Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH:5]1[CH2:18][C:8]2=[CH:9][C:10]3[C:11](=[O:17])[NH:12][C:13](=[O:16])[C:14]=3[CH:15]=[C:7]2[CH2:6]1)[CH2:2][CH3:3].C([O-])([O-])=O.[K+].[K+].[CH2:28](Br)[CH3:29]>CN(C=O)C>[CH2:19]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:18][C:8]2=[CH:9][C:10]3[C:11](=[O:17])[N:12]([CH2:28][CH3:29])[C:13](=[O:16])[C:14]=3[CH:15]=[C:7]2[CH2:6]1)[CH2:20][CH3:21]
Reactant: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)NC3=O
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(CC)C3=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 6-(dipropylamino)-6,7-dihydrocyclopent[f]isoindole-1,3(2H,5H)-dione (93, 0.15 g, 0.52 mmol) in DMF (10 mL) at 0° C. was added anhydrous K2CO3 (0.14 g, 1.04 mmol) followed by ethyl bromide (0.06 mL, 0.79 mmol). The reaction was stirred at 0° C. for 2 hr then allowed to warm to r.t. Continued stirring overnight then quenched with H2O. The solution was extracted with CH2Cl2 and the organic layers were washed with brine, dried (MgSO4), and concentrated. The residue was further concentrated on the high vac to remove any excess DMF and the resulting greenish solid was purified using silica gel, eluting with 3:1 hexane/acetone to give 95 as an off-white solid. The solid was converted to an HCl salt and recrystallized from hot MeOH/EtOAc to give 95 as a white solid (m.p. 225-230° C.).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([C:9]2[O:13][C:12]([CH3:14])=[N:11][C:10]=2[CH3:15])([OH:8])[CH3:7])=[CH:2]1.[H-].[Na+].CI.[C:20](=O)([O-])O.[Na+]>CN(C)C=O>[CH3:20][O:8][C:6]([C:9]1[O:13][C:12]([CH3:14])=[N:11][C:10]=1[CH3:15])([C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)[CH3:7]
Reactant: Cc1nc(C)c(C(C)(O)c2ccoc2)o1
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(C)(c1ccoc1)c1oc(C)nc1C
Reaction time: 0.33 h

Procedure:
1-(3-Furyl)-1-(2,4-dimethyl-5-oxazolyl)ethanol (2g) in dry N,N-dimethylformamide (15 ml) was added to a stirred suspension of sodium hydride (80%, 300 mg) in dry N,N-dimethylformamide (10 ml) at 0° C. After 20 minutes, methyl iodide (1.5 g) was added dropwise. The mixture was allowed to warm to room temperature and after 30 minutes aqueous sodium hydrogen carbonate was added.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH:7]1[C:15]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:9]=[CH:8]1.[C:16]([CH:20]([C:36]1[CH:41]=[CH:40][C:39]2[O:42][CH2:43][O:44][C:38]=2[CH:37]=1)[O:21][C:22]1[C:29]([CH2:30][CH2:31][CH3:32])=[CH:28][C:25]([CH2:26]Br)=[CH:24][C:23]=1[CH2:33][CH2:34][CH3:35])([O:18][CH3:19])=[O:17]>CN(C=O)C>[C:16]([CH:20]([C:36]1[CH:41]=[CH:40][C:39]2[O:42][CH2:43][O:44][C:38]=2[CH:37]=1)[O:21][C:22]1[C:29]([CH2:30][CH2:31][CH3:32])=[CH:28][C:25]([CH2:26][N:9]2[C:10]3[CH:11]=[N:12][CH:13]=[CH:14][C:15]=3[N:7]=[CH:8]2)=[CH:24][C:23]=1[CH2:33][CH2:34][CH3:35])([O:18][CH3:19])=[O:17]
Reactant: CCCc1cc(CBr)cc(CCC)c1OC(C(=O)OC)c1ccc2c(c1)OCO2
Reactant: c1cc2[nH]cnc2cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1cc(Cn2cnc3ccncc32)cc(CCC)c1OC(C(=O)OC)c1ccc2c(c1)OCO2
Reaction time: 0.25 h
Yield: 15.8 %

