Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[O:9])[NH:5][CH:6]=1.[C:17](O)(=[O:20])[C:18]#[CH:19].N1(C(N2C=CN=C2)=O)C=CN=C1>>[Br:1][C:2]1[NH:3][C:4]2[N:5]([CH:6]=1)[C:17](=[O:20])[CH:18]=[CH:19][C:7]=2[C:8](=[O:9])[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1
Reactant: C#CC(=O)O
Reactant: O=C(Cc1nc(Br)c[nH]1)c1ccc(F)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=C(c1ccc(F)cc1)c1ccc(=O)n2cc(Br)[nH]c12

Procedure:
The compound is prepared as described in example 6 with 446.0 mg (1.58 mmol) of 2-(4-bromo-1H-imidazol-2-yl)-1-(4-fluorophenyl)ethanone (example XXXII), 172.43 mg (2.36 mmol) of propiolic acid and 459.82 mg (2.84 mmol) of 1-(1H-imidazol-1-ylcarbonyl)-1H-imidazole.
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[C:5]([O:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20](O)=[O:21])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1.[NH2:30][CH2:31][CH2:32][C:33]#[N:34].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C1COCC1.CN(C=O)C>[C:31]([CH2:32][CH2:33][NH:34][C:20]([C:19]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1/[CH:11]=[CH:10]/[C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH:2]([F:1])[F:29])[C:5]=1[O:23][CH2:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:21])#[N:30]
Reactant: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)O)cccc1OC(F)F
Reactant: N#CCCN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)NCCC#N)cccc1OC(F)F

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 7A (80 mg, 0.189 mmol) with 3-aminopropanenitrile (14.56 mg, 0.208 mmol) in the presence of EDCI hydrochloride (72 mg, 0.378 mmol), DMAP (21 mg, 0.189 mmol) in a mixture of THF and DMF (1:1, 4 mL) to give 60 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.08 (s, 9H), 2.82-2.86 (m, 2H), 3.52-3.60 (m, 4H), 7.16 (t, J=73.5 Hz, 1H), 7.18-7.30 (m, 2H), 7.37-7.52 (m, 2H), 7.72-7.88 (m, 2H), 8.00-8.06 (m, 1H), 8.59 (br s, 1H); APCI-MS (m/z) 475.28 (MH)+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][CH2:17][CH3:18])(=[O:15])[CH3:14].[Br:19][C:20]1[CH:37]=[CH:36][C:23]([O:24][C:25]2[CH:35]=[CH:34][C:28]([O:29][CH:30]([CH3:33])[CH:31]=[O:32])=[CH:27][CH:26]=2)=[C:22]([F:38])[CH:21]=1.[NH4+].[Cl-]>CCOCC.CCCCCC>[CH2:17]([O:16][C:13](=[O:15])[CH2:14][CH:31]([OH:32])[CH:30]([O:29][C:28]1[CH:34]=[CH:35][C:25]([O:24][C:23]2[CH:36]=[CH:37][C:20]([Br:19])=[CH:21][C:22]=2[F:38])=[CH:26][CH:27]=1)[CH3:33])[CH3:18]
Reactant: CC(C=O)Oc1ccc(Oc2ccc(Br)cc2F)cc1
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CCOC(=O)CC(O)C(C)Oc1ccc(Oc2ccc(Br)cc2F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
A solution of 1.54 ml (11 mmol) of diisopropylamine in 20 ml of ether was cooled under N2 to -78° C. and 6.9 ml (11 mmol) of 1.6M n-butyllithium in hexane was slowly added. After 15 min of -78° C. 0.97 g (11 mmol) of ethyl acetate in 3 ml of ether was added dropwise. The resulting mixture was stirred at -78° C. for 15 min when a solution of 3.39 g (10 mmol) of 2-(4-(4-bromo-2-fluorophenoxy)phenoxy)propanaldehyde in 5 ml of ether was slowly added. The mixture was allowed to warm to room temperature, poured into aqueous NH4Cl and the aqueous phase separated and extracted with ether. The combined organic layers were dried over MgSO4 and evaporated to dryness and the residue purified by prep LC, eluting with 85:15 hexane:acetone. The resulting colorless oil was thoroughly dried to leave 2.99 g of product. Structure was confirmed by IR and NMR analysis. Calc. for C17H20BrFO5 : C, 53.41, H, 4.72. Found: C, 53.10, H, 4.66.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[CH:11][S:12][C:3]=12.[C:13]([O:17][C:18](=[O:28])[NH:19][C:20]1[S:21][C:22]([CH2:25][CH2:26][NH2:27])=[CH:23][N:24]=1)([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C>C(O)C>[C:13]([O:17][C:18](=[O:28])[NH:19][C:20]1[S:21][C:22]([CH2:25][CH2:26][NH:27][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]3[CH:10]=[CH:11][S:12][C:3]=23)=[CH:23][N:24]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)Nc1ncc(CCN)s1
Reactant: N#Cc1cnc2ccsc2c1Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ncc(CCNc2c(C#N)cnc3ccsc23)s1
Yield: 40.9 %

