Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:4]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.[N+](C1C=CC([C:30]([O-])=[O:31])=CC=1)([O-])=O>ClCCl>[CH:30]([NH:1][CH2:2][C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=2)[C:4]=1[C:15]1[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=1)=[O:31]
Reactant: NCc1[nH]nc(-c2ccc(F)cc2)c1-c1ccncc1
Reactant: O=C([O-])c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: O=CNCc1[nH]nc(-c2ccc(F)cc2)c1-c1ccncc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 5-aminomethyl-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole (Example C-1) (8.04 g, 30 mmol) in 120 mL dichloromethane was added p-nitrophenylformate (6.01 g, 36 mmol) as a solid. The suspension was stirred for 24 h at room temperature and the solvents removed under reduced pressure. The residue was triturated with ether and filtered to obtain the desired 5-(N-formylaminomethyl)-4-(4-pyridyl)-3-(4-fluorophenyl)pyrazole derivative as a white solid: MS (M+H): 297 (base peak).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[OH-:6].[K+].Cl[C:9](Cl)(Cl)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17].Cl>O>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][C:9]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:6]
Reactant: Clc1ccccc1CC(Cl)(Cl)Cl
Reactant: [OH-]
Reactant: CCCCO
Agent: Cl
Agent: [K+]
Solvent: O
Product: CCCCOC(=O)Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Forty ml. of butanol was added to 9.2 g. of potassium hydroxide, which contained about 14% water, and was stirred at ambient temperature for 1 hour. To the mixture was added in one portion, 4 g. of 1,1,1-trichloro-2-(2-chlorophenyl)ethane. The mixture was heated to reflux and stirred at that temperature for 6 hours, and was cooled overnight to ambient temperature. It was then poured into 125 ml. of 1 N hydrochloric acid and stirred at ambient temperature for 30 minutes. The layers were then separated, and the aqueous layer was washed twice with about 60 ml. portions of diethyl ether. The organics were combined, and washed with two 25 ml. portions each of 10% sodium bicarbonate solution, water, and saturated sodium chloride solution. The washed organic portion was then dried over sodium sulfate, filtered and evaporated under vacuum to obtain 3.23 g. of crude product, which was found to be 87.6% pure by chromatography. A 2.5 g. portion of the above was distilled at 135° and 8 torr to obtain 1.9 g. of purified product, 97.0% pure by chromatography.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]#[N:7])(=[O:4])=[O:3].[C:8](=O)([O-])[O-].[K+].[K+].[CH2:14]1[O:22][C:21]2[CH:20]=[CH:19][C:18]([N:23]=[C:24]=[S:25])=[CH:17][C:16]=2[O:15]1.CI>CC(C)=O>[O:22]1[C:21]2[CH:20]=[CH:19][C:18]([NH:23][C:24]([S:25][CH3:8])=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[C:6]#[N:7])=[CH:17][C:16]=2[O:15][CH2:14]1
Reactant: CS(=O)(=O)CC#N
Reactant: O=C([O-])[O-]
Reactant: S=C=Nc1ccc2c(c1)OCO2
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CSC(Nc1ccc2c(c1)OCO2)=C(C#N)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 65.4 %

Procedure:
A solution of methanesulfonylacetonitrile (2.85 g, 23.9 mmol) in dry acetone (50 ml) was stirred while dry potassium carbonate (6.61 g, 47.8 mmol) and 3,4-methylenedioxyphenyl isothiocyanate (4.50 g, 25.1 mmol) were added. The resulting mixture was stirred at room temperature under nitrogen for 20 h. Excess of potassium carbonate was filtered off, methyl iodide (4.43 ml, 71.8 mmol) was added to the filtrate, and stirring was continued for 4 h at 50° C. The mixture was evaporated and the residue was dissolved in dichloromethane and extracted with water and brine. The organic phase was dried over magnesium sulphate, filtered and evaporated to afford 4.88 g (65%) of the title compound as golden brown crystals. Mp 168-170° C.1H NMR (200 MHz, DMSO-d6): δ=2.30 (s, 3H), 3.33 (s, 3H), 6.06 (s, 2H), 6.79 (dd, 1H), 6.94 (d, 1H), 6.97 (d, 1H), 9.98 (br s, 1H).