Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[NH:21]1[CH2:25][CH2:24][CH:23]([NH:26][C:27](=[O:29])[CH3:28])[CH2:22]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:21]3[CH2:25][CH2:24][CH:23]([NH:26][C:27](=[O:29])[CH3:28])[CH2:22]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CC(=O)NC1CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NC1CCN(C(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)C1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with N-(pyrrolidin-3-yl)acetamide (79286-74-1) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=395.5 [MH+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:13][C:12]([CH3:14])=[C:11]([CH:15]=[O:16])[CH:10]=1.[CH:17]1([Mg]Br)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.O1CCCC1>>[CH:17]1([CH:15]([C:11]2[CH:10]=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[O:13][C:12]=2[CH3:14])[OH:16])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Cc1oc(-c2ccc(F)cc2F)cc1C=O
Reactant: Br[Mg]C1CCCCC1
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(F)cc2F)cc1C(O)C1CCCCC1
Yield: 76 %

Procedure:
An operation similar to that in Example 3 (2) was performed using 5-(2,4-difluorophenyl)-2-methyl-3-furaldehyde (2.4 g) and 1N cyclohexylmagnesium bromide-tetrahydrofuran solution (16.5 mL) to give the title compound (2.6 g, 76%) as a white crystal.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[N-](S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.[CH3:49][O:50][C:51]1[CH:56]=[C:55]([CH:57]2[CH2:62][CH2:61][N:60]([CH3:63])[CH2:59][CH2:58]2)[CH:54]=[CH:53][C:52]=1[NH2:64]>CN(C=O)C>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21]([NH:64][C:52]4[CH:53]=[CH:54][C:55]([CH:57]5[CH2:58][CH2:59][N:60]([CH3:63])[CH2:61][CH2:62]5)=[CH:56][C:51]=4[O:50][CH3:49])=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Reactant: COc1cc(C2CCN(C)CC2)ccc1N
Agent: O=S(=O)([N-]S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C2CCN(C)CC2)ccc1Nc1ncc2ccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12.4 %