Procedure:
A stirred mixture of 7-chloro-thieno[3,2-b]pyridine-6-carbonitrile (47.8 mg, 0.25 mmol), [5-(2-amino-ethyl)-thiazol-2-yl]-carbamic acid tert-butyl ester (J Med Chem, 1992, 35, 3239-3246) (54.6 mg, 0.22 mmol), and triethylamine (0.04 ml, 0.28 mmol) in 3 ml of ethanol was heated to reflux for 17 hr. Ethanol was evaporated, and the residue was partitioned between dichloromethane and aqueous NaHCO3. The organic layer was washed with H2O, dried over MgSO4, filtered, and concentrated in vacuum. The resulting residue was purified by silica gel chromatography (MeOH/CH2Cl2/NH3=1/20/0.1) to give 36.1 mg (40%) of yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.49 (s, 1H), 7.82 (d, J=5.4 Hz, 1H), 7.52 (d, J=5.4 Hz, 1H), 7.18 (s, 1H), 5.32 (m, 1H), 4.08 (q, J=7.2 Hz, 2H), 3.20 (t, J=7.2 Hz, 2H), 1.55 (s, 9H); LC-MS (ESI) m/z 402.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][CH:3]=1.[C:9]([O-:12])([O-])=O.[K+].[K+]>[Cu]>[OH:12][CH2:9][C:3]1[CH:4]=[CH:5][C:6]([N:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]2=[O:8])=[N:7][CH:2]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cccc(=O)[nH]1
Agent: [Cu]
Agent: [K+]
Product: Cc1cccc(=O)n1-c1ccc(CO)cn1
Reaction time: 8 h

Procedure:
2-bromo(5-hydroxymethyl)pyridine (3.00 g, 15.95 mmol), 6-methylpyridone (2.08 g, 19.14 mmol), Copper (2.64, 19.14 mmol) and K2CO3 (0.635 g, 10.0 mmol) were heated at 140° C. for 3 hrs. Added CHC13 to reaction when still warm and let stirred overnight. Filterred the mixture through a frit, concentrated in vacuo and the residue was chromatographed (silica gel, 0-4% MeOH-EtOAc solution). Obtained the title compound as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][O:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([N:21]=[C:22]=[O:23])(=[O:20])=[O:19])=[O:11]>C(#N)C>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[NH:1][C:22]([NH:21][S:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]([O:9][CH3:8])=[O:11])(=[O:20])=[O:19])=[O:23]
Reactant: Nc1ncccn1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: CC#N
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1ncccn1
Temperature: 25 °C
Yield: 65.7 %