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N:17]1CCO[CH2:19][CH2:18]1.O[N:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[C:1]1([C:7]2[N:8]=[CH:9][C:10]([C:13]([NH:17][CH2:18][CH2:19][NH:24][C:28]3[CH:27]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:15])=[CH:11][N:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: On1nnc2ccccc21
Reactant: CN1CCOCC1
Reactant: O=C(O)c1cnc(-c2ccccc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(NCCNc1ccccc1)c1cnc(-c2ccccc2)nc1
Reaction time: 8 h
Yield: 72.3 %

Procedure:
To a stirring mixture consisting of 2-phenylpyrimidine-5-carboxylic acid (Compound 17; synthesis described in Example 1, Steps 1-3 of WO 2007/041634 to Aldous et al., entitled “Pyrimidine Amide Compounds as PGDS Inhibitors”; 200 mg) in N,N-dimethylformamide (15 mL) was added successively N-methylmorpholine (Aldrich, 0.33 mL), N-phenethylenediamine (Acros, 173 mg), 1-hydroxybenzotriazole (209 mg), and 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (EDAC, 227 mg). The reaction mixture was stirred overnight under an argon atmosphere and was subsequently concentrated slightly under reduced pressure. The concentrate was partitioned between ethyl acetate (200 mL) and saturated aqueous sodium bicarbonate (200 mL). The layers were separated and the organic phase was washed twice with water (2×200 mL) and once with brine solution (200 mL), was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give an off-white solid. Trituration with a small amount of absolute ethanol at room temperature, collection by vacuum filtration, and suction drying afforded the title compound as a white powder (0.230 g, 72.3% yield); 1H-NMR (300 MHz; CDCl3) δ 9.13 (s, 2H), 8.51 (dd, 2H), 7.61-7.51 (m, 3H), 7.21 (t, 2H), 6.79 (t, 1H), 6.70 (d, 2H), 6.57 (broad m, 1H), 3.99 (broad m, 1H), 3.75 (m, 2H), 3.48 (t, 2H); MS (APCl+) m/z 319.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[O:19][C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:5]1.C[CH2:27][O:28]CC.C(OCC)=O>CO>[OH:28][CH:27]=[C:5]1[C:6]2([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]2)[O:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:4]1=[O:3]
Reactant: CCOCC
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1ccccc1O2
Agent: [H-]
Agent: [Na+]
Solvent: CCOC=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ccccc1C(=O)C2=CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
NaH (1.89 g, 47.3 mmol) was added in small portions to a mixture of tert-butyl 4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (3.0 g, 9.5 mmol), Et2O (75 mL), and MeOH (120 μL) at rt. The mixture was allowed to stir for 1 h before ethyl formate (9.2 mL, 110 mmol) was added dropwise. The mixture was allowed to stir at 25° C. overnight before it was quenched with 1M aqueous HCl. The layers were separated and the aqueous layer was extracted with ethyl acetate (3×). The combined organics were washed with brine, dried over sodium sulfate, and concentrated in vacuo. Column chromatography (0-100% ethyl acetate in hexanes) provided tert-butyl 3-(hydroxymethylene)-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (1.2 g, 36%) as a light yellow solid. ESI-MS m/z calc. 345.2. found 246.2 (M+1-Boc)+; Retention time: 2.62 minutes (4 min run). 1H NMR (400 MHz, CDCl3) δ 15.13 (d, J=8.3 Hz, 1H), 7.93 (d, J=8.1 Hz, 1H), 7.88 (dd, J=7.8, 1.5 Hz, 1H), 7.50-7.44 (m, 1H), 7.06 (t, J=7.5 Hz, 1H), 6.96 (d, J=8.2 Hz, 1H), 4.10-3.95 (m, 2H), 3.25-3.15 (m 2H), 2.15 (d, J=12.7 Hz, 2H), 1.80-1.66 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[Cs+].