Procedure:
Cesium carbonate (156 mg, 0.48 mmol) was added to imidazo[4,5-c]pyridine (28.6 mg, 0.24 mmol) in DMF (3 mL) at room temperature under nitrogen. After stirring for 15 min, a solution of 4-(1-carbomethoxy-1-(3,4-methylenedioxyphenyl)-methoxy)-3,5-dipropylbenzyl bromide (121 mg, 0.26 mmol) in DMF (3 mL) was added and the mixture stirred at 50° C. for 18 h. The mixture was poured onto ice/water and extracted with ethyl acetate (3×30 mL). The combined organic phase was washed with water, brine, dried (magnesium sulfate) and the solvent removed in vacuo. The crude material was purified by flash column chromatography (0 to 5% methanol/methylene chloride) to afford the less polar isomer of the titled compound (19 mg).
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4].[OH-].[Ca+2:15].[OH-]>O>[C:1]([O-:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([O-:11])=[O:10])([C:5]([O-:7])=[O:6])[OH:4].[Ca+2:15].[C:1]([O-:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([O-:11])=[O:10])([C:5]([O-:7])=[O:6])[OH:4].[Ca+2:15].[Ca+2:15]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Temperature: 56.666666666666664 °C

Procedure:
A calcium citrate sample was prepared by reacting 2763.8 lbs. of citric acid with 1600 lbs. calcium hydroxide (97-98% Ca(OH)2 by analysis) in the presence of 1250.5 gallons of water. The mole ratio of calcium hydroxide to citric acid was very slightly less than 3:2, actually 2.92:2. The citric acid (Pfizer fine grannular, food grade) was mixed in a large batch tank with 600 gallons of cold water. The calcium hydroxide (Mississippi Lime, hydrated lime, food codex) was mixed in a separate batch tank with 600 gallons of cold water. The calcium hydroxide slurry is then pumped into the citric acid solution at a rate to deliver the entire slurry in 10-15 minutes. It is necessary to have good agitation during the entire reaction and mixing process. The remaining 50.5 gallons of water is used to rinse the calcium hydroxide tank and transport lines. Due to the heat of reaction, the temperature of the resultant slurry was increased from an initial value of 15° C. (60° F.) to a maximum of 57° C. (134° F.). After the reaction is complete, the batch is cooled to 80°-90° F. The final pH of this concentrated slurry should fall within the range 3.8-4.6 or can be adjusted up or down using the reacting ingredients. The slurry is then dried via spray drying utilizing a rotary wheel (7600 rpm). The outlet temperature was adjusted to 225° F. and the inlet temperature was 450° F.
Reaction SMILES: [CH3:1][C:2]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)([CH3:11])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.CC(O)=O>C1COCC1.[Zn]>[CH3:11][C:2]([C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=1)([CH3:1])[CH2:3][CH2:4][N:5]1[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1
Reactant: CC(C)(CCN1CCOCC1)c1ccc([N+](=O)[O-])cc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(CCN1CCOCC1)c1ccc(N)cc1
Reaction time: 1 h

Procedure:
To a solution of 4-[3-methyl-3-(4-nitro-phenyl)-butyl]-morpholine (0.50 g, 1.8 mmol, Step E) in THF (40 mL) was added AcOH (1.97 mmol, 34.5 mmol) followed by zinc (9.1 g, 137 mmol). The mixture was stirred for 1 h and filtered on Celite®. The mixture was diluted with H2O, and aqueous NaHCO3 and the THF was evaporated. The residue was extracted with EtOAc, dried and evaporated to give the title intermediate. Calc'd for C15H24N2O:248.19.
Reaction SMILES: C[Si](C)(C)[N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Cl[CH:11]([C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:20])[CH3:12]>C(Cl)(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:12][CH:11]([C:7]1[N:3]=[CH:4][NH:5][CH:6]=1)[C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:20]
Reactant: Cc1cccc(C)c1C(C)Cl
Reactant: C[Si](C)(C)n1ccnc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1cccc(C)c1C(C)c1c[nH]cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 33 %

