Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Br:9])[C:3]=1[OH:10].C([O:14][C:15]1[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:17](Cl)=[O:18])(=O)C.C(OC1C(=CC=CC=1)C(O)=O)(=O)C>CC(C)=O.N1C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([Br:9])[C:3]=1[OH:10])[NH:8][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=1[OH:14]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: Nc1cc(Br)c(O)c(Br)c1
Agent: CC(=O)Oc1ccccc1C(=O)O
Solvent: c1ccncc1
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O=C(Nc1cc(Br)c(O)c(Br)c1)c1ccccc1O
Yield: 78 %

Procedure:
2,6-Dibromo-4-aminophenol (0.6 g.) was dissolved in acetone (30 ml.) to which pyridine (0.32 ml.) was added. Then the solution was added by drops and with stirring to an acetone solution (10 ml.) containing acetylsalicyloyl chloride which was prepared from acetyl-salicylic acid (0.38 g.). The resulting solution was evaporated to dryness under reduced pressure to give a residue which was dissolved in ethyl acetate. After washing first with water and then with 1 N hydrochloric acid the solution was evaporated under reduced pressure to remove the ethyl acetate. The residue was redissolved in a mixture of methanol and 2 N sodium hydroxide (10 ml. each). Stirring this solution for several hours and acidifying with 2 N hydrochloric acid precipitated the product which was recrystallized from aqueous methanol to give light brown crystals of 3',5'-dibromo-2,4'-dihydroxybenzanilide (0.88 g.). Yield: 78%. The melting point of the compound is 182°-187° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:14]=[C:13]([CH:15]=O)[NH:12][C:8]=2[N:9]=[CH:10][N:11]=1.[NH:20]([CH2:24][CH2:25][OH:26])[CH2:21][CH2:22][OH:23]>C(O)C.CN1C(=O)N(C)CCC1.C(O)(=O)C.[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:14]=[C:13]([CH2:15][N:20]([CH2:24][CH2:25][OH:26])[CH2:21][CH2:22][OH:23])[NH:12][C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: OCCNCCO
Reactant: O=Cc1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Agent: [Ni]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CN1CCCN(C)C1=O
Product: OCCN(CCO)Cc1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1

Procedure:
109 mg (0.40 mmol) of 4-(3-chloroanilino)-6-formyl-7H-pyrrolo[2,3-d]pyrimidine (stage 1.6) and 84 mg (0.8 mmol) of diethanolamine in 6 ml of ethanol, 60 drops of DMPU and 50 μl of acetic acid are stirred at RT for a few hours. 30 mg of Raney nickel are then added and the mixture is hydrogenated at 50° C. The catalyst is filtered off and the filtrate is evaporated. Column chromatography (SiO2, CH2Cl2/methanol=10:1) and crystallization from ethyl acetate/diethyl ether yields 4-(3-chloroanilino)-6-[bis(2-hydroxyethyl)aminomethyl]-7H-pyrrolo[2,3-d]pyrimidine; HPLC: tRet(Grad20)=7.0; TLC-Rf=0.1 (CH2Cl2/methanol=10:1); FAB-MS: (M+H)+=362.
Reaction SMILES: [N:1]1([CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO[C:17]1[C:21](OC)=[N:20][S:19](=[O:25])(=[O:24])[N:18]=1.[NH3:26]>>[NH2:26][C:17]1[C:21]([NH:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]#[C:8][CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:20][S:19](=[O:25])(=[O:24])[N:18]=1
Reactant: N
Reactant: NCCCCC#CCN1CCCCC1
Reactant: COC1=NS(=O)(=O)N=C1OC
Product: NC1=NS(=O)(=O)N=C1NCCCCC#CCN1CCCCC1

