Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].I[CH2:21][CH2:22][CH2:23][C:24]([F:27])([F:26])[F:25].C([O-])([O-])=O.[K+].[K+]>>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21][CH2:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: FC(F)(F)CCCI
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1(C)C(=O)N(CCCC(F)(F)F)c2cc([N+](=O)[O-])c(N)cc21
Yield: 65.6 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (2 g) is alkylated in a high pressure reaction vessel using 1-iodo-4,4,4-trifluoro-butane (3.62 g; 15.2 mmol) and K2CO3 (2.1 g; 15.2 mmol) at 60° C. for 3 days. After aqueous work-up and purification by RP chromatography the pure material (1.92 g) is de-acetylated in MeOH (200 ml) using DBU (1.6 ml) at reflux. After aqueous work-up 5-amino-3,3-dimethyl-6-nitro-1-(4,4,4-trifluoro-butyl)-1,3-dihydro-indol-2-one (1.65 g) is obtained and used without further purification.
Reaction SMILES: [NH4+].[Cl-].[CH2:3]([O:10][C:11]1[C:12]([F:25])=[CH:13][C:14]([N+:22]([O-])=O)=[C:15]([CH:21]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O.C(O)(C)C.C1COCC1>[NH2:22][C:14]1[CH:13]=[C:12]([F:25])[C:11]([O:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:21][C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)c1cc(OCc2ccccc2)c(F)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CCOC(=O)c1cc(OCc2ccccc2)c(F)cc1N
Temperature: 90 °C
Yield: 82 %

Procedure:
1.76 g of NH4Cl dissolved in 21 ml of water are added to a mixture heated to 90° C. of 7.0 g of the compound obtained in Step 4.1, and 4.44 g of Fe(0) in 400 ml of isopropanol and 100 ml of THF. The reaction mixture is heated for 4 hours at 90° C. A further 0.88 g of NH4Cl is added and the mixture is heated for 2 hours at 90° C. The resulting mixture is filtered while hot and the filtrate is evaporated under reduced pressure. The residue is taken up in EtOAc and washed twice with saturated NaHCO3 solution. The organic phase is dried over MgSO4 and filtered, and the filtrate is evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a PE/EtOAc mixture from (100/0, v/v) to (40/60, v/v) to give 5.2 g of the expected product.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([C:16]4[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=4)=[CH:12][CH:11]=3)[NH:7][C:6]=2[CH:23]=1.CN(C(C(C)C)C)C.C[Si](C)(C)CCOCCl.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>ClCCl.C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:22][C:21]1[C:16]([C:13]2[CH:14]=[CH:15][C:10]([C:8]3[NH:7][C:6]4[CH:23]=[C:2]([N:41]5[CH2:46][CH2:45][O:44][CH2:43][CH2:42]5)[CH:3]=[CH:4][C:5]=4[N:9]=3)=[CH:11][CH:12]=2)=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: Clc1cccnc1-c1ccc(-c2nc3ccc(Br)cc3[nH]2)cc1
Reactant: C1COCCN1
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)C(C)N(C)C
Agent: C[Si](C)(C)CCOCCl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Clc1cccnc1-c1ccc(-c2nc3ccc(N4CCOCC4)cc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.1 %