Procedure:
With stirring at ambient temperature, 1.0 g of 2-aminopyrimidine in 25 ml of anhydrous acetonitrile was added to 2.4 g of 2-methoxycarbonylbenzenesulfonylisocyanate. After stirring that mixture for 24 hours, the resultant precipitate was filtered off to yield 2.2 g of the desired compound which melted at 188°-192°. Its showing infrared absorption peaks at 1700, 1680 and 1580 cm-1 is consistent for N-[(pyrimidin-2-yl)aminocarbonyl]-2-methoxycarbonylbenzenesulfonamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:13][CH:12]2[CH2:11][N:10]([CH2:14][CH2:15][CH2:16][N:17]2[CH:22]=[C:21]([I:23])[C:20](=[O:24])[N:19](C(C4C=CC=CC=4)=O)[C:18]2=[O:33])[CH2:9]3)=[CH:4][CH:3]=1.CO>N>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:13][CH:12]2[CH2:11][N:10]([CH2:14][CH2:15][CH2:16][N:17]2[CH:22]=[C:21]([I:23])[C:20](=[O:24])[NH:19][C:18]2=[O:33])[CH2:9]3)=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)n1c(=O)c(I)cn(CCCN2CC3CC3(c3ccc(Cl)cc3)C2)c1=O
Agent: N
Solvent: CO
Product: O=c1[nH]c(=O)n(CCCN2CC3CC3(c3ccc(Cl)cc3)C2)cc1I
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.6 %

Procedure:
(1R,5S/1S,5R)-(1-{3-[1-(4-chlorophenyl)-3-azabicyclo[3.1.0]hex-3-yl]propyl}-5-iodo-3-(phenylcarbonyl)-2,4(1H,3H)-pyrimidinedione (Prep 80, 190 mg, 0.330 mmol) was dissolved in 3% ammonia in MeOH (4 ml, 5.55 mmol). The mixture was stirred at room temperature for 3 hours the solvent was then evaporated under vacuum and the crude purified by SPE Si cartridge (20 g) eluting with Toluene/acetone 80/20 to give an oil that was then loaded through SCX (5 g) cartridge to recover the title compound (130 mg, 0.276 mmol, 4.97% yield) as a light yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=2)[N:3]=1.[Cl:20][C:21]1[CH:26]=[C:25](B(O)O)[CH:24]=[CH:23][N:22]=1>>[Cl:20][C:21]1[CH:26]=[C:25]([C:2]2[N:3]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=3)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=2)[CH:24]=[CH:23][N:22]=1
Reactant: Fc1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1F
Reactant: OB(O)c1ccnc(Cl)c1
Product: Fc1ccc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)cc1F

Procedure:
The title compound was prepared from 2-chloro-6-(3,4-difluoro-phenyl)-4-trifluoromethyl-pyrimidine (example A.46) (1.5 g, 5.09 mmol) and commercially available 2-chloro-pyridine-4-boronic acid (0.96 g, 6.1 mmol) according to the general procedure IVb. Obtained as a light brown solid (0.51 g, 27%). MS (ISP) 372.0 [(M+H)+]; mp 151.5° C.
Reaction SMILES: [N:1]1([CH2:6][C@H:7]2[CH2:12][CH2:11][C@H:10]([NH:13]C(=O)OC(C)(C)C)[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:21].O>C1COCC1>[ClH:21].[ClH:21].[N:1]1([CH2:6][C@H:7]2[CH2:8][CH2:9][C@H:10]([NH2:13])[CH2:11][CH2:12]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CN2CCCC2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: N[C@H]1CC[C@H](CN2CCCC2)CC1
Temperature: 65 °C

Procedure:
To a solution of tert-butyl (trans-4-(pyrrolidin-1-ylmethyl)cyclohexyl)carbamate (1.28 g, 4.53 mmol) in THF (15 mL) was added aqueous 6 N HCl (6 mL) and water (6 mL) and the reaction mixture was heated at 65° C. for 3 h. The reaction mixture was cooled to room temperature and concentrated to afford the desired product (1.2 g, >99%) as an off-white solid. ESI MS m/z 183 [C11H22FN2+H H]+
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[N:13]([CH2:14][CH3:15])[N:12]=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH:10]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([N:36]([CH3:44])[CH2:37][CH2:38][C:39]([O:41]CC)=[O:40])=[O:35])=[CH:30][CH:29]=1>>[CH:1]1([CH:7]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]([N:36]([CH3:44])[CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:35])=[CH:32][CH:33]=2)[C:9]2[N:13]([CH2:14][CH3:15])[N:12]=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: CCn1nc(-c2ccc(OC(F)(F)F)cc2)cc1C(O)C1CCCCC1
Product: CCn1nc(-c2ccc(OC(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 9.9 %