Procedure:
In a manner similar to Example 1, reaction of 7-piperidinohept-5-ynylamine and 3,4-dimethoxy-1,2,5-thiadiazole-1,1-dioxide followed by reaction with ammonia gives the title compound.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:14]([SH:15])=[N:13][N:12]=[N:11]1)(O)=[O:2].[C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[C:31]([SH:32])=[N:30][N:29]=[N:28]1)(O)=[O:17]>>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:14]([SH:15])=[N:13][N:12]=[N:11]1)(=[O:2])[NH2:27].[C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[C:31]([SH:32])=[N:30][N:29]=[N:28]1)(=[O:17])[NH2:10]
Reactant: O=C(O)CCCCCCCCn1nnnc1S
Reactant: O=C(O)CCCCCCn1nnnc1S
Product: NC(=O)CCCCCCCCn1nnnc1S
Product: NC(=O)CCCCCCn1nnnc1S

Procedure:
1-(6-Carbamoylhexyl)tetrazole-5-thiol and 1-(8-carbamoyloctyl)tetrazole-5-thiol are prepared from 1-(6-carboxyhexyl)tetrazole-5-thiol and 1-(8-carboxyoctyl)tetrazole-5-thiol according to the procedure described in Example 5.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH3:10][C:11]1[CH:30]=[CH:29][CH:28]=[CH:27][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([NH2:26])=[N:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][CH:15]=1>C1COCC1>[CH3:10][C:11]1[CH:30]=[CH:29][CH:28]=[CH:27][C:12]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21]3=[N:26][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:22]3[CH:23]=[CH:24][CH:25]=2)=[CH:18][CH:19]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Cc1ccccc1Oc1ccc(-c2cccnc2N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccccc1Oc1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Reaction time: 0.08 h

Procedure:
To a suspension of NaH (60%, 284 mg) in THF (dry) (15 mL) was added 2-chloroethanesulfonyl chloride (0.448 mL) at 0° C. and the mixture was stirred for 5 min at the same temperature. A solution of 3-(4-(2-methylphenoxy)phenyl)pyridin-2-amine (392 mg) in THF (dry) (20 mL) was added at 0° C. and the mixture was stirred at room temperature for 5 hr. The mixture was quenched with water at 0° C. Water, EtOAc and IPE were added and the precipitates were collected, washed with water/EtOAc, dried in vacuo to give the title compound (415.4 mg) as a white solid. A part of this was recrystallized from MeCN/IPE.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12](I)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:24]1[CH2:25][CH2:26][O:27][CH2:28][CH:29]=1)CCC>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:24]3[CH2:29][CH2:28][O:27][CH2:26][CH:25]=3)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCOCC1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(I)cc2C1
Product: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(C3=CCOCC3)cc2C1

Procedure:
Prepared in analogy to Example A49(a) from 5-chloro-6-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A3(c)) and tributyl-(3,6-dihydro-2H-pyran-4-yl)-stannane. Yellow solid. MS (m/e): 282.3 ({37Cl}[M+H-Me2C═CH2]+, 49%), 280.3 ({35Cl}[M+H-Me2C═CH2]+, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:25])[C:5]([C:8](=[N:23][OH:24])[CH2:9][NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:33]([CH3:35])[CH3:34].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([Cl:25])[C:5]([C:8](=[N:23][O:24][CH:33]([CH3:35])[CH3:34])[CH2:9][NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:19])([F:21])[F:20])=[N:6][CH:7]=1
Reactant: CC(C)I
Reactant: O=C(NCC(=NO)c1ncc(Br)cc1Cl)c1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)ON=C(CNC(=O)c1ccccc1C(F)(F)F)c1ncc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 13 h
Yield: 63.8 %