Procedure:
In a 10 mL sealed tube, to N-tert-Butyl-3-(2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide (100 mg, 0.289 mmol) and N,N-Diisopropylethylamine (0.202 mL, 1.16 mmol) in 3.0 mL of anhydrous DMF was added N-Phenylbis(trifluoromethane-sulfonimide (113 mg, 0.318 mmol). After stirring at room temperature for 30 minutes, 2-Methoxy-4-(1-methyl-piperidin-4-yl)-phenylamine (84 mg, 0.36 mmol) was added. The reaction mixture was heated at 65° C. overnight. The reaction was conc. in vacuo. The reaction mixture was purified via silica gel column chromatography using 500:12:8 DCM:MeOH:7N NH3/MeOH as the eluant. The collected fractions afforded N-tert-Butyl-3-{2-[2-methoxy-4-(1-methyl-piperidin-4-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-benzenesulfonamide as a yellow solid (19.66 mg, 11%). MP 189-198° C. LCMS (E/I+) 549.21 (M+H). 1H NMR (DMSO-d6)-9.01 (s, 1H), 8.56 (s, 1H), 8.35 (d, 1H, J=7.88 Hz), 7.99 (d, 1H, J=8.56 Hz), 7.85 (s, 1H), 7.83 (s, 1H), 7.69 (t, 1H, J=7.82 Hz), 7.62 (s, 1H), 7.23 (d, 1H, J=4.72 Hz), 7.01 (d, 1H, J=4.76 Hz), 6.94 (s, 1H), 6.92 (s, 1H), 3.87 (s, 3H), 2.96-2.83 (m, 2H), 2.28-2.17 (s, 3H), 2.10-1.94 (m, 2H), 1.80-1.58 (m, 3H), 1.32-1.21 (m, 1H), 1.12 (s, 9H).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[CH:8]1([CH2:11][O:12][C:13]2[C:14]([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:26](=[O:33])[N:25]([CH3:34])[CH:24]=3)=[N:15][C:16](S(C)(=O)=O)=[N:17][CH:18]=2)[CH2:10][CH2:9]1.C(O)(=O)C>CN(C=O)C>[CH:8]1([CH2:11][O:12][C:13]2[C:14]([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:26](=[O:33])[N:25]([CH3:34])[CH:24]=3)=[N:15][C:16]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[N:17][CH:18]=2)[CH2:9][CH2:10]1
Reactant: CS(N)(=O)=O
Reactant: Cn1cc(-c2nc(S(C)(=O)=O)ncc2OCC2CC2)c2ccccc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cn1cc(-c2nc(NS(C)(=O)=O)ncc2OCC2CC2)c2ccccc2c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
Sodium hydride (0.93 g, 23.37 mmol, 60% in mineral oil) was added to MeSO2NH2 (2.22 g, 23.37 mmol) in dry DMF (30 mL) at 0° C. over 15 min. The mixture was stirred at 0° C. for 1 h and the title compound of step 5 (3.00 g, 7.79 mmol) was added. The mixture was heated at 60° C. for 6 h. After cooling, ice water was added and the pH was adjusted to 5 with acetic acid. The suspended solids were collected and washed with MTBE (50 mL) to afford the title compound (3 g, yield: 96.7%) as an off-white solid. 1H NMR (CDCl3, 400 MHz) δ 9.80 (s, 1H), 8.53 (d, J=8.0 Hz, 1H), 8.42 (s, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.70 (m, 2H), 7.56 (t, J=7.6 Hz, 1H), 3.87 (d, J=7.2 Hz, 2H), 3.70 (s, 3H), 3.39 (s, 3H), 1.12 (m, 1H), 0.58 (m, 2H), 0.24 (m, 2H). LCMS: 401.1 (M+1)+
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]([CH3:21])[C:9]2[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=2[O:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:7])=[CH:4][C:3]=1[C:24]1[CH:25]=[N:26][C:27]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:29]=1[C:30]#[N:31].[C:36]([O:42][CH2:43]Cl)(=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38].C(N(CC)CC)C.[Na+].[I-]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]([CH3:21])[C:9]2[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=2[O:11][CH2:12][CH2:13][C:14]([O:16][CH2:43][O:42][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])=[O:15])=[O:7])=[CH:4][C:3]=1[C:24]1[CH:25]=[N:26][C:27]([C:32]([F:35])([F:33])[F:34])=[CH:28][C:29]=1[C:30]#[N:31]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CN(C(=O)c1ccc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)c1)c1ccccc1OCCC(=O)O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN(C(=O)c1ccc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)c1)c1ccccc1OCCC(=O)OCOC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 3-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionic acid 11-4 (500 mg, 0.95 mmol), chloromethyl pivalate (276.4 μL, 1.9 mmol), triethylamine (399 μL, 2.85 mmol), NaI (142.5 mg, 0.95 mmol) in DMF (5 mL) was stirred at rt for 2 days. Ethyl acetate was added and the mixture was washed with water and brine, dried over MgSO4, filtered and concentrated. The residue was purified via silica gel flash column chromatography eluting with 20% ethyl acetate in hexane to afford 2,2-dimethyl-propionic acid 3-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionyloxymethyl ester 36-1 as a white foam. MS [M+H]: 618.2; tR=32.7 min (method 5).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:48]=[CH:47][C:9]([CH2:10][NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:40]=[CH:39][C:22]([C:23]([NH:25][CH2:26][C:27]([CH3:38])([CH3:37])[CH2:28][NH:29]C(=O)OC(C)(C)C)=[O:24])=[CH:21][CH:20]=3)[CH:15]=[C:14]([O:41][CH2:42][C:43]([F:46])([F:45])[F:44])[N:13]=2)=[CH:8][CH:7]=1.[C:49]([OH:55])([C:51]([F:54])([F:53])[F:52])=[O:50].C(Cl)Cl>>[C:49]([OH:55])([C:51]([F:54])([F:53])[F:52])=[O:50].[NH2:29][CH2:28][C:27]([CH3:38])([CH3:37])[CH2:26][NH:25][C:23](=[O:24])[C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:16]2[CH:15]=[C:14]([O:41][CH2:42][C:43]([F:44])([F:46])[F:45])[N:13]=[C:12]([NH:11][CH2:10][C:9]3[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][CH2:2][Br:1])=[CH:48][CH:47]=3)[N:17]=2)=[CH:40][CH:39]=1
Reactant: CC(C)(CNC(=O)OC(C)(C)C)CNC(=O)c1ccc(Nc2cc(OCC(F)(F)F)nc(NCc3ccc(OCCCBr)cc3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(CN)CNC(=O)c1ccc(Nc2cc(OCC(F)(F)F)nc(NCc3ccc(OCCCBr)cc3)n2)cc1