Procedure:
Using cyclohexyl{1-ethyl-3-[4-(trifluoromethoxy)phenyl]-1H-pyrazol-5-yl}methanol, (0.39 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.32 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.06 g, 11%) was obtained as a white solid.
Reaction SMILES: [C:1](Cl)(=O)[CH2:2][CH2:3][CH3:4].CCN([CH2:12][CH3:13])CC>C(Cl)Cl>[CH2:1]1[C:12]2[C:13](=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCN(CC)CC
Reactant: CCCC(=O)Cl
Solvent: ClCCl
Product: c1ccc2c(c1)CCCC2
Reaction time: 3 h
Yield: 85 %

Procedure:
The compound of Example 1 (0.2 g, 0.92 mmol) was reacted with butyryl chloride (0.14 g, 0.69 mmol) in 50 mL methylene chloride in the presence of Et3N chilled by an ice water bath. The reaction was continued for 3 hours and the solvent removed in vacua. The crude product was dissolved in ethyl acetate and extracted with saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate, and chromatographed over a silica gel column. The pure compound was eluted with 1:4 EtOAc:hexane, yielding (R,S)-trans-7-methoxy-2-[N-(propynyl)-N-butyro)amino]tetralin in very good yield, 0.22 g (85% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][C:9]1[CH:10]=[C:11]([O:28][C:29]([F:32])([F:31])[F:30])[CH:12]=[C:13]2[C:18]=1[O:17][CH:16]([C:19]([F:22])([F:21])[F:20])[C:15]([C:23]([O:25]CC)=[O:24])=[CH:14]2>CC(O)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][C:9]1[CH:10]=[C:11]([O:28][C:29]([F:32])([F:30])[F:31])[CH:12]=[C:13]2[C:18]=1[O:17][CH:16]([C:19]([F:22])([F:21])[F:20])[C:15]([C:23]([OH:25])=[O:24])=[CH:14]2
Reactant: CCOC(=O)C1=Cc2cc(OC(F)(F)F)cc(C#Cc3ccccn3)c2OC1C(F)(F)F
Solvent: CC(=O)O
Product: O=C(O)C1=Cc2cc(OC(F)(F)F)cc(C#Cc3ccccn3)c2OC1C(F)(F)F

Procedure:
The ester from Step 1 was hydrolyzed via a method similar to that described in Example 621c, Step 2 using HOAc in the acidification step to give the product as a pale yellow solid: ESHRMS m/z 430.0507 (M+H, C,9H10F6NO4, Calc'd 430.0509); 1H NMR (dmso-d6, 300 MHz) 13.55 (brs, 1H), 8.62 (d, 1H, J=4.2 Hz), 7.93 (s, 1H), 7.90-7.84 (m, 1H), 7.73-7.62 (m, 3H), 7.47-7.42 (m, 1H), 6.18 (q, 1H, J=7.1 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[S:7][C:8]([C:10](O)=[O:11])=[CH:9][C:5]=2[CH:4]=1.C1(C)C=CC=CC=1.S(Cl)(Cl)=O.[N:28]1C=CC=CC=1>>[CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[S:7][C:8]([C:10]([NH2:28])=[O:11])=[CH:9][C:5]=2[CH:4]=1
Reactant: c1ccncc1
Reactant: COc1cc2cc(C(=O)O)sc2cc1OC
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COc1cc2cc(C(N)=O)sc2cc1OC

