dried over MgSO4 and concentrated to dryness. The crude material was purified over silica gel (40-100% EtOAc/Hex) to afford N-(4-(3-(1-(cyanomethyl)-1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-1-(4-Fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (30 mg, 24% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.45 (s, 1H); 8.91 (s, 1H); 8.61 (dd, J=7.4, 2.1 Hz, 1H); 8.55 (m, 1H); 8.44 (s, 1H); 8.29 (d, J=5.7 Hz, 1H); 8.24 (s, 1H); 8.16 (dd, J=6.6, 2.2 Hz, 1H); 7.67 (dd, J=11.0, 7.3 Hz, 1H); 7.60 (dd, J=8.7, 4.9 Hz, 2H); 7.42 (t, J=8.7 Hz, 2H); 6.75 (m, 2H); 5.54 (s, 2H); MS (ESI) m/z: 543.1 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)C1
Reaction time: 1 h

Procedure:
To (S)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (2.0 g, 10.9 mmol) in CH2Cl2 (50 mL) at 0° C. was added Et3N (1.4 g, 1.9 mL, 13.4 mmol) and methanesulfonyl chloride (1.38 g, 0.94 mL, 12.1 mmol). After 1 h, brine was added and the mixture extracted with CH2Cl2 (2×). The combined organics were dried to give 3-methanesulfonyloxy-pyrrolidine-1-carboxylic acid tert-butyl ester that was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([CH2:24][C:25]([O:27]C)=[O:26])[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][CH:21]1[CH2:23][CH2:22]1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[Li+].[OH-]>C1COCC1>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([CH2:24][C:25]([OH:27])=[O:26])[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][CH:21]1[CH2:22][CH2:23]1)[S:9]([CH3:12])(=[O:10])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cc1ccc(OCC2CC2)c(N(C(=O)OC(C)(C)C)S(C)(=O)=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(c1cc(CC(=O)O)ccc1OCC1CC1)S(C)(=O)=O
Yield: 94.8 %

Procedure:
To a solution of methyl 2-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-(cyclopropylmethoxy)phenyl)acetate (1.2 g, 2.90 mmol) in THF:water=1:1 (35 ml), LiOH (0.695 g, 29.0 mmol) was added, and the mixture was reacted for 30 minutes at RT. THF was evaporated, and the aqueous residue was acidified with HCl 6N (pH=7). The mixture was extracted with EtOAc (3×), and the combined organic layers were dried over Na2SO4. The solvent was removed under vacuum affording 2-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-(cyclopropylmethoxy)phenyl)acetic acid (1.1 g, 2.75 mmol, 95% yield, MS/ESI+ 400.0 [MH]+). This intermediate was used without any additional purification.
Reaction SMILES: [C:1]([C:4]1[N:9]=[N:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17]C(=O)OC(C)(C)C)=[CH:6][C:5]=1[NH:25][C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH2:33][CH2:34][CH3:35])[N:27]=1)(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCl>[NH2:17][C@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]1[NH:10][C:7]1[N:8]=[N:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([NH:25][C:26]2[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH2:33][CH2:34][CH3:35])[N:27]=2)[CH:6]=1
Reactant: CCCc1cc(C)cc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1cc(C)cc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)nnc2C(N)=O)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.8 %

Procedure:
To a solution of tert-butyl (1S,2R)-2-(6-carbamoyl-5-(4-methyl-6-propylpyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (91 mg, 188 μmol) in dichloromethane (2.9 mL) was added trifluoroacetic acid (429 mg, 290 μL, 3.76 mmol) and the mixture stirred at room temperature for 16 h. The mixture was concentrated in vacuo then diluted with NH4OH and dichloromethane. The mixture was washed with water, then the organic phase was concentrated in vacuo and purified by chromatography (silica, 3 to 15% methanol in dichloromethane) to give 6-((1R,2S)-2-aminocyclohexylamino)-4-(4-methyl-6-propylpyridin-2-ylamino)pyridazine-3-carboxamide (46 mg, 120 μmol, 64%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.59 (s, 1H), 8.34 (s, 1H), 8.08 (s, 1H), 7.63 (s, 1H), 6.80 (d, J=7.2 Hz, 1H), 6.70 (s, 1H), 6.60 (s, 1H), 3.88 (s, 1H), 3.25 (s, 1H), 2.67 (t, J=7.4 Hz, 1H), 2.26 (s, 3H), 1.71 (m, 2H), 1.54-1.71 (m, 6H), 1.35 (s, 2H), 0.93 (t, J=7.2 Hz, 3H); MS (EI/CI) m/z: 384.1 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([Cl:16])=O)=[CH:12][CH:11]=1.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]=[C:14]([Cl:16])[C:13]2[CH:17]=[CH:18][C:10]([CH3:9])=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(Cl)=Nc2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-(4-bromo-phenyl)-4-methyl-benzimidoyl chloride used is prepared by the following procedure. To a solution of 4-bromoaniline (29.2 mg, 0.17 mmol) and 4-methyl benzoyl chloride (22.5 μL, 0.17 mmol) in dichloromethane was added triethylamine (28 μL, 0.20 mmol). After stirred at room temperature for 30 minutes, the solvent was removed. The residue was added 0.5 mL of thionyl chloride. The reaction mixture was heated at 80° C. for 1 h, concentrated. The product was used in the next step reaction.
Reaction SMILES: [OH-].[Na+:2].[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:10][CH2:11][C:12]([P:18]([OH:21])([OH:20])=[O:19])([P:14]([OH:17])([OH:16])=[O:15])[OH:13])[CH3:9]>O.C(#N)C>[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:10][CH2:11][C:12]([P:18]([O-:21])([OH:20])=[O:19])([P:14]([OH:17])([OH:16])=[O:15])[OH:13])[CH3:9].[Na+:2]
Reactant: CCCCCN(C)CCC(O)(P(=O)(O)O)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CCCCCN(C)CCC(O)(P(=O)([O-])O)P(=O)(O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.8 %