Procedure:
tert-butyl (3-(4-((2-((4-(3-bromopropoxy)benzyl)amino)-6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)amino)benzamido)-2,2-dimethylpropyl)carbamate (35 mg, 0.047 mmol) was stirred in TFA/DCM (1:1) solution (2 mL) for 1 h. The solution was concentrated and free TFA to give N-(3-amino-2,2-dimethylpropyl)-4-((2-((4-(3-bromopropoxy)benzyl)amino)-6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)amino)benzamide which was carried to the next step without purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:18]1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][CH2:41][CH2:42][CH:43](O)[CH2:44][CH2:45][CH2:46][C:47]2[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=2)[CH:35]=1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[NH:18][CH:43]([CH2:44][CH2:45][CH2:46][C:47]2[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=2)[CH2:42][CH2:41][CH2:40][C:36]2[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: On1nnc2ccccc21
Reactant: OC(CCCc1cccnc1)CCCc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NC(CCCc2cccnc2)CCCc2cccnc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.8 %

Procedure:
1-tert-Butoxycarbonyl-piperidine-4-carboxylic acid (0.5 g; 2.18 mmol) is dissolved in DMF (10 mL) at ambient temperature. 1-Hydroxybenzotriazole (0.37, 2.74 mmol), triethylamine (0.46 mL, 3.3 mmol), 1,7-di-(3-pyridyl)-heptan-4-ol (0.59 g; 2.4 mmol) as prepared according to WO 98/20893 A1 assigned to Vertex Pharmaceuticals, and N-(3-dimethylamino-propyl)-N′-ethylcarbodiimide hydrochloride (0.46 g; 2.4 mmol) are added sequentially. The mixture is stirred at ambient temperature for 18 hours. The mixture is then poured onto ethyl acetate (150 mL) and washed successively with water (50 mL), saturated aqueous sodium bicarbonate (10 mL), and brine (30 mL). The organic layer is dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified via silica gel chromatography with gradient elution (0%→25% methanol in methylene chloride) affording the desired product (0.3754 g) as a yellow solid. ESMS: MH+ 482.4.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[Cl:16])[C:12]([F:18])([F:17])[O:11][C:10]3([F:20])[F:19])[N:5]=[C:4]([C:21]#[N:22])[CH:3]=1.[F:23][C:24]([F:29])([F:28])[S:25]([O-])=[O:26].[Na+].S(C1C=CC(C)=CC=1)(O)(=O)=O.CNC.S(Cl)(Cl)=O>C1(C)C=CC=CC=1.O>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[Cl:16])[C:12]([F:18])([F:17])[O:11][C:10]3([F:20])[F:19])[N:5]=[C:4]([C:21]#[N:22])[C:3]=1[S:25]([C:24]([F:29])([F:28])[F:23])=[O:26]
Reactant: N#Cc1cc(N)n(-c2cc3c(cc2Cl)C(F)(F)OC3(F)F)n1
Reactant: O=S([O-])C(F)(F)F
Agent: CNC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1nn(-c2cc3c(cc2Cl)C(F)(F)OC3(F)F)c(N)c1S(=O)C(F)(F)F
Temperature: 55 °C
Reaction time: 10 h
Yield: 18.6 %