[Cs+].Cl[C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[N:14]([S:29]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=3)(=[O:31])=[O:30])[C:15]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=4)[N:19]([CH3:28])[CH:18]=3)=[CH:16][C:9]=12.C1(P(C2CCCCC2)C2C=CC=CC=2[C:52]2C=CC=C[C:53]=2[N:58](C)[CH3:59])CCCCC1>COCCOC.N1CCOCC1>[N:58]1([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([S:29]([C:32]4[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=4)(=[O:31])=[O:30])[C:15]([C:17]4[C:25]5[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=5)[N:19]([CH3:28])[CH:18]=4)=[CH:16][C:9]=23)[CH2:59][CH2:1][O:4][CH2:52][CH2:53]1
Reactant: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: COc1ccc2c(c1)c(-c1cc3c(Cl)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: C1COCCN1
Product: COc1ccc2c(c1)c(-c1cc3c(N4CCOCC4)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Temperature: 80 °C

Procedure:
Into a tube containing cesium carbonate (153 mg) was added (i) a solution of 4-chloro-2-(5-methoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine [50 mg, Reference Example 13(i)] in 1,2-dimethoxyethane (1 mL), (ii) tris-(dibenzylideneacetone)-dipalladium(0) (15 mg) in 1,2-dimethoxyethane (0.5 mL), (iii) 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)-biphenyl (42 mg) in 1,2-dimethoxyethane (0.5 mL) and (iv) morpholine (30 mg). This mixture was heated under agitation at 80° C. for 15 hours and then filtered on a silica plug that was then washed with dichloromethane and methanol (1 mL each). The combined filtrate plus washings were evaporated using a centrifuge evaporator. The residue was dissolved in dimethylsulfoxyde (1 mL) and then subjected to LC-MS triggered purification (injections corresponding to 20 mg crude compound) affording 4-(morpholine-4-yl)-2-(5-methoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine which was resuspended in methanol (2 mL) and magnesium turnings (89 mg, 15 equivalents from the mass measured after evaporation of the chromatographic solvent) were added. The suspension was then agitated for 15 hours at room temperature and then filtered on Celite. The filtrate was evaporated and the residue was solubilized in dimethylsulfoxide and subjected to LC-MS triggered purification according affording the title compound. LC-MS: METHOD C: RT=3.27 minutes, 363.3[M+H]+.
Reaction SMILES: Cl.C([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:22]=3[F:28])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:29][CH3:30])C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[Br:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:14]2[C:13]3[C:18](=[CH:19][C:10]([OH:9])=[C:11]([O:29][CH3:30])[CH:12]=3)[N:17]=[CH:16][N:15]=2)=[C:22]([F:28])[CH:23]=1
Reactant: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCc1ccccc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1O
Yield: 81.4 %

Procedure:
A solution of 7-benzyloxy-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline hydrochloride (9.4 g, 19.1 mmol) in TFA (90 ml) was heated at reflux for 50 minutes. The mixture was allowed to cool and was poured on to ice. The resulting precipitate was collected by filtration and dissolved in methanol (70 ml). The solution was adjusted to pH 9–10 with concentrated aqueous ammonia solution. The mixture was concentrated to half initial volume by evaporation. The resulting precipitate was collected by filtration, washed with water and then ether, and dried under vacuum to give 4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (5.66 g, 82%).