Procedure:
To a mixture of N-(trimethylsilyl)imidazole (1.4 g) and titanium tetrachloride (1.6 ml) in dry chloroform (20 ml) a solution of 1-chloro-1-(2,6-dimethylphenyl)ethane (1.7 g) in dry chloroform (10 ml) was added. After stirring for 5 h at room temperature the product mixture was poured onto water, washed with ether and neutralized with sodium hydrogen carbonate. Filtration and extraction with methylene chloride gave 4-[(α-methyl)-2,6-dimethylbenzyl]imidazole, yield 33%.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[N:27]1([C:33]2[CH:42]=[N:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]=2)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:30]2[CH2:31][CH2:32][N:27]([C:33]3[CH:42]=[N:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=3)[CH2:28][CH2:29]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: c1ccc2nc(N3CCNCC3)cnc2c1
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3cnc4ccccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-piperazin-1-yl-quinoxaline
Reaction SMILES: [NH2:1][C@H:2]([C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)[CH2:3][C:4](O)=[O:5].CO>C1COCC1>[NH2:1][C@H:2]([C:7]1[CH:8]=[CH:9][C:10]([Br:13])=[CH:11][CH:12]=1)[CH2:3][CH2:4][OH:5]
Reactant: N[C@@H](CC(=O)O)c1ccc(Br)cc1
Solvent: CO
Solvent: C1CCOC1
Product: N[C@@H](CCO)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65.5 %

Procedure:
Borane-tetrahydrofuran complex (71.7 mL, 71.70 mmol) was added dropwise to a stirred suspension of (S)-3-amino-3-(4-bromophenyl)propanoic acid (3.5 g, 14.34 mmol) in THF (80 mL) at 0° C. over a period of 30 minutes under nitrogen. The resulting suspension was stirred at 0° C. for 30 minutes then at 22° C. for 5 hours. The reaction mixture was added portionwise to methanol (250 mL). The solution was stirred at room temperature for 24 hours. The mixture was concentrated, redissolved in methanol (250 mL) and reconcentrated (this process was repeated three times). The residue was dissolved in DCM (75 mL) and washed with 1N NaOH (50 mL). The aqueous layer was extracted with DCM (3×100 mL) and the extracts combined with the organic layer. The combined organics were washed with saturated brine (50 mL), dried over MgSO4 and concentrated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 2 to 6% MeOH/ammonia in DCM. Pure fractions were evaporated to dryness to afford (S)-3-amino-3-(4-bromophenyl)propan-1-ol (2.160 g, 65.5%) as a colourless gum.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>C1COCC1.O>[CH2:17]([O:16][C:14]([N:4]1[CH2:5][CH2:6][C@@H:2]([OH:1])[CH2:3]1)=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O[C@@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CC[C@@H](O)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a stirred mixture of (R)-3-hydroxypyrrolidine (4.35 g, 50 mmol) in THF (50 mL) and aqueous sodium carbonate (10.6 g, 100 mmol in 50 mL water) cooled to 0° C. was added a solution of benzyl chloroformate in THF (60 mmol, 8.6 mL in 10 mL THF) over a period of 5-10 min. After stirring at 0° C. for 2 h, the reaction mixture was diluted with 200 mL water and extracted with methylene chloride (3×100 mL). The combined extracts were washed with 1N sulfuric acid (3×75 mL) followed by brine solution (3×50 mL). This extract was then dried over anhydrous sodium sulfate and the solvent evaporated to give a light yellow oil (10.5 g, 95% yield) which was used for the next reaction without any purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)cc1
Solvent: CO
Product: Nc1ccc(OCc2cccc(F)c2)cc1
Reaction time: 17 h

Procedure:
3 g (12.1 mmol) of 1-(3-fluorobenzyloxy)-4-nitro-benzene is dissolved in 125 ml of methanol. 150 mg of Pt 5% on charcoal is added and hydrogenation done under normal pressure for about 17 h. The catalyst is filtered and the solution evaporated to yield 2.51 g (95%) of crude brownish material. MS: m/e=218.4 (M++H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[S:10])[NH2:9].Cl[CH2:12][C:13](=O)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C([O-])(O)=O.[Na+].C(=O)=O>C1COCC1.CCOC(C)=O>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][C:13]1[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[OH:1])[S:10][CH:12]=1)[CH3:19]
Reactant: NC(=S)c1ccccc1O
Reactant: CCOC(=O)CC(=O)CCl
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)Cc1csc(-c2ccccc2O)n1
Yield: 92.6 %