Procedure:
To a suspension wherein 5-amino-1-(6-chloro-1,1,3,3-tetrafluoro-1,3-dihydroisobenzofuran-5-yl)-3-cyanopyrazole (600 mg, 1.80 mmol), sodium trifluoro-methanesulfinate (366 mg, 2.35 mmol) and dimethylamine tosylate (587 mg, 2.70 mmol) are in toluene (5 ml), thionyl chloride (278 mg, 2.34 mmol) was added dropwise over a period of about 10 minutes and then stirred at 50 to 60° C. for 10 hours. After allowing time to cool, the reaction solution was poured into water, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography to give 150 mg of 5-amino-1-(6-chloro-1,1,3,3-tetrafluoro-1,3-dihydroisobenzofuran-5-yl)-3-cyano-4-trifluoromethylsulfinylpyrazole.
Reaction SMILES: [C:1]1(O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:8]1[CH:13]=CC=C[CH:9]=1>>[C:1]1([CH:8]([CH3:13])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:2]=[CH:1][CH3:6]
Reactant: c1ccccc1
Reactant: Oc1ccccc1
Product: C=CC
Product: CC(C)c1ccccc1

Procedure:
The present invention is a phenol producing apparatus including a reaction tower for forming cumene by benzene and propylene, an oxidation tower for forming cumene hydroperoxide by oxidizing the cumene at downstream of the reaction tower, a concentration tower for concentrating the cumene hydroperoxide at downstream of the oxidation tower, a disintegration tower for forming coarse phenol and coarse acetone by disintegrating the concentrated cumene hydroperoxide by the acid material at down stream of the concentration tower and each kinds of distillation tower for separating and refining the coarse phenol and the coarse acetone at downstream of the disintegration tower, which is provided with the hydrophilic contaminants removing assembly in at least one portion on the passage between the oxidation tower and the concentration tower, between the disintegration tower and the distillation tower, or on the passage provided for feeding back the excess cumene from the concentration tower to the upstream side of the oxidation tower.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH:5](Br)[CH3:6])[CH3:2].[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH2:1]([O:3][C:4](=[O:8])[CH:5]([NH:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:6])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(C)NCc1ccccc1
Temperature: 20 °C
Yield: 97 %

Procedure:
To a solution of 2-bromo-propionic acid ethyl ester (17.90 mL, 1 eq.) in 250 mL of MeCN were added benzylamine (13.45 mL, 0.9 eq.) and potassium carbonate (28.60 g, 1.5 eq.). The reaction was refluxed for 2 h then cooled to 20° C. The crude was filtered, washed with EtOAc. The filtrate was concentrated under reduced pressure, then purified by chromatography on silica gel (elution with heptane/EtOAc: 9/1 to 7/3) to afford 2-benzylamino-propionic acid ethyl ester (24.74 g, yield=97%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([O:22][CH2:23][CH3:24])[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[O:11])=[C:4]([F:25])[CH:3]=1.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:20]([C:17]1[CH:18]=[CH:19][C:14]([CH2:13][NH:12][C:10](=[O:11])[CH:9]([C:5]2[C:6]([F:8])=[CH:7][C:2]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:3][C:4]=2[F:25])[O:22][CH2:23][CH3:24])=[CH:15][CH:16]=1)#[N:21]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)cc(Br)cc1F
Product: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)cc(-c2ccccc2)cc1F

Procedure:
In analogy to example 247.1, (RS)-2-(4-bromo-2,6-difluoro-phenyl)-N-(4-cyano-benzyl)-2-ethoxy-acetamide was reacted with phenylboronic acid to give (RS)-N-(4-cyano-benzyl)-2-(3,5-difluoro-biphenyl-4-yl)-2-ethoxy-acetamide. Yellow solid. MS 407.3 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[N:11]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=3)[CH2:12][C:13](O)([C:15]([F:18])([F:17])[F:16])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[N:11]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:27])=[O:28])=[CH:22][CH:21]=3)[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C2=NC(O)(C(F)(F)F)CN2c2ccc(S(C)(=O)=O)cc2)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(-c2nc(C(F)(F)F)cn2-c2ccc(S(C)(=O)=O)cc2)cc1Cl