Procedure:
A mixture of 5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid (68.8 g), dry toluene (350 ml), thionyl chloride (126 ml) and pyridine (1.75 ml) was stirred and heated at reflux for 4 hours. The resultant mixture was cooled, evaporated to dryness under vacuum and the residue was purged with dry toluene (3×250 ml). The resulting crude acid chloride was suspended in dioxan (160 ml) then cooled in an ice bath and treated in one portion with concentrated ammonium hydroxide solution (33% w/w, 900 ml). This gave a suspension of brown solid which was stirred for two hours then filtered, washed with water and dried under vacuum over calcium chloride at 60° C. to give 5,6-dimethoxy-benzo[b]thiophene-2-carboxamide (62.5 g), m.p. 211°-213° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=2)[N:9]2[CH2:12][C:11](=[C:13]([S:34]([CH3:37])(=[O:36])=[O:35])[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20](OC4C(F)=C(F)C(F)=C(F)C=4F)=[O:21])[CH:15]=3)[CH2:10]2)=[CH:4][CH:3]=1.[NH2:45][N:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1>CN(C)C=O.C(OCC)(=O)C>[Cl:44][C:41]1[CH:42]=[CH:43][C:38]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]2[CH2:12][C:11](=[C:13]([S:34]([CH3:37])(=[O:35])=[O:36])[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[O:21])[NH:45][N:46]4[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]4)[CH:15]=3)[CH2:10]2)=[CH:39][CH:40]=1
Reactant: CS(=O)(=O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)c1
Reactant: NN1CCCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cccc(C(=O)NN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 0.45 g of 1-[bis(4-chlorophenyl)methyl]-3-{(methylsulfonyl)[3-(pentafluorophenoxycarbonyl)phenyl]methylene}azetidine, 0.07 cm3 of 1-aminopiperidine in 4 cm3 of dimethylformamide is stirred for 18 hours at room temperature. The mixture is taken up in 30 cm3 of ethyl acetate. The organic phase is washed with 3 times 50 cm3 of water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). 0.2 g of 1-[bis-(4-chlorophenyl)methyl]-3-{(methylsulfonyl)[3-(N-piperidylcarbamoyl)phenyl]methylene}azetidine is obtained melting at 175° C. [NMR spectrum in DMSO-d6, T=300K, δ in ppm (400 MHz): 1.40 (2H, m, CH2), 1.60 (4H, m, 2CH2), 2.85 (4H, m, 2NCH2), 3.00 (3H, s, SCH3), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.80 (1H, s, NCH), between 7.45 and 7.60 (10H, m, 10CH arom.), 7.75 (2H, m, 2CH arom.), 9.45 (1H, s, NH)].
Reaction SMILES: [CH2:1]([N:4]1[C:8]2[CH:9]=[CH:10][C:11]([NH2:13])=[CH:12][C:7]=2[N:6]=[CH:5]1)[CH2:2][CH3:3].[Br:14]Br.N.CO.C(Cl)Cl>CC(O)=O>[CH2:1]([N:4]1[C:8]2[CH:9]=[CH:10][C:11]([NH2:13])=[C:12]([Br:14])[C:7]=2[N:6]=[CH:5]1)[CH2:2][CH3:3]
Reactant: CCCn1cnc2cc(N)ccc21
Reactant: BrBr
Agent: N
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CCCn1cnc2c(Br)c(N)ccc21
Yield: 48 %

Procedure:
To a solution of 1-propyl-5-aminobenzimidazole (1.2 g, 7.1 mmol) in 10 ml of AcOH was added solution of Br2 in AcOH until it produces a precipitation. The reaction mixture was concentrated in vacuo to provide a brown solid which was subjected to column chromatography (5% NH3 sat'd MeOH/CH2Cl2) to provide 0.83 g (3.4 mmol, 48%) of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.Cl.Cl.[CH3:28][NH:29][CH2:30][CH:31]([C:33]1[NH:37][N:36]=[CH:35][CH:34]=1)[OH:32].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:29]([CH2:30][CH:31]([OH:32])[C:33]4[NH:37][N:36]=[CH:35][CH:34]=4)[CH3:28])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Reactant: CNCC(O)c1ccn[nH]1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(CN(C)CC(O)c2ccn[nH]2)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 60 °C
Reaction time: 48 h