Procedure:
A stirred solution of 2-hydroxybenzenecarbothioamide 3a (5.36 g, 35.0 mmol), ethyl 4-chloroacetoacetate (6.34 g, 38.5 mmol) in dry THF (70 mL) was heated to reflux under nitrogen for 2.5 days. At ambient temperature, the mixture was diluted with EtOAc (200 mL), then cautiously treated with saturated aq. NaHCO3 (40 mL), and followed by adding solid NaHCO3 in small portions until CO2 evolution ceased. The organic layer was separated, washed with brine (40 mL×2), dried over MgSO4, and filtered. After concentration in vacuo, the oily residue was chromatographed on silica gel gradient EtOAc/CH2Cl2 :0-4%) to provide 4a (8.53 g, 93%) as a white solid, which was recrystallized from toluene/hexane at -30° C. mp 35.5-36.5° C.; IR (neat) 3120, 1740, 480, 1225 cm-1 ; 1H NMR (DMSO-d6) δ1.15 (3H, t, J=7.1 Hz, CH3), 3.84 (2H, t, CH2), 4.07 (2H, q, J=7.1 Hz, CH2), 6.89 (1H, S, J=7.8 Hz, Ar), 6.97 (1H, d, J=7.8 Hz, Ar), 7.26 (1H, t, J=7.8 Hz, Ar), 7.48 (1H, s, 7.93 (1H, d, J=7.8 Hz, Ar, 11.29 (1H, s, OH); FABMS m/z 263 (M30 ), 264 (M+ +1); Anal. Calcd for C13H13NO3S: C, 59.30; H, 4.98; N, 5.32. Found: C, 59.16; H, 4.97; N, 5.50.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:11]=[C:10]([C:21]([F:24])([F:23])[F:22])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:25]([NH:29][S:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[CH:38]=[C:37]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=4)[CH:11]=[C:10]([C:21]([F:22])([F:23])[F:24])[N:9]=3)[CH:3]=2)[CH:36]=[CH:35][CH:34]=1)(=[O:32])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-c2cccc(Br)c2)n1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)c2)c1

Procedure:
3′-[4-(4-Chloro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide was prepared from 2-(3-bromo-phenyl)-4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidine (example E.4) (0.41 g, 1.0 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.31 g, 1.2 mmol) according to the general procedure VI. Obtained as white foam (0.47 g), which was subsequently deprotected.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:31][CH2:30][CH2:29][C@H:9]1[C:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[CH:17]([OH:28])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:11])=[O:7])(C)(C)C.Cl.O1CCOCC1.[CH2:39]([N:46]=C=O)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[CH2:39]([NH:46][C:6]([N:8]1[CH2:31][CH2:30][CH2:29][C@H:9]1[C:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[CH:17]([OH:28])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:11])=[O:7])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C=NCc1ccccc1
Reactant: COc1ccc(OCC(O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(OCC(O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)NCc2ccccc2)cc1

Procedure:
By the same procedure as in Example 21-B), (2S)-1-[N-(t-butoxycarbonyl)-L-prolyl]-2-[1-hydroxy-2-(4-methoxyphenoxy) ethyl]pyrrolidine (722 mg) was treated with 4N hydrochloric acid/1,4-dioxane, followed by reaction with benzylisocyanate (0.21 ml) to give 596 mg of the title compound as crystals. C) (2S)-1-(N-Benzylaminocarbonyl-L-prolyl)-2-(4-methoxyphenoxyacetyl)pyrrolidine
Reaction SMILES: C(OC([N:6]1[CH:10]=[C:9]([C:11]2[C:12]3[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:13]=3[N:14]=[CH:15][N:16]=2)[CH:8]=[N:7]1)C)C.Cl.[OH-].[Na+]>C1COCC1.O>[NH:6]1[CH:10]=[C:9]([C:11]2[C:12]3[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:13]=3[N:14]=[CH:15][N:16]=2)[CH:8]=[N:7]1
Reactant: CCOC(C)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.9 %