Procedure:
To a solution of 162 mg (0.42 mmol) 6-bromo-2-(4-(3-chloropyridin-2-yl)phenyl)-1H-benzoimidazole in 6 mL dichloromethane were added 0.2 mL (1.15 mmol) N,N-dimethylisopropylethylamine and 0.1 mL (0.57 mmol) 2-(trimethylsilyl)ethoxymethyl chloride, followed by stirring at room temperature for 16 hours. After vacuum concentration, 26 μL (0.30 mmol) morpholine, 56.3 mg (0.013 mmol) tris(dibenzylidine acetone)dipalladium(0), 10 mg (0.038 mmol) 2-(di-t-butylphosphino)biphenyl, and 38.8 mg (0.41 mmol) sodium-t-botoxide were added to the concentrate, which was then dissolved in 2.5 mL toluene and allowed to react at 90° C. for 10 min in a microwave reactor. After being cooled to room temperature, the product was dissolved in 5 mL ethyl acetate and filtered with diatomite. The filtrate was dried over magnesium sulfate and vacuum concentrated. The concentrate was dissolved in 3 mL of a mixture of trifluoro fluoroacetic acid and methylene:chloride (1:1) and stirred for 12 hours. Neutralization with 10% NaOH, extraction with ethyl acetate, drying with magnesium sulfate and vacuum concentration were sequentially conducted in that order. The residue thus obtained was separated using column chromatography (developing solvent: hexane/ethyl acetate=1/1) to produce 115 mg of 2-[4-(3-chloropyridin-2-yl)phenyl]-6-morpholin-4-yl-1H-benzoimidazole (yield 70%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[O:9])=[CH:6][N:5]=[C:4](S(CC)(=O)=O)[N:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[O:9])=[CH:6][N:5]=[C:4]([NH:33][C:32]2[CH:31]=[CH:30][C:29]([N:26]3[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]3)=[CH:35][CH:34]=2)[N:3]=1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CCS(=O)(=O)c1ncc(C(=O)c2cccc(F)c2)c(N)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: CN1CCN(c2ccc(Nc3ncc(C(=O)c4cccc(F)c4)c(N)n3)cc2)CC1
Temperature: 105 °C
Yield: 62.1 %

Procedure:
A suspension of (4-amino-2-ethanesulfonyl-pyrimidin-5-yl)-(3-fluoro-phenyl)-methanone (20.1 mg, 0.0650 mmol, Example 3), 4-(4-methylpiperazino)aniline (15.8 mg, 0.0826 mmol, Appolo Chemical) and p-toluenesulfonic acid hydrate (15 mg, 0.0777 mmol, Aldrich) in isopropanol (2.5 mL) was placed in a sealed tube and heated at 100 to 110° C. under microwave conditions for 1 hour. The resulting mixture was evaporated in vacuo and the crude product was purified on silica gel with 95:5 of dichloromethane/methanol to give [4-amino-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-5-yl]-(3-fluoro-phenyl)-methanone as a light yellow solid (16.4 mg, 68% yield). HRMS, observed: 407.1994; Calcd for (M+H)+: 407.1990.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([CH2:13][N:14]([CH3:28])[S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:9][CH2:8]1.[CH2:29]([NH:32][CH3:33])[CH:30]=[CH2:31]>CO>[CH2:29]([N:32]([CH3:33])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([CH2:13][N:14]([CH3:28])[S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:9][CH2:8]1)[CH:30]=[CH2:31]
Reactant: CN(C[C@H]1CC[C@H](CCCCCBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: C=CCNC
Solvent: CO
Product: C=CCN(C)CCCCC[C@H]1CC[C@H](CN(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
153 mg (0.315 mmol) trans-N-[4-(5-bromo-pentyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide (example 1.6) dissolved in 2.0 ml of methanol were treated with 0.5 ml of N-allyl-methyl-amine and the reaction mixture stirred for 6 h at 50° C. It was then evaporated, poured into 50 ml of an ice/water mixture and extracted 3 times with 50 ml of dichloromethane. The combined dichloromethane phases were washed with sodium carbonate solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue formed was chromatographed on silica gel with a 9:1:0.1 v/v/v mixture of dichloromethane, methanol and saturated ammonia solution as the eluent giving 0.110 g (73.3%) trans-N-{4-[5-(allyl-methyl-amino)-pentyl]-cyclohexylmethyl}-N-methyl-4-trifluoromethyl-benzenesulfonamide as colorless solid, MS: 475 (MH+).
Reaction SMILES: [CH2:1]([CH2:5][C:6](=O)[CH3:7])[C:2]([CH3:4])=O.C(O)(=O)C.[NH2:13][C:14]1[CH:34]=[C:33]([CH3:35])[C:17]2[O:18][C:19]3[C:28]([CH3:29])=[CH:27][C:26]([C:30]([OH:32])=[O:31])=[CH:25][C:20]=3[S:21](=[O:24])(=[O:23])[CH2:22][C:16]=2[CH:15]=1>C1(C)C=CC=CC=1>[CH3:7][C:6]1[N:13]([C:14]2[CH:34]=[C:33]([CH3:35])[C:17]3[O:18][C:19]4[C:28]([CH3:29])=[CH:27][C:26]([C:30]([OH:32])=[O:31])=[CH:25][C:20]=4[S:21](=[O:24])(=[O:23])[CH2:22][C:16]=3[CH:15]=2)[C:2]([CH3:4])=[CH:1][CH:5]=1
Reactant: Cc1cc(N)cc2c1Oc1c(C)cc(C(=O)O)cc1S(=O)(=O)C2
Reactant: CC(=O)CCC(C)=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Cc1cc(-n2c(C)ccc2C)cc2c1Oc1c(C)cc(C(=O)O)cc1S(=O)(=O)C2
Yield: 51 %