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (100 mg, 0.25 mmol), 2-(methylamino)-1-(1H-pyrazol-5-yl)ethanol dihydrochloride Preparation 97)(67 mg, 0.38 mmol) and diisopropylethylamine (201 μL, 1.14 mmol) in dry DMF (5 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 48 hours at that temperature. After cooling to room temperature, the solution was diluted with water (15 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile (5 mL, dissolved with warming and then cooled to 0° C. overnight) gave the title compound (63 mg) as a white solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](OC(C)(C)C)=O)[CH2:13][CH2:12]1)=O.O>C1COCC1>[CH3:18][NH:17][C@H:14]1[CH2:15][CH2:16][C@H:11]([CH2:9][OH:8])[CH2:12][CH2:13]1
Reactant: COC(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN[C@H]1CC[C@H](CO)CC1
Temperature: 0 °C

Procedure:
A solution of 1.52 g (40 mmol) LAH in 7 ml THF was refluxed and treated for 2.5 h with a solution of 5.15 g (20 mmol) of trans-4-tert-butoxycarbonylamino-cyclohexanecarboxylic acid methyl ester in 35 ml THF. The reaction was heated for 15 h, cooled (0° C.) and hydrolyzed with 10 ml water. The mixture was diluted with THF, dried over Na2SO4, filtered and evaporated. The residue was dissolved in CH2Cl2, dried over Na2SO4, filtered and evaporated to yield 2.89 g (100%) of trans-(4-Methylamino-cyclohexyl)-methanol, mp: 87-88° C.; MS: 143 (M).
Reaction SMILES: [C:1]1([CH:11]([CH3:13])[CH3:12])[C:2](S([O-])(=O)=O)=[CH:3][CH:4]=[CH:5][CH:6]=1.[Na+].[Mg].[OH2:16]>>[CH2:2]([OH:16])[CH2:1][CH2:6][CH2:5][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][CH:11]([CH3:12])[CH3:13]
Reactant: CC(C)c1ccccc1S(=O)(=O)[O-]
Reactant: O
Agent: [Mg]
Agent: [Na+]
Product: CC(C)CCCCCCCCCCO