Procedure:
A solution of crude Suzuki coupling product (15) in THF (22 mL) was treated with water (108 mL) and a solution of 10% aqueous HCl prepared by mixing 19.6 mL of concentrated HCl with 64 mL of H2O at room temperature. The resulting reaction mixture was stirred at room temperature for 4-6 h. When TLC and HPLC showed the de-protection reaction was deemed complete, a 30% aqueous sodium hydroxide (NaOH) solution prepared by dissolving 10.4 g of NaOH in 21.0 mL of H2O was added slowly to the reaction mixture while maintaining the temperature below 25° C. The solid gradually dissolved and re-precipitated after 10 min. The mixture was stirred at room temperature for 1-2 h before the solids were collected by filtration and washed with H2O (50 mL). The wet cake was transferred to a 250 mL three-necked flask and treated with acetonitrile (MeCN, 112 mL) at room temperature. The mixture was heated to reflux for 2 h before being cooled gradually to room temperature and stirred at room temperature for 1 h. The solids were collected by filtration, washed with MeCN (36 mL) and dried at 40-45° C. in a vacuum oven to afford 4-(1H-pyrazol-4-yl)-7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (5, 15.3 g, 20.7 g theoretical, 73.9% yield) as white crystalline solids (99.4 area % by HPLC), which was found to be identical in every comparable aspect to the material made from Method A, B, and C.
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:8]=[CH:9][C:10]2[NH:16][C:15]3[N:17]=[C:18]([C:21]([F:24])([F:23])[F:22])[CH:19]=[CH:20][C:14]=3[CH2:13][N:12]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:11]=2[CH:39]=1)([CH3:6])[C:3](O)=[O:4].[CH:40]([NH2:43])([CH3:42])[CH3:41]>>[CH:40]([NH:43][C:3](=[O:4])[C:2]([CH3:6])([C:7]1[CH:8]=[CH:9][C:10]2[NH:16][C:15]3[N:17]=[C:18]([C:21]([F:23])([F:22])[F:24])[CH:19]=[CH:20][C:14]=3[CH2:13][N:12]([S:25]([C:28]3[CH:29]=[CH:30][C:31]([O:34][C:35]([F:38])([F:36])[F:37])=[CH:32][CH:33]=3)(=[O:26])=[O:27])[C:11]=2[CH:39]=1)[CH3:1])([CH3:42])[CH3:41]
Reactant: CC(C)N
Reactant: CC(C)(C(=O)O)c1ccc2c(c1)N(S(=O)(=O)c1ccc(OC(F)(F)F)cc1)Cc1ccc(C(F)(F)F)nc1N2
Product: CC(C)NC(=O)C(C)(C)c1ccc2c(c1)N(S(=O)(=O)c1ccc(OC(F)(F)F)cc1)Cc1ccc(C(F)(F)F)nc1N2