Procedure:
Acetonylacetone (0.040 g, 0.35 mmol)) and acetic acid (0.1 mL, 1.7 mmol) were added to a solution of the methylester of Example 36j in toluene (10 mL). The reaction mixture was refluxed for 6 h, concentrated and triturated with PE60-80° C. The organic extract was concentrated and the crude obtained was purified using flash chromatography (silica gel, EtOAc/PE60-80° C.). It was then subjected to hydrolysis as described in Example 11 to obtain the title compound (J. Chem. Soc., Chem. commun, 800-801, (1982)). Yield: 51%; 1H NMR (DMSO-d6): δ 2.0 (s, 6H, 2CH3), 2.40 (s, 3H, CH3), 2.65 (s, 3H, CH3), 5.20 (s, 2H, CH2), 5.70 (s, 2H, pyrrolyl), 7.30 (s, 1H, Ar), 7.35 (s, 1H, Ar), 8.20 (s, 1H, Ar), 8.35 (s, 1H, Ar); MS: m/e (ES+) 411 (M+).
Reaction SMILES: [ClH:1].C([NH:21][C@@H:22]([C:33]12[CH2:42][CH:37]3[CH2:38][CH:39]([CH2:41][C:35]([OH:43])([CH2:36]3)[CH2:34]1)[CH2:40]2)[C:23]([N:25]1[C@H:30]([C:31]#[N:32])[CH2:29][C@H:28]2[C@@H:26]1[CH2:27]2)=[O:24])(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>CO>[CH2:29]1[C@@H:30]([C:31]#[N:32])[N:25]([C:23]([C@@H:22]([NH2:21])[C:33]23[CH2:34][C:35]4([OH:43])[CH2:41][CH:39]([CH2:38][CH:37]([CH2:36]4)[CH2:42]2)[CH2:40]3)=[O:24])[C@@H:26]2[C@H:28]1[CH2:27]2.[ClH:1]
Reactant: N#C[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C12CC3CC(CC(O)(C3)C1)C2
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: N#C[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)[C@@H](N)C12CC3CC(CC(O)(C3)C1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.1 %

Procedure:
A mixture of aqueous hydrochloric acid (34.5% w/w) (2.3 g) and methanol (20 ml) was added to a mixture of (1S,3S,5S)-2-[(2S)-2-tritylamino-2-(3-hydroxyadamantan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile (10.0 g) in methanol (80 ml), and the mass was stirred at 25° C. for 3 hours. Completion of the reaction was verified by HPLC. Solvent was distilled from the reaction mixture to give a residue. Ethyl acetate (100 ml) was mixed with the residue for 30 minutes at ambient temperature. The solid was filtered and washed with ethyl acetate (2×5 ml). The solid was dried under vacuum at 50-60° C. for 8 hours to give the title product (6.0 g). (Yield=90%; HPLC purity=99.5%)
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH2:29]([N:31]([CH2:34][CH2:35]Cl)[CH2:32][CH3:33])[CH3:30]>CN(C=O)C>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:30][CH2:29][N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)CCCl
Reactant: Oc1cccc2c1c1ccccc1n2Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1cccc2c1c1ccccc1n2Cc1ccccc1
Temperature: 100 °C
Reaction time: 2.3 h
Yield: 91.9 %