Procedure:
To a suspension of 1.80 g of the N-[2-(5-bromo-3-chloropyridin-2-yl)-2-(hydroxyimino)ethyl]-2-(trifluoromethyl)benzamide prepared in Step 3 in Synthetic Example 20 and 0.86 g of potassium carbonate in 10 ml of N,N-dimethylformamide, 1.30 g of 2-iodopropane was added, and the mixture was stirred at room temperature for 13 hours. After completion of the reaction, the reaction mixture was mixed with 100 ml of water and extracted with ethyl acetate (50 ml×2), the resulting organic layers were combined, washed with water (100 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 1:4 to 2:2) as the eluent to obtain 1.26 g of the desired product as a pale yellow resinous substance.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:10])=[C:5]([C:7]([OH:9])=O)[N:6]=1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][CH:44]=1)[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([N:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=2)[CH:32]=1>CN(C)C=O.CN(C)C(=O)C>[CH:39]1([C:37]([NH:36][C:34]2[N:35]=[C:30]3[CH:29]=[CH:28][C:27]([O:26][C:25]4[CH:24]=[C:23]([NH:22][C:7]([C:5]5[N:6]=[C:2]([CH3:1])[S:3][C:4]=5[CH3:10])=[O:9])[CH:44]=[CH:43][CH:42]=4)=[CH:32][N:31]3[N:33]=2)=[O:38])[CH2:40][CH2:41]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Reactant: Cc1nc(C(=O)O)c(C)s1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)c(C)s1
Yield: 63.1 %

Procedure:
In the same manner as in Example 18-4 and using 2,5-dimethyl-1,3-thiazole-4-carboxylic acid (314 mg, 2.00 mmol), tetrahydrofuran (50 mL), oxalyl chloride (191 μL, 2.20 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (309 mg, 1.00 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (6 mL) as starting materials, the title compound (283 mg, 63%) was obtained as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7](O)=[O:8])([O-:3])=[O:2].S(Cl)([Cl:18])=O>C1C=CC=CC=1.C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7]([Cl:18])=[O:8])([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1

Procedure:
Typically, the 3,4-dinitrobenzoic acid starting material is dissolved in an aprotic solvent such as benzene or toluene and refluxed with thionylchloride for a period of about 2-6 hours to form the desired 3,4-dinitrobenzoyl chloride.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([NH:16][NH2:17])=[O:15])(=[O:10])=[O:9])[CH2:4][CH2:3]1.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([OH:31])=[C:26]([C:28](=O)[CH3:29])[CH:27]=1>CO.C(O)(=O)C>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([OH:31])=[C:26](/[C:28](=[N:17]/[NH:16][C:14](=[O:15])[C:13]2[CH:18]=[CH:19][CH:20]=[C:11]([S:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)(=[O:10])=[O:9])[CH:12]=2)/[CH3:29])[CH:27]=1
Reactant: CN1CCN(S(=O)(=O)c2cccc(C(=O)NN)c2)CC1
Reactant: CC(=O)c1cc(Cl)ccc1O
Solvent: CC(=O)O
Solvent: CO
Product: C/C(=N\NC(=O)c1cccc(S(=O)(=O)N2CCN(C)CC2)c1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 53.3 %

Procedure:
3-((4-methylpiperazin-1-yl)sulfonyl)benzohydrazide (85 mg, 0.285 mmol) and 1-(5-chloro-2-hydroxyphenyl)ethanone (48.6 mg, 0.285 mmol) was dissolved in methanol (Volume: 4 ml) in the presence of acetic acid as a catalyst and then the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Reaction was monitored by TLC. After completion of the reaction, following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) afforded the product (E)-N′-(1-(5-chloro-2-hydroxyphenyl)ethylidene)-3-((4-methylpiperazin-1-yl)sulfonyl)benzohydrazide (70 mg, 0.152 mmol, 53.4% yield) as a solid. 1H NMR (CD3OD, 400 MHz): δ 8.29 (s, 1H), 8.21 (d, 1H, J=7.2 Hz), 7.99 (d, 1H, J=8.0 Hz), 7.78 (t, 1H, J=7.6 Hz), 7.59 (d, 1H, J=2.4 Hz), 7.27 (dd, 1H, J=2.4 & 9.2 Hz), 6.92 (d, 1H, J=8.8 Hz), 3.09 (m, 4H), 2.54 (m, 4H), 2.48 (s, 3H), 2.28 (s, 3H). Mass [M+H]+:450.9
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH:17][C:18]1[CH:23]=[C:22]([CH2:24][C:25]([OH:27])=O)[C:21]([OH:28])=[CH:20][C:19]=1[CH2:29][C:30]([OH:32])=O>CCOC(C)=O.CCCCCC>[CH2:2]([O:9][C:10]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:30](=[O:32])[CH2:29][C:19]1[CH:20]=[C:21]([OH:28])[C:22]([CH2:24][C:25]([N:12]2[CH2:13][CH2:14][CH2:15][C@@H:11]2[C:10]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:16])=[O:27])=[CH:23][C:18]=1[OH:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Reactant: O=C(O)Cc1cc(O)c(CC(=O)O)cc1O
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)Cc1cc(O)c(CC(=O)N2CCC[C@@H]2C(=O)OCc2ccccc2)cc1O
Yield: 23.9 %