Procedure:
A solution of sodium hydroxide (0.63 g) in water:acetonitrile (20:80 v/v, 12.5 ml) was added dropwise to a solution of amorphous ibandronic acid (5 g) in water:acetonitrile (20:80 v/v, 50 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for an additional 20 minutes to obtain a pH of 3.80. Then the reaction mixture was cooled to room temperature and stirred for 16 hrs. The precipitate was isolated by vacuum filtration, washed with acetonitrile (2×10 ml), and dried in a vacuum oven at 50° C. for 22.5 hours to obtain 4.0 g of ibandronate sodium crystal form Q.
Reaction SMILES: C1C=CC=CC=1.[H-].[Na+].Br[CH2:10][CH2:11][CH2:12][C:13]1([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][C:14]1=[O:22]>O>[CH2:26]([O:25][C:23]([C:13]12[CH2:12][CH2:11][CH2:10][CH:15]([C:16]3[C:21]1=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14]2=[O:22])=[O:24])[CH3:27]
Reactant: CCOC(=O)C1(CCCBr)C(=O)Cc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C12CCCC(C1=O)c1ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred mixture of benzene (400 ml.) and sodium hydride (5.3 g. of a 57% suspension in nujol), which is free of nujol, is added dropwise, under dry nitrogen, 1-(3-bromopropyl)-1-ethoxycarbonyl-2-indanone (39.3 g.) in 100 ml. of benzene. The mixture is stirred at room temperature for 18 hours. Water is added and the organic layer is separated, washed with aqueous sodium chloride, dried, concentrated and distilled to give after a small forecut, 20.5 g. of the title product with b.p. 130°-145° at 0.5 mm.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][C:19]([NH:21][C:22](=O)C(F)(F)F)=[CH:20][C:13]=3[N:12]=2)=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].CI>CS(C)=O.C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][C:19]([NH:21][CH3:22])=[CH:20][C:13]=3[N:12]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cn1c(CCc2ccc(C#N)cc2)nc2cc(NC(=O)C(F)(F)F)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CS(C)=O
Product: CNc1ccc2c(c1)nc(CCc1ccc(C#N)cc1)n2C
Temperature: 35 °C
Reaction time: 4 h

Procedure:
11.2 g (30.0 mmol) of N-{2-[2-(4-cyanophenyl)-ethyl]-1-methyl-benzimidazol-5-yl}-trifluoroacetamide, 10.5 g (76.0 mmol) of potassium carbonate and 2.0 mL of methyliodide were stirred for 3 hours in 80 mL of dimethylsulphoxide at 40-50° C. Then the mixture was diluted with 100 mL of ethyl acetate, poured onto water and extracted. The organic phase is again washed with water, dried and concentrated by evaporation. The residue is chromatographed on silica gel. The methylated trifluoroacetamide is taken up in MeOH, with 10 mL of conc. aqueous ammonia solution and stirred for 4 h at 30-40° C. The methanol is distilled off, the residue is taken up in 75 mL of ethyl acetate, washed with water, dried and evaporated down. The product is crystallised from diethylether.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:15]=[C:14]([N:16]2[C@H:20]([CH3:21])[CH2:19][CH2:18][S:17]2(=[O:23])=[O:22])[CH:13]=[CH:12][C:6]=1[C:7](OCC)=[O:8])(=[O:4])=[O:3].[CH:24]1([C:27]2[C:28]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[N:29][CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=2)[CH2:26][CH2:25]1>>[CH:24]1([C:27]2[C:28]([N:37]3[CH2:42][CH2:41][N:40]([C:7]([C:6]4[CH:12]=[CH:13][C:14]([N:16]5[C@H:20]([CH3:21])[CH2:19][CH2:18][S:17]5(=[O:22])=[O:23])=[CH:15][C:5]=4[S:2]([CH3:1])(=[O:3])=[O:4])=[O:8])[CH2:39][CH2:38]3)=[N:29][CH:30]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:32]=2)[CH2:25][CH2:26]1
Reactant: FC(F)(F)c1cnc(N2CCNCC2)c(C2CC2)c1
Reactant: CCOC(=O)c1ccc(N2[C@H](C)CCS2(=O)=O)cc1S(C)(=O)=O
Product: C[C@@H]1CCS(=O)(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C(F)(F)F)cc3C3CC3)CC2)c(S(C)(=O)=O)c1
Yield: 58.5 %

Procedure:
Using ethyl (R)-2-methanesulfonyl-4-(3-methyl-1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoate (181 mg) described in Preparation Example 28 and 1-(3-cyclopropyl-5-trifluoromethylpyridin-2-yl)piperazine (136 mg) described in Preparation Example 90 and by the reaction and treatment in the same manner as in Example 109, the title compound (172 mg) was obtained.