Procedure:
A mixture of 9-benzyl-9H-Carbazol-4-ol (0.0305 g, 0.1116 mmol), potassium carbonate (0.0308 g, 0.2232 mmol), and DMF (1.0 mL) is stirred at 100° C. Diethylaminoethyl chloride hydrochloride (0.0230 g, 0.1339 mmol) is added in aliquots over 40 min. After 2.3 h, an additional 0.032 g of potassium carbonate and 0.023 g of diethylaminoethyl chloride hydrochloride are added. The mixture is stirred overnight and then the solvent is removed and the residue partitioned between CH2Cl2 and aq. sodium bicarbonate. The organic layers are dried over sodium sulfate. Chromatography on silica gel (15 mL) using acetone-hexane (20/80) gave 0.0382 g of the title compound as a solid; mp 79-80.5° C.; IR (drift) 2965, 1581, 1457, 1439, 1356, 1342, 1333, 1268, 1147, 1112, 1053, 782, 750, 729, 713 cm−1; 1H NMR (CDCl3) δ1.14, 2.75, 3.13, 4.36, 5.50, 6.71, 6.98, 7.12, 7.2-7.4, 8.38. Anal. Calcd for C25H28N2O: C, 80.61; H, 7.58; N, 7.52. Found: C, 79.90; H, 7.52; N, 7.43.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:20][C@H:19]([CH2:21][OH:22])[C@@H:17]([OH:18])[C@H:12]2[O:13][CH2:14][CH2:15][CH3:16])=[C:4](N)[N:3]=1.NC1N=C2C(N=CN2[C@@H]2O[C@H](CO)[C@@H](OCCC)[C@H]2[OH:36])=C(N)N=1.[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1O.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>P([O-])([O-])([O-])=O.CS(C)=O>[CH2:14]([O:13][C@@H:12]1[C@H:17]([OH:18])[C@@H:19]([CH2:21][OH:22])[O:20][C@H:11]1[N:8]1[C:9]2[N:10]=[C:2]([NH2:1])[NH:3][C:4](=[O:36])[C:5]=2[N:6]=[CH:7]1)[CH2:15][CH3:16]
Reactant: CCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N)nc(N)nc21
Reactant: CCCO[C@H]1[C@@H](O)[C@H](n2cnc3c(N)nc(N)nc32)O[C@@H]1CO
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(N)nc21

Procedure:
A mixture of 2,6-Diamino-9-(2'-O-propyl-β-D-ribofuranosyl)purine and 2,6-Diamino-9-(3'-O-propyl-β-D-ribofuranosyl)purine (4.6 gm) and adenosine deaminase (200 mg, Sigma Chemicals Type II) were stirred at room temperature overnight in 0.1 M tris buffer (150 ml, pH 7.4), DMSO (100 ml) and 0.1 M sodium phosphate buffer (10 ml). A further aliquot of adenosine deaminase (140 mg) in 0.1 M phosphate buffer (30 ml) and DMSO (20 ml) was added and the reaction stirred an addition 24 hrs. The solvent was evaporated in vacuo and the residue flash chromatographed on silica gel utilizing 5→20% MeOH/CH2Cl2. Product-containing fractions were evaporated in vacuo and the residue crystallized from H2O to yield 2.6 gm of product. m.p. dec >270° C. 1H NMR (DMSO-d6) δ 0.75 (t, 3, CH3), 1.42 (tq, 2, CH2), 3.3-3.6 (m, 4, H-5', O-CH2), 3,85 (m, 1), 4.2 (m, 1), 4.23 (m, 1), 5.10 (t, 1, 5'-OH), 5.13 (d, 1, 3'-OH), 5.75 (d, 1, H-1') , 6.45 (br s, 2, NH2), 7.95 (s, 1, H-8) and 10.67 (br s, 1, NH). Anal. Calcd. for C13H19N5O5 : C, 47.99; H, 5.89; N, 21.53. Found: C, 47.90, H, 5.85; N, 21.44.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][CH2:16]1)=[CH:11][C:10](Br)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[F:30][C:31]1[CH:36]=[C:35](B2CC(C)(C)C(C)(C)C2)[CH:34]=[C:33]([F:46])[C:32]=1[OH:47]>>[C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][CH2:16]1)=[CH:11][C:10]([C:35]1[CH:36]=[C:31]([F:30])[C:32]([OH:47])=[C:33]([F:46])[CH:34]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Reactant: CC1(C)CB(c2cc(F)c(O)c(F)c2)CC1(C)C
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(F)c3)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1