Procedure:
Using General Procedure A with 10.7 g (44.2 mmol) D-Proline benzyl ester hydrochloride and 5.0 g (22.1 mmol) 2,5-dihydroxy-1,4-phenylenediacetic acid afforded, after flash chromatography (gradient: 70-100% EtOAc/hexane), 3.17 g (24%) of the title compound as a colorless foam.
Reaction SMILES: [CH3:1][C:2]([N+:12]([O-])=O)([CH3:11])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH3:15][C:16]([OH:18])=[O:17].CCO>[Pd].CO>[C:16]([OH:18])(=[O:17])[CH3:15].[NH2:12][C:2]([CH3:11])([CH3:1])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: CC(C)(Cc1ccc(O)cc1)[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(N)Cc1ccc(O)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
A one-gallon high-pressure reactor was charged with 4(2-methyl-2-nitropropyl)phenol (120 g, 614 mmol), HOAc (35.2 mL, 614 mmol), 5% Palladium on carbon (24 g) wetted with 2B3 EtOH (60 mL), and MeOH (1230 mL). The mixture was heated to 50° C. with agitation (600 rpm), and the reactor was purged with N2 and pressurized to 50 psi with H2. After 15.5 h the reactor was purged with N2, and the cooled mixture was filtered. The filter cake was washed with MeOH and the filtrate was concentrated to 514 g of slurry on a rotary evaporator. To this slurry was added EtOAc (2 L) with vigorous agitation. After stirring for 1 h, the resulting crystals were filtered and washed with a small amount of EtOAc. The product was dried overnight in a 45° C. vacuum oven to yield 118.83 g (86%) of product as small white needles (mp 211-216° C. dec). This material was 99% pure by HPLC analysis, and while another 9.00 g of material was obtained from the mother liquor it was found to be only 88 % pure.
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:18][N:17]=[C:16]([CH2:19][OH:20])[CH:15]=3)=[CH:10][CH:9]=2)[O:6][C:5]([CH3:22])([CH3:21])[N:4]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].N1C=CC=CC=1.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:18][N:17]=[C:16]([CH2:19][O:20][S:37]([CH3:36])(=[O:39])=[O:38])[CH:15]=3)=[CH:10][CH:9]=2)[O:6][C:5]([CH3:22])([CH3:21])[N:4]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3cc(CO)no3)cc2)OC1(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3cc(COS(C)(=O)=O)no3)cc2)OC1(C)C
Reaction time: 1 h