Reaction SMILES: Br.COC(=O)[NH:5][CH2:6][C@H:7]([CH2:12][C:13](=[O:23])N[C@H](C1C=CC=CC=1)C)[CH2:8][CH:9]([CH3:11])[CH3:10].[OH-:25].[Na+]>O>[CH3:11][CH:9]([CH2:8][C@H:7]([CH2:6][NH2:5])[CH2:12][C:13]([OH:23])=[O:25])[CH3:10]
Reactant: [OH-]
Reactant: COC(=O)NC[C@H](CC(=O)N[C@@H](C)c1ccccc1)CC(C)C
Agent: Br
Agent: [Na+]
Solvent: O
Product: CC(C)C[C@H](CN)CC(=O)O
Temperature: 25 °C
Yield: 90 %

Procedure:
A flask was loaded with 47% HBr (12 ml), water (6 ml), and compound 26 (6 g), and then was heated to reflux for 3 hours. The solution was cooled to room temperature, and water (12 ml) was added. An aqueous 47% sodium hydroxide solution was added to obtain pH of 3. The solution was then extracted twice with isobutanol (15 ml), the combined organic layers were evaporated and fresh isobutanol was added (15 ml). Bu3N (3.8 g) was added. The mixture was cooled to 2° C. for 1 hour, then (S)-Pregabalin was filtered, and washed with of iso-butanol (3 ml). After drying at 55° C. under vacuum, (S)-Pregabalin was obtained as white crystals in a 90% yield.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[F:7][C:8]([F:18])([F:17])[C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.[C:19]1([NH:25][CH2:26][CH2:27][OH:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.S(=O)(=O)(O)N>>[OH:28][CH2:27][CH2:26][N:25]([CH:13]([C:12]1[CH:15]=[CH:16][C:9]([C:8]([F:18])([F:17])[F:7])=[CH:10][CH:11]=1)[C:5]#[N:6])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: C[Si](C)(C)C#N
Reactant: OCCNc1ccccc1
Agent: NS(=O)(=O)O
Product: N#CC(c1ccc(C(F)(F)F)cc1)N(CCO)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Trimethylsilyl cyanide (723 μL) was added to a mixture of 4-(trifluoromethyl)benzaldehyde (CAS #455-19-6, 1 g), N-phenylethanolamine (870 mg) and sulfamic acid (28 mg), and the mixture was stirred at room temperature for 20 hours. The reaction solution was partitioned with water and chloroform. The organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent:heptane:ethyl acetate=9:1→1:1) to obtain 775 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[N:3]=1.[F:14][C:15]1[C:24]([CH:25]=O)=[CH:23][C:22]([O:27][CH3:28])=[C:21]2[C:16]=1[CH2:17][CH2:18][CH2:19][O:20]2.C[Si]([C:33]#[N:34])(C)C.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3]>C1COCC1>[F:14][C:15]1[C:24]([CH:25]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([C:4]3[N:3]=[C:2]([CH3:1])[O:6][N:5]=3)=[CH:8][CH:9]=2)[C:33]#[N:34])=[CH:23][C:22]([O:27][CH3:28])=[C:21]2[C:16]=1[CH2:17][CH2:18][CH2:19][O:20]2
Reactant: COc1cc(C=O)c(F)c2c1OCCC2
Reactant: Cc1nc(-c2ccc(N)cc2)no1
Reactant: C[Si](C)(C)C#N
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Product: COc1cc(C(C#N)Nc2ccc(-c3noc(C)n3)cc2)c(F)c2c1OCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After adding 940 mg of 4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamine, 1.125 g of 5-fluoro-8-methoxychromane-6-carbaldehyde, 1 g of MS3A and 1.43 ml of trimethylsilyl cyanide to a solution of 330 mg of Yb(OTf)3 in 20 ml of THF under a nitrogen atmosphere, the mixture was stirred overnight at room temperature. The reaction mixture was filtered through celite, and the celite was washed with ethyl acetate. The organic layer was concentrated under reduced pressure to give (5-fluoro-8-methoxychroman-6-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]acetonitrile (crude product).
Reaction SMILES: C[Al](C)C.CCCCCC.[C:11]123[CH2:24][S:21](=[O:23])(=[O:22])[NH:20][C@@H:12]1[CH2:13][CH:14]([C:17]2([CH3:19])[CH3:18])[CH2:15][CH2:16]3.[NH2:25][CH2:26][C:27]([O-])=[O:28].CO[2H]>C1(C)C=CC=CC=1>[NH2:25][CH2:26][C:27]([C:12]12[NH:20][S:21](=[O:23])(=[O:22])[CH2:24][C:11]31[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:13]2)[CH2:15][CH2:16]3)=[O:28]
Reactant: CC1(C)C2CCC13CS(=O)(=O)N[C@@H]3C2
Reactant: NCC(=O)[O-]
Agent: C[Al](C)C