Procedure:
Following general procedure D, tert-butyl trans-4-(3-acetyl-6-bromoquinolin-4-ylamino)cyclohexylcarbamate (47 mg, 0.100 mmol) was reacted with 2,6-difluoro-4-(3,3,4,4-tetramethylborolan-1-yl)phenol (97 mg, 0.382 mmol) to afford the desired product (30 mg, 59%) as a yellow solid: ESI MS m/z 512 [C28H31F2N3O4+H]+.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH:15]=[CH2:16])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH3:25][O:26][CH2:27][CH:28]([C:36]1[CH:37]=[CH:38][C:39]([CH:42]=[O:43])=[N:40][CH:41]=1)[O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1.C(N(CC)CC)C.O1CCCC1>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH2:15][CH2:16][C:42]([C:39]3[CH:38]=[CH:37][C:36]([CH:28]([O:29][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][O:31]4)[CH2:27][O:26][CH3:25])=[CH:41][N:40]=3)=[O:43])=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: COCC(OC1CCCCO1)c1ccc(C=O)nc1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COCC(OC1CCCCO1)c1ccc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)nc1
Yield: 79.5 %

Procedure:
A mixture of 4-[4-(cyclopropylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (0.50 g), 5-[2-methoxy-1-(tetrahydro-2H-pyran-2-yloxy)ethyl]pyridine-2-carbaldehyde (0.42 g), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (38 mg), triethylamine (0.1 mL), tetrahydrofuran (5 mL) and ethanol (5 mL) was stirred with heating under reflux for 2 hr. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography, and the title compound (0.70 g, yield 79%) was obtained as a pale-yellow oil from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). MS: 614 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([NH:10][C:11](=[O:30])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]34[CH2:29][CH:24]5[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]5)[CH2:21]3)[CH2:27]4)=[CH:16][CH:15]=2)[CH:7]=[N:6][CH:5]=1.[I-].[Li+]>N1C=CC=CC=1>[C:20]12([C:17]3[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:11]([NH:10][C:8]4[CH:7]=[N:6][CH:5]=[C:4]([CH:9]=4)[C:3]([OH:31])=[O:2])=[O:30])=[CH:15][CH:16]=3)[CH2:27][CH:26]3[CH2:28][CH:22]([CH2:23][CH:24]([CH2:25]3)[CH2:29]1)[CH2:21]2
Reactant: COC(=O)c1cncc(NC(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)c1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cncc(C(=O)O)c1
Yield: 33.5 %

Procedure:
A solution of 5-[2-(4-adamantan-1-yl-phenoxy)acetylamino]-nicotinic acid methyl ester (50 mg, 0.11 mmol) and lithium Iodide (189 mg, 1.11 mmol) in pyridine (3 mL) was heated to reflux until reaction completion, then cooled and distilled off the solvent under reduced pressure. The residue was taken up in water, neutralized and extracted with methanol/MC mixture (10%). The combined extracts were washed with brine and water, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The resultant crude product was purified by HPLC (MeOH/MC-10%) to afford 5-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-nicotinic acid as a colorless solid (0.015 g, 30% yield).
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13](F)[CH:12]=1.[OH-].[Na+]>CN(C=O)C>[Br:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:12]=1
Reactant: Oc1ccccc1
Reactant: N#Cc1ccc(Br)cc1F
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Br)cc1Oc1ccccc1
Temperature: 25 °C

Procedure:
Sodium hydride (12 g, 300 mmol) (60% by wt) was weighed into a flask and washed free of oil with several hexane rinsings. The hexanes were decanted and discarded and DMF was added to the flask. A solution of phenol (23.5 g, 250 mmol) in DMF (100 mL) was added dropwise and the mixture was stirred at room temperature. To the mixture was added a solution of 4-bromo-2-fluoro-benzonitrile (50 g, 250 mmol, 100 mL DMF), dropwise. Upon complete addition, the reaction was refluxed for 20 h. The reaction was cooled to room temperature and poured into cold 1 N NaOH. A fine, tan precipitate formed and was collected by vacuum filtration to give Compound 5c. MS m/z (MH+) 277.
Reaction SMILES: [OH-].[Na+:2].[CH:3]1[N:7]=[CH:6][N:5]([CH2:8][C:9]([P:15]([OH:18])([OH:17])=[O:16])([P:11]([OH:14])([OH:13])=[O:12])[OH:10])[CH:4]=1>O.CO.C(O)C.CN(C=O)C>[CH:3]1[N:7]=[CH:6][N:5]([CH2:8][C:9]([P:11]([O-:14])([O-:13])=[O:12])([P:15]([O-:17])([OH:18])=[O:16])[OH:10])[CH:4]=1.[Na+:2].[Na+:2].[Na+:2]
Reactant: O=P(O)(O)C(O)(Cn1ccnc1)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Solvent: CN(C)C=O
Product: O=P([O-])([O-])C(O)(Cn1ccnc1)P(=O)([O-])O
Temperature: 25 °C