Procedure:
A mixture of 2-(3-chloro-4-methoxyphenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-4,5-dihydro-1H-imidazole (10 mmol) and p-toluenesulfonic acid monohydrate (1 mmol) in toluene (100 mL) is heated to reflux for 72 hours. The reaction mixture is cooled and the solvent removed under reduced pressure. The crude residue is redissolved in methylene chloride and washed with water, aqueous sodium bicarbonate and brine. After drying (Na2SO4), filtration and concentration in vacuo, the crude mixture is chromatographed on silica gel using toluene/ethyl acetate to give pure 2-(3-chloro-4-methoxyphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazole.
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([Cl:9])[CH:6]=[CH:7][CH:8]=1.[CH3:10][CH:11]1[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[CH2:12]1.Cl>C(OCC)C>[Cl:9][C:5]1[CH:4]=[C:3]([C:13]2([OH:17])[CH2:14][CH2:15][CH2:16][CH:11]([CH3:10])[CH2:12]2)[CH:8]=[CH:7][CH:6]=1
Reactant: CC1CCCC(=O)C1
Reactant: Clc1cccc(Br)c1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CC1CCCC(O)(c2cccc(Cl)c2)C1
Temperature: 0 °C
Yield: 42.8 %

Procedure:
For example, magnesium turnings (6.4 g, 0.26 mole) were flame-dried, the containing glassware was cooled, and 3-bromochlorobenzene (50 g, 0.26 mole), in 50 ml of diethyl ether was added. As the reaction began, an additional 200 ml of diethyl ether was added, and the reaction mixture was heated under reflux for 0.5 hour. To the refluxing reaction mixture was added dropwise, during a 0.5 hour period, 3-methylcyclohexanone (29.2 g, 0.26 mole) in 100 ml of diethyl ether. Upon complete addition, the reaction mixture was heated under reflux for an additional 0.5 hour, then poured into 500 ml of ice-water containing 50 ml of hydrochloric acid. The mixture was extracted with three 200 ml portions of diethyl ether. The combined extract was washed twice with 100 ml portions of an aqueous solution saturated with sodium chloride. After separation, the organic layer was dried over sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to an oil. The oil was purified by distillation using a Kugelrohr distilling system at 85°/0.05 mm for 2.5 hours to give 1-(3-chlorophenyl)-3-methylcyclohexan-1-ol (25 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[C:6]2[C:11]=1[NH:10][C:9](=O)[CH:8]=[CH:7]2.O=P(Cl)(Cl)[Cl:24].[Cl-].C([NH+](CC)CC)C>C(#N)C>[Cl:24][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:10]=1
Reactant: O=c1ccc2c(OCCN3CCOCC3)ccc(Cl)c2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: CC[NH+](CC)CC
Agent: [Cl-]
Solvent: CC#N
Product: Clc1ccc2c(OCCN3CCOCC3)ccc(Cl)c2n1
Temperature: 120 °C
Reaction time: 3 h
Yield: 119.2 %

Procedure:
8-chloro-5-(2-morpholinoethoxy)quinolin-2(1H)-one (200 mg, 0.6 mmol, 1 eq.) was placed in acetonitrile (1.7 mL) in the presence of POCl3 (301 μL, 3.2 mmol, 5 eq.) and triethylammonium chloride (738 mg, 3.2 mmol, 5 eq.). The reaction mixture was stirred at 120° C. for 3 hours. The mixture was then concentrated under reduced pressure and, after adding water to the residue (5 mL), was stirred at room temperature during 30 minutes. Then the resulting precipitate was washed with water and filtered to give 4-(2-((2,8-dichloroquinolin-5-yl)oxy)ethyl)morpholine (234 mg, 100%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([S:14][CH3:15])=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].I[CH:25]([CH3:27])[CH3:26]>CN(C)C=O>[F:17][C:2]([F:1])([F:16])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([S:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH:25]([CH3:27])[CH3:26])[CH:6]=1)=[O:4]
Reactant: CSc1ccc2c(C(=O)C(F)(F)F)c[nH]c2c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1ccc2c(C(=O)C(F)(F)F)cn(C(C)C)c2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.1 %