Procedure:
The title compound was prepared from 2-methyl-2-[6-{[4-(trifluoromethoxy)phenyl]sulfonyl}-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-8-yl]propanoic acid (Example 382) and isopropylamine using the procedure described in Example 516 to afford the title compound; Mass Spectrum: m/e=617 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[S:5][C:6]=1[NH:7][C:8](=[O:14])[CH:9]([CH3:13])[CH2:10][S:11][CH3:12].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:28][CH3:29].O>CN(C)C=O>[Cl:1][C:2]1[N:3]=[C:4]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[S:5][C:6]=1[N:7]([CH2:28][CH3:29])[C:8](=[O:14])[CH:9]([CH3:13])[CH2:10][S:11][CH3:12]
Reactant: CCI
Reactant: CSCC(C)C(=O)Nc1sc(-c2cccnc2)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(C(=O)C(C)CSC)c1sc(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a dry 50 ml round bottom flask equipped with magnetic stirrer, addition funnel, and nitrogen inlet was charged 1.0 g (3.05 mmoles) of N-(4-chloro-2-(pyridin-3-yl)-1,3-thiazol-5-yl)-2-methyl-3-(methylthio)propanamide and 10 mLs of anhydrous N,N-dimethyl formamide. To the resulting solution was then added 1.1 g (3.36 mmoles) of cesium carbonate powder in one portion, followed by the dropwise addition of 0.523 g (3.36 mmoles) of iodoethane in 5 mLs of anhydrous N,N-dimethyl formamide. The heterogeneous mixture was stirred at ambient temperature for 12 hours. Analysis of an aliquot indicated incomplete reaction. An additional 100 ul of iodoethane was added and the reaction was heated at 60° C. for 3 hours, then poured into 200 mLs of water and extracted with methylene chloride (3×100 mLs). The combined organic extracts were washed with water (100 mLs), saturated aqueous sodium chloride solution (100 mLs) dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum on a rotary evaporator. The crude product was purified by silica gel flash chromatography, eluting with a gradient of 100% hexane to 100% ethyl acetate over 20 minutes to yield a yellow oil which crystallized upon standing (0.38 g, 35%): mp 80-81° C.; 1H NMR (400 MHz, CDCl3) δ 9.12 (d, J=1.9 Hz, 1H), 8.72 (dd, J=4.8, 1.4 Hz, 1H), 8.22 (ddd, J=8.0, 2.2, 1.8 Hz, 1H), 7.43 (ddd, J=8.0, 4.8, 0.6 Hz, 1H), 4.03-3.80 (m, 1H), 3.80-3.59 (m, 1H), 2.97-2.68 (m, 2H), 2.60-2.39 (m, 1H), 2.03 (s, 3H), 1.30-1.16 (m, 6H); 13C NMR (101 MHz, DMSO-d6) δ 175.66, 162.63, 151.89, 147.14, 138.19, 133.49 133.23, 128.58, 123.90, 44.81, 38.94, 37.93, 18.16, 16.83, 12.90.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[CH:14]1([CH2:17][NH2:18])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:14]1([CH2:17][NH:18][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=2)[CH2:16][CH2:15]1
Reactant: NCC1CC1
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(NCC2CC2)cc1C(F)(F)F
Temperature: 20 °C
Yield: 99.1 %

Procedure:
A mixture of 4-fluoro-2-(trifluoromethyl)benzonitrile (9.45 g, 50 mmol), 1-cyclopropylmethanamine (5.0 g, 70 mmol), and potassium carbonate (10 g) was stirred for 12 h in acetonitrile (50 mL) at 55° C. The mixture was cooled to 20° C., filtered, and the filter-cake was washed with acetonitrile (3×25 mL). The filtrate was concentrated under vacuum to obtain 11.9 g (99%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J=8.6 Hz, 1H), 6.83 (d, J=2.4 Hz, 1H), 6.65 (dd, J=8.6, 2.4 Hz, 1H), 4.62 (bs, 1H), 3.02 (d, J=7.1 Hz, 2H), 1.09 (m, 1H), 0.61 (m, 2H), 0.27 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:24]1([C:30]#[CH:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:24]1([C:30]#[C:31][C:2]2[CH:16]=[CH:15][C:5]3[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=3[CH:3]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCNC(=O)Nc1nc2ccc(Br)cc2s1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1nc2ccc(C#Cc3ccccc3)cc2s1
Yield: 8 %

Procedure:
A mixture of 1-(6-bromo-2-benzothiazolyl)-3-ethylurea, Pd(PPh3)2Cl2, triethylamine, and phenylacetylene in 1 mL of anhydrous DMF was reacted according to the procedure of Example 213 to give 0.008 g (8%) of the desired compound. LC/MS 322 (M+1); LC retention time 3.65 min.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[C:8]([Br:10])[O:7][C:6]=1[CH2:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=[O:4].[Li+].[OH-].C1COCC1>O>[Br:10][C:8]1[O:7][C:6]([CH2:11][NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:5]([C:3]([OH:4])=[O:2])[CH:9]=1
Reactant: COC(=O)c1cc(Br)oc1CNCc1ccc(OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CNCc2oc(Br)cc2C(=O)O)cc1
Yield: 100.1 %

Procedure:
A solution of 5-bromo-2-[(4-methoxy-benzylamino)-methyl]-furan-3-carboxylic acid methyl ester (643.8 mg, 1.82 mmol) and LiOH (115 mg, 2.74 mmol) in 1:1 THF:H2O (30 mL) is refluxed for 3 hours. The solvent is evaporated in vacuo to afford the title compound (620 mg, 99%) which is used in the next step without further purification.