Procedure:
A solution of sodium hydroxide (1.4 g) in a mixture of water (80% v/v)/Ethanol or Methanol or IPA (20% v/v, 10 volumes per grams of ZLD-Ac form XII) (38 ml) was added drop-wise to a suspension of Zoledronic acid form XII (5.0 g) in a mixture of water (80% v/v)/Ethanol or Methanol or EPA (20% v/v, 10 volumes per grams of ZLD-Ac) (212 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 16 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed and dried in a vacuum oven at 50° C. for 24 hours to give Zoledronate trisodium crystal form IX.
Reaction SMILES: [ClH:1].Cl.[CH:3]1[CH:12]=[CH:11][C:10]2[CH2:13][CH2:14][N:8]3[C:9]=2[C:4]=1[C@H:5]1[CH2:17][NH:16][CH2:15][C@H:6]1[CH2:7]3.C=O.[C:20](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClCCCl.CCOCC>[ClH:1].[ClH:1].[CH3:20][N:16]1[CH2:17][C@H:5]2[C@H:6]([CH2:7][N:8]3[CH2:14][CH2:13][C:10]4[CH:11]=[CH:12][CH:3]=[C:4]2[C:9]3=4)[CH2:15]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: c1cc2c3c(c1)[C@H]1CNC[C@H]1CN3CC2
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCCl
Product: CN1C[C@H]2CN3CCc4cccc(c43)[C@H]2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a solution of (±)-cis-4,5,7,7a,8,9,10,10a-octahydrodipyrrolo[3,4-c:3′,2′,1′-ij]quinoline free base from EXAMPLE 109 (140 mg, 0.70 mmol) in 10 mL of 1,2-dichloroethane was added 37% aqueous formaldehyde (0.125 mL, 1.4 mmol) and sodium triacetoxyborohydride (0.45 g, 2.1 mmol). The resulting mixture was stirred at ambient temperature for 1 h and then the reaction was quenched with water. The mixture was partitioned between chloroform and saturated aqueous sodium carbonate. The organics were washed with brine, dried (K2CO3) and concentrated in vacuo. The residue was dissolved in 1 mL ethanol and 5 mL of ether and then there was added 2M HCl in ether (1.05 mL, 2.1 mmol). A solid precipitated out of solution. The solvents were decanted and the solid was triturated twice with ether and dried in vacuo to afford 100 mg (50%) of the title compound of EXAMPLE 110 as an off white powder LRMS (ES)+: 214.9 (M+H)+.
Reaction SMILES: N1C2C(=CC=CC=2)CC1=O.OC1C=C(OC)C(C2C=CC(OC)=CC=2)=CC=1C=O.[OH:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[C:34]([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)=[CH:33][C:32]=1[CH:47]=[C:48]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[NH:50][C:49]1=[O:57]>>[OH:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[C:34]([C:39]2[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=2)=[CH:33][C:32]=1[CH2:47][CH:48]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[NH:50][C:49]1=[O:57]
Reactant: COc1ccc(-c2cc(C=C3C(=O)Nc4ccccc43)c(O)cc2OC)cc1
Agent: COc1ccc(-c2cc(C=O)c(O)cc2OC)cc1
Agent: O=C1Cc2ccccc2N1
Product: COc1ccc(-c2cc(CC3C(=O)Nc4ccccc43)c(O)cc2OC)cc1
Yield: 75 %

Procedure:
2-Oxindole was condensed with 4-hydroxy-6,4′-dimethoxybiphenyl-3-carbaldehyde using method B to give a mixture of isomers of 3-(4-hydroxy-6,4′-dimethoxybiphenyl-3-ylmethylene)-1,3-dihydroindol-2-one, followed by reduction using method E to give 4.5 mg (75%) of 3-(4-hydroxy-6,4′-dimethoxybiphenyl-3-ylmethyl)-1,3-dihydroindol-2-one as a white solid.