Agent: [2H]OC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC1(C)C2CCC13CS(=O)(=O)NC3(C(=O)CN)C2
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 158.7 %

Procedure:
Over 20 minutes, 2 M trimethylaluminum in hexane (40 ml, 1.2 eq) was added to (2R)-bornane-10,2-sultam (15.7 g, 1.1 eq) in toluene (110 ml) at 0° C., then left for 30 minutes. Ethyl N-(diphenylmethylene)[1,2-13C2, 15N, 2,2-2H2]glycinate (18.1 g, 66.4 mmol) in toluene (10 ml) was added and the reaction stirred overnight. Heating to 50° C. for 3-4 hours drove the reaction to completion. Workup was effected by cooling the reaction in ice and carefully adding MeOD (20 ml). After 1 hour, D2O (30 ml) was carefully added. Filtering, extracting with ethyl acetate (2×250 ml), drying over MgSO4 and purifying by silica gel flash chromatography (Hexane: Ethyl Acetate 10:1 to 1:1) gave (2R)-N-(diphenylmethylene)[1,2-13C2, 15N, 2,2-2H2]glycylbornane-10,2-sultam (28.7 g, 99% yield) as an orange oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([N:12]([CH2:24][CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Cl:23])[CH:17]=3)=[O:14])[CH2:9]2)=[CH:4][CH:3]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:23][C:18]1[CH:17]=[C:16]([NH:15][C:13](=[O:14])[N:12]([CH:8]2[CH2:9][C:10]3[CH:11]=[C:2]([NH:1][S:35]([CH3:34])(=[O:37])=[O:36])[CH:3]=[CH:4][C:5]=3[CH2:6][CH2:7]2)[CH2:24][CH2:25][CH2:26][N:27]2[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]2)[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: CN1CCN(CCCN(C(=O)Nc2ccc(F)c(Cl)c2)C2CCc3ccc(N)cc3C2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(CCCN(C(=O)Nc2ccc(F)c(Cl)c2)C2CCc3ccc(NS(C)(=O)=O)cc3C2)CC1
Reaction time: 3 h
Yield: 85.7 %

Procedure:
To a solution of 1-(7-amino-1,2,3,4-tetrahydro-naphthalen-2-yl)-3-(3-chloro-4-fluoro-phenyl)-1-[3-(4-methyl-piperazin-1-yl)-propyl]-urea (from Preparative Example 27, 0.035 g, 0.074 mmol) in CH2Cl2 (0.2 mL) at 0° C. were added methanesulfonyl chloride (0.0058 mL, 0.074 mmol) and DIEA (0.039 mL, 0.22 mmol). The mixture was stirred from 0° C. to room temperature for 3 hours, then concentrated in vacuo, and the residue was purified by preparative HPLC to give 0.035 g (88%) of N-(7-{3-(3-chloro-4-fluoro-phenyl)-1-[3-(4-methyl-piperazin-1-yl)-propyl]-ureido}-5,6,7,8-tetrahydro-naphthalen-2-yl)-methanesulfonamide as a light yellow gum. 1H NMR (300 MHz, CD3OD): δ 7.59 (dd, 1H, J=6.6, 2.7 Hz), 7.30 (ddd, 1H, J=9.0, 4.2, 2.7 Hz), 7.14 (t, 1H, J=9.0 Hz), 7.08 (d, 1H, J=8.4 Hz), 7.04-6.98 (m, 2H), 4.30 (m, 1H), 3.66 (m, 8H), 3.46 (m, 2H), 2.99 (m, 6H), 2.90 (s, 3H), 2.11 (m, 4H). MS-ESI: 552.0 (M+H+).
Reaction SMILES: [OH:1][C:2]1C(=O)N2C(C3(CCCC3)OCC2)=N[C:3]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[CH2:22](O)CO>C1C=CC=CC=1.CCOCC.CC1C=CC(S(O)(=O)=O)=CC=1.O>[O:18]1[C:17]2([CH2:3][CH2:2][O:1][CH2:22]2)[O:19][CH2:20][CH2:21]1
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CCOC21CCCC1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Solvent: CCOCC
Product: C1CC2(CO1)OCCO2
Reaction time: 17 h
Yield: 80.1 %

Procedure:
A mixture of ethyl 3′-hydroxy-4′-oxo-6′,7′-dihydro-4′H-spiro[cyclopentane-1,9′-pyrimido[2,1-c][1,4]oxazine]-2′-carboxylate (15.79 g, 183.5 mmol), ethylene glycol (16.7 mL, 300 mmol) and cat. TsOH.H2O (100 mg) in benzene (100 mL) was heated at reflux using Dean-Stark trap. After 17 h, the reaction mixture was cooled, diluted with ether (150 mL), washed with sat. Na2CO3 and brine (50 mL each), dried (Na2SO4), filtered and concentrated to give yellow liquid. Distillation under reduced pressure afforded the title compound as a yellow liquid (19.13 g, 80%). 1H NMR (500 MHz, CDCl3) δ: 3.9.4 (2H, t, J=7.0 Hz), 3.94-3.90 (4H, m), 3.68 (2H, s), 2.09 (2H, t, J=7.0 Hz).