Procedure:
A solution of 2,2,2-trifluoro-1-(6-methylsulfanyl-1H-indol-3-yl)-ethanone (200 mg, 0.77 mmol) in N,N-dimethylformamide (2 mL) at 25° C. was treated with potassium carbonate (160 mg, 1.16 mmol). The reaction was stirred at 25° C. for 15 min and then was treated with 2-iodopropane (0.11 mL, 1.16 mmol). The reaction was stirred at 25° C. for 18 h and then was heated at 60° C. for 2 h. At this time, the reaction was cooled to 25° C. and was partitioned between water (50 mL) and ethyl acetate (50 mL). The layers were separated. The aqueous layer was extracted with ethyl acetate (1×50 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 3/1 hexanes/ethyl acetate) afforded 2,2,2-trifluoro-1-(1-isopropyl-6-methylsulfanyl-1H-indol-3-yl)-ethanone (216 mg, 93%) as an off-white solid: mp 67-69° C.; (ES)+-HRMS m/e calcd for C14H14F3NOS (M+) 301.0748, found 301.0740.
Reaction SMILES: [OH-:1].[Na+:2].CO.[CH:5]1[N:9]=[CH:8][N:7]([CH2:10][C:11]([P:17]([OH:20])([OH:19])=[O:18])([P:13]([OH:16])([OH:15])=[O:14])[OH:12])[CH:6]=1>O>[CH:5]1[N:9]=[CH:8][N:7]([CH2:10][C:11]([P:13]([O-:16])([OH:15])=[O:14])([P:17]([O-:19])([OH:20])=[O:18])[OH:12])[CH:6]=1.[OH2:1].[OH2:12].[OH2:12].[OH2:12].[Na+:2].[Na+:2]
Reactant: O=P(O)(O)C(O)(Cn1ccnc1)P(=O)(O)O
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=P([O-])(O)C(O)(Cn1ccnc1)P(=O)([O-])O
Temperature: 25 °C
Yield: 97 %

Procedure:
A solution of sodium hydroxide (1.4 g) in a mixture of water (20% v/v)/Methanol (80% v/v, 10 volumes per grams of ZLD-Ac form I) (10 ml) was added drop-wise to a suspension of Zoledronic acid form I (5.0 g) in a mixture of water (20% v/v)/Methanol (80% v/v, 10 volumes per grams of ZLD-Ac) (53 ml) at reflux temperature. The reaction mixture was heated at reflux temperature for additional 17 hours. Then the reaction mixture was cooled to room temperature. Further cooling was performed using an ice-bath. The precipitate was then filtered, washed with Methanol (1×10 ml) and dried in a vacuum oven at 50° C. for 26 hours to give 5.6 g (97%) of Zoledronate disodium crystal form XIV (LOD by TGA=1.4%). Purity by HPLC 99.9%.
Reaction SMILES: [N+:1]([C:4]1[CH:45]=[CH:44][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][C@H:13]2[CH2:37][N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[N+:53]([C:56]1[CH:66]=[CH:65][C:59]([CH2:60][O:61][C:62](Cl)=[O:63])=[CH:58][CH:57]=1)([O-:55])=[O:54]>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:14][C@H:13]2[CH2:37][N:38]2[CH2:43][CH2:42][N:41]([C:62]([O:61][CH2:60][C:59]3[CH:58]=[CH:57][C:56]([N+:53]([O-:55])=[O:54])=[CH:66][CH:65]=3)=[O:63])[CH2:40][CH2:39]2)=[O:11])=[CH:44][CH:45]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCN(C[C@@H]2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 1 h
Yield: 85.7 %

Procedure:
To a solution of (2S,4S)-1-(4-nitrobenzyloxycarbonyl)-2-(piperazin-1-yl)methyl-4-(triphenylmethylthio)pyrrolidine (2.51 g) and triethylamine (0.73 ml) in dichloromethane (25 ml) was added 4-nitrobenzyloxycarbonyl chloride (0.91 g) under ice-cooling and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo to give a residue. The residue was chromatographed on silica gel (100 g) eluting with a mixture of dichloromethane and acetone (20:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-1-(4-nitrobenzyloxycarbonyl)-2-[4-(4-nitrobenzyloxycarbonyl)piperazin-1-yl]methyl-4-(triphenylmethylthio)pyrrolidine (2.77 g).