Procedure:
A process for the preparation of solid active-ingredient concentrates, which comprises preparing a spray solution from sodium cumenesulphonate, methylhydroxyethylcellulose and water which is sprayed onto a mixture of magnesium perphthalate powder and sodium alkylbenzoate powder in a fluidized-bed drier at an air intake temperature of from about 60 to 80° C., and coating the granules formed with a melt of isotridecanol ethoxylate.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][C@H:6]1[C@@H:13]([OH:14])[C@H:12]([CH3:15])[O:11][C@@H:8]([O:9][CH3:10])[CH2:7]1)=[O:4].B(F)(F)F.[CH3:22]COCC.[N+](=C)=[N-]>C(Cl)Cl>[CH3:22][O:14][C@H:13]1[C@H:12]([CH3:15])[O:11][C@@H:8]([O:9][CH3:10])[CH2:7][C@H:6]1[NH:5][C:3](=[O:4])[C:2]([F:1])([F:16])[F:17]
Reactant: CO[C@H]1C[C@@H](NC(=O)C(F)(F)F)[C@@H](O)[C@H](C)O1
Reactant: CCOCC
Agent: C=[N+]=[N-]
Agent: FB(F)F
Solvent: ClCCl
Product: CO[C@H]1C[C@@H](NC(=O)C(F)(F)F)[C@@H](OC)[C@H](C)O1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
A solution of 11.7 g; 45 mmol of methyl 2,3,6-trideoxy-3-trifluroacetamido-α-L-ribohexopyranoside (V) in 100 ml of anhydrous methylene dichloride was treated at -70° C. with 0.6 ml of boron trifluoride etherate. While maintaining the temperature at -70° C., an excess of diazomethane in anhydrous methylene dichloride was added until a faint yellow color persisted. After 60 minutes at -70° C., a white solid (polymethylene) which precipitated out, was removed by filtration. The filtrate was washed successively with a 10% sodium bicarbonate solution and water, and then dried over anhydrous sodium sulphate. The filtrate was then evaporated to leave a residue, which was then chromatographed on a silica gel column. Elution of the column with chloroform gave pure methyl 4-O-methyl-2,3,6-trideoxy-3-trifluoroacetamido-α-L-ribohexopyranoside (VI) as an amorphous solid; m.p. 55°-60° C; [α]D23° =-110° (c=0.5 in CHCl3); mass spectrum: m/e 271 (M+). The p.m.r. spectrum showed absorption at: 1.30 (d, CH3 --C--5), 2.95 (dd, J=9.5 and 4.0 Hz, C--4--H), 3.42 and 3.43 (s,2 CH3O--), 3.70 (dq, J=6.0 and 9.0 Hz, C--5--H), 4.45-4.85 (m, C--3--H) and 4.75 δ (broad s WH =5.5 Hz, C--1--H).
Reaction SMILES: [Na+:1].[Na+].[Na+].[NH2:4][C:5]1[C:14]2[C:13]([S:15]([O-:18])(=[O:17])=[O:16])=[CH:12][C:11]([S:19]([O-:22])(=[O:21])=[O:20])=[CH:10][C:9]=2[C:8]([S:23]([O-:26])(=[O:25])=[O:24])=[CH:7][CH:6]=1.O.O.O.C([O-])(=O)C.[Na+].[N+:35]([C:38]1[CH:39]=[C:40]([CH3:47])[CH:41]=[CH:42][C:43]=1[C:44](Cl)=[O:45])([O-:37])=[O:36].C([O-])(=O)C.[Na+].Cl>O.CCOCC>[Na+:1].[Na+:1].[Na+:1].[N+:35]([C:38]1[CH:39]=[C:40]([CH3:47])[CH:41]=[CH:42][C:43]=1[C:44]([NH:4][C:5]1[C:14]2[C:13]([S:15]([O-:18])(=[O:17])=[O:16])=[CH:12][C:11]([S:19]([O-:22])(=[O:20])=[O:21])=[CH:10][C:9]=2[C:8]([S:23]([O-:26])(=[O:25])=[O:24])=[CH:7][CH:6]=1)=[O:45])([O-:37])=[O:36]
Reactant: Cc1ccc(C(=O)Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccc(S(=O)(=O)[O-])c2cc(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Cc1ccc(C(=O)Nc2ccc(S(=O)(=O)[O-])c3cc(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c23)c([N+](=O)[O-])c1
Yield: 778.9 %

Procedure:
To a stirred solution of 22.5 g of 8-amino-1,3,5-naphthalenetrisulfonic acid trisodium salt in 160 ml of water is added 11.0 g of the preceding product with a small amount of ether. Stirring is continued, and after one hour 1.0 g of sodium acetate trihydrate and 1.0 g of 3-nitro-p-toluoyl chloride are added. The mixture is stirred an additional 3 hours and the above addition of sodium acetate and 3-nitro-p-toluoyl chloride is repeated. The mixture is stirred an additional hour, acidified to Congo Red indicator paper with hydrochloric acid and filtered. The filtrate is neutralized with sodium hydroxide, concentrated, dissolved in 50 ml of water and added to 1 liter of ethanol with stirring for 16 hours. The solid is filtered and forms a gel on washing with ethanol. The gel is dissovled in water and evaporated. The residue is dissolved in 35 ml of hot water and 320 ml of absolute ethanol is added with stirring. The mixture solidifies and water is added to allow filtration. The solid is washed with ether and dried in vacuo. The filtrate is treated by stirring with one liter of ethanol, the separated solid is collected, washed with ether, and dried to yield a combined total of 23.9 g of 8-(3-nitro-p-toluamido)-1,3,5-naphthalenetrisulfonic acid trisodium salt.