Procedure:
(4S,5R)-tert-butyl 4-(fluoromethyl)-5-(4-(3-(hydroxymethyl)isoxazol-5-yl)phenyl)-2,2-dimethyloxazolidine-3-carboxylate (see US2004/0082553, page 67 (page 68 of pdf version)) (1000 mg, 2.45 mmol) in CH2Cl2 (25 mL) at 5° C. is treated with pyridine (0.23 mL, 2.95 mmol) and methanesulfonylchloride (0.19 mL, 2.45 mmol) then stirred for 1 hour, washed with saturated aqueous sodium bicarbonate, concentrated and used as is (1130 mg). m/z (Cl) 485 [M+H].
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:10]=[C:7]([CH:8]=[O:9])[C:6]([OH:11])=[CH:5][CH:4]=1.[N+:12]([O-])([OH:14])=[O:13]>C(O)(=O)C>[Cl:1][CH2:2][C:3]1[CH:10]=[C:7]([CH:8]=[O:9])[C:6]([OH:11])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: O=Cc1cc(CCl)ccc1O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=Cc1cc(CCl)cc([N+](=O)[O-])c1O
Temperature: 30 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
179 g. (0.01 mole) of 5-chloromethylsalicylaldehyde, prepared according to Angyal, S. J. et al, J. Chem. Soc. 1950, 2145, was dissolved in 20 ml. of glacial acetic acid. To this solution there was added a solution of 0.63 g. fuming nitric acid in 10 ml. glacial acetic acid over 30 minutes, keeping the mixture at 30° C., followed by stirring at 30° C. for 2 hours. The solution was then poured over ice to give a precipitate which was crystallized from methylene chloride giving the title product. Another crop was obtained by extraction of the aqueous phase, drying with anhydrous sodium sulfate, evaporation and crystallization from methylene chloride. Total yield: 53%.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([S:5]([C:8]2[CH:26]=[CH:25][C:11]3[N:12]([CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[C:13]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:14][C:10]=3[CH:9]=2)(=[O:7])=[O:6])[CH2:2]1.C(N(CC)CC)C.Cl[CH2:35][CH2:36][OH:37]>O>[CH3:23][N:22]([CH3:24])[CH2:21][CH2:20][N:12]1[C:11]2[CH:25]=[CH:26][C:8]([S:5]([CH:3]3[CH2:4][N:1]([CH2:35][CH2:36][OH:37])[CH2:2]3)(=[O:6])=[O:7])=[CH:9][C:10]=2[N:14]=[C:13]1[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: OCCCl
Reactant: CN(C)CCn1c(CC(C)(C)C)nc2cc(S(=O)(=O)C3CNC3)ccc21
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C)CCn1c(CC(C)(C)C)nc2cc(S(=O)(=O)C3CN(CCO)C3)ccc21
Temperature: 60 °C
Reaction time: 9 h
Yield: 38.6 %

Procedure:
A mixture of 2-(5-(azetidin-3-ylsulfonyl)-2-neopentyl-1H-benzo[d]imidazol-1-yl)-N,N-dimethylethanamine (prepared in STEP A of Example 22, 554 mg, 1.46 mmol), triethylamine (226 microL, 1.61 mmol) and 2-chloroethanol (3.53 g, 43.9 mmol) was stirred at 60° C. for 9 h. The resulting mixture was diluted with water (30 mL) and extracted with dichloromethane (50 mL×3). The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude product was purified by reverse phase HPLC (0.4% aqueous ammonia-acetonitrile=96:4 to 4:96) to give the title compound (238 mg, 39%) as a clear grease.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([NH:14][C@H:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][NH2:24])[CH2:17][C@H:16]2[O:25][CH3:26])=[O:13])=[CH:4][C:3]=1[Cl:27].CS[C:30]1[N:35]=[C:34]([OH:36])[CH:33]=[CH:32][N:31]=1>C(#N)C>[OH2:11].[NH2:1][C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([NH:14][C@H:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][NH:24][C:30]3[N:35]=[C:34]([OH:36])[CH:33]=[CH:32][N:31]=3)[CH2:17][C@H:16]2[O:25][CH3:26])=[O:13])=[CH:4][C:3]=1[Cl:27].[NH2:1][C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([NH:14][C@H:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][NH:24][C:30]3[N:35]=[C:34]([OH:36])[CH:33]=[CH:32][N:31]=3)[CH2:17][C@H:16]2[O:25][CH3:26])=[O:13])=[CH:4][C:3]=1[Cl:27]
Reactant: CO[C@@H]1CN(CCCN)CC[C@@H]1NC(=O)c1cc(Cl)c(N)c2c1OCCC2
Reactant: CSc1nccc(O)n1
Solvent: CC#N
Product: CO[C@@H]1CN(CCCNc2nccc(O)n2)CC[C@@H]1NC(=O)c1cc(Cl)c(N)c2c1OCCC2
Product: O
Yield: 35.2 %