Reaction SMILES: [I:1][CH3:2].[Cl:3][C:4]1[N:5]=[CH:6][N:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH2:18])=[S:17])=[CH:11][C:10]=2[O:19][CH3:20])[CH:8]=1>C(O)C>[IH:1].[Cl:3][C:4]1[N:5]=[CH:6][N:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([S:17][CH3:2])=[NH:18])=[CH:11][C:10]=2[O:19][CH3:20])[CH:8]=1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(Cl)c1
Reactant: CI
Solvent: CCO
Product: COc1cc(NC(=N)SC)ccc1-n1cnc(Cl)c1
Product: I
Temperature: 70 °C
Yield: 109.4 %

Procedure:
Step A (5): Iodomethane (0.890 mL, 14.3 mmol) was added to a solution of 1-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)thiourea (3.85 g, 13.6 mmol) in absolute ethanol (100 mL). The resulting mixture was heated at 70° C. for 3 h. After cooling to rt, the reaction was concentrated in vacuo. The residual volatiles were removed in vacuo to afford methyl 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylcarbamimidothioate, hydroiodide (6.32 g, 109% yield) as a white solid. LC-MS (M+H)+ 297.1. 1H NMR (500 MHz, methanol-d4) δ ppm 7.86 (d, J=1.22 Hz, 1 H) 7.55 (d, J=8.24 Hz, 1 H) 7.40 (d, J=1.22 Hz, 1 H) 7.28 (d, J=2.14 Hz, 1 H) 7.08 (dd, J=8.39, 2.29 Hz, 1 H) 3.94 (s, 3 H) 2.76 (s, 3 H).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH2:26][CH2:27]O)(=[O:25])=[O:24])=[CH:19][CH:18]=2)[C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CS(Cl)(=O)=O>ClCCl>[CH:1]1([CH2:6][CH:7]([C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH:9]=2)[C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH:26]=[CH2:27])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(CCO)c1ccc(C(CC2CCCC2)c2cc3cccnc3[nH]2)cc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cccnc3[nH]2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
To a solution of (2-{4-[2-cyclopentyl-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)-ethyl]-benzenesulfonyl}-ethanol (prepared as in Example 91, 600 mg, 1.5 mmol) and triethylamine (0.42 ml, 3.0 mmol) in dichloromethane (15 mL) at 0° C. was added a solution of methanesulfonyl chloride (0.18 ml, 2.2 mmol) in dichloromethane. The mixture was stirred at 0° C. for 30 min. The reaction was quenched with a water (20 mL). The mixture was extracted with dichloromethane (2×50 mL), washed with brine (3×20 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 50% ethyl acetate/dichloromethane) afforded 2-[2-cyclopentyl-1-(4-ethenesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridine (380 mg, 66%) as a solid: LC/MS m/e calcd for C22H24N2O2S [M+H]+ 381.51, observed 381.0.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[NH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([N:18]=[CH:19][N:20]([CH3:22])[CH3:21])=[C:13]([Cl:23])[CH:12]=1>C(O)C>[Cl:17][C:15]1[CH:16]=[C:11]([N:10]=[CH:1][C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[OH:4])[CH:12]=[C:13]([Cl:23])[C:14]=1[N:18]=[CH:19][N:20]([CH3:22])[CH3:21]
Reactant: O=Cc1ccccc1O
Reactant: CN(C)C=Nc1c(Cl)cc(N)cc1Cl
Solvent: CCO
Product: CN(C)C=Nc1c(Cl)cc(N=Cc2ccccc2O)cc1Cl

Procedure:
A mixture of 3.7 g. of salicylaldehyde and 7.0 g. of N'-[4-amino-2,6-dichlorophenyl]-N,N-dimethylformamidine is heated neat at 80° C. for 18 hours. The mixture is cooled and ethanol is added to give crystals. The mixture is heated and then cooled to recrystallize the product. The product is collected, washed with cold ethanol then ether to give 9.0 g. of the product of the Example as yellow crystals, m.p. 113°-115° C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][C:16]1[C:21]([CH2:22][OH:23])=[CH:20][CH:19]=[CH:18][N:17]=1.CCN(CC)CC.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:31][S:32]([O:23][CH2:22][C:21]1[C:16]([O:15][C:3]2[CH:4]=[CH:5][C:6]3[N:7]([CH2:11][CH:12]4[CH2:13][CH2:14]4)[N:8]=[N:9][C:10]=3[C:2]=2[Br:1])=[N:17][CH:18]=[CH:19][CH:20]=1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cccnc1Oc1ccc2c(nnn2CC2CC2)c1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cccnc1Oc1ccc2c(nnn2CC2CC2)c1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(2-{[4-bromo-1-(cyclopropylmethyl)-1H-1,2,3-benzotriazol-5-yl]oxy}pyridin-3-yl)methanol (195) (1 g, 2.62 mmol, 1.0 equiv.) and Et3N (1.1 ml, 7.85 mmol, 3.0 equiv.) in DCM (13 ml) were cooled to 0° C., followed by MsCl (265 ul, 3.40 mmol, 1.3 equiv.), then stirred @ 0° C. for 1 hour. The reaction mixture then quenched with NaHCO3(sat) and extracted with DCM (2×40 ml). The combined DCM layer was washed with brine and dried over Na2SO4, filtered and concentrated down solvent. LRMS m/z (M+H) 486.8 and 488.8 found, 487.0 and 489.0 required.