Procedure:
A mixture of 5 parts of cis-5-amino-N-[1 -(3-aminopropyl)-3-methoxy-4-piperidinyl]-6-chloro-3,4-dihydro-2H-1-benzopyran-8-carboxamide, 3.2 parts of 2-methylthio-4-pyrimidinol and 79 parts of acetonitrile was stirred over weekend at reflux temperature. The reaction mixture was evaporated and the residue was partitioned between dichloromethane and ammonia (aq.). The aqueous layer was separated and re-extracted with dichloromethane (2x). The combined dichloromethane layers were dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /CH3OH(NH3) 95:5). The eluent of the two desired fractions was evaporated and the residues were separately crystallized from acetonitrile. The product was filtered off and dried in vacuo at 70° C., yielding a first fraction of 2.22 parts (35.2%) of cis-5-amino-6-chloro-3,4-dihydro-N-[1-[3-[(4-hydroxy-2-pyrimidinyl)amino]propyl]-3-methoxy-4piperidinyl]-2H-1-benzopyran-8-carboxamide hemihydrate; mp. 142.6° C. and a second fraction of 1.00 part (15.9%) of cis-5-amino-6-chloro-3,4-dihydro-N-[1-[3-[(4-hydroxy-2-pyrimidinyl)amino]propyl]-3-methoxy-4-piperidinyl]-2H-1-benzopyran-8-carboxamide hemihydrate; mp. 143.5° C. Total yield: 3.22 parts (51.1%) of product (comp. 128).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH:12]([N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:20][C:21](Br)([CH3:23])[CH3:22]>C(O)CCCC.CN(C=O)C>[Br-:20].[Br-:20].[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH:12]([N+:15]3[CH:19]=[CH:18][N:17]([CH2:22][CH2:21][CH2:23][N+:17]4[CH:18]=[CH:19][N:15]([CH:12]5[CH2:13][CH2:14][N:10]([C:7]6[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=6)[CH2:11]5)[CH:16]=4)[CH:16]=3)[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(Br)Br
Reactant: O=[N+]([O-])c1ccc(N2CCC(n3ccnc3)C2)cc1
Solvent: CCCCCO
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCC(n3cc[n+](CCCn4cc[n+](C5CCN(c6ccc([N+](=O)[O-])cc6)C5)c4)c3)C2)cc1
Product: [Br-]
Temperature: 115 °C
Yield: 189.3 %

Procedure:
3.5 g (0.0135 mol) of 1-[1-(4-nitrophenyl)pyrrolidin-3-yl]-1H-imidazole were heated to 100° C. in 12 ml of a pentanol/DMF mixture (50/50). 1 g (0.005 mol) of dibromopropane was added. The reaction medium was heated at 115° C. for 17 hours. The precipitate was filtered off while hot and washed with pentanol and then with ether. After draining by suction and drying the precipitate, 3.4 g of yellow powder (4) were obtained. 33% yield.
Reaction SMILES: F[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[C:16](=O)[CH2:15][C:14]([CH3:19])([CH3:18])[CH2:13][C:12]3=[O:20])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.NC1C=C([Cl:31])C=CC=1C(O)=O.C(O)(=O)[C:33]1[C:34](=CC=CC=1)[NH2:35]>>[Cl:31][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]4[C:12](=[O:20])[CH2:13][C:14]([CH3:19])([CH3:18])[CH2:15][C:16]=4[N:35]=[C:34]([CH3:33])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: CC1(C)CC(=O)C(c2c[nH]c3cc(F)ccc23)C(=O)C1
Reactant: Nc1ccccc1C(=O)O
Product: Cc1nc2c(c3c1[nH]c1cc(Cl)ccc13)C(=O)CC(C)(C)C2

Procedure:
Utilizing the procedures described in Example 3 a-c except substituting 2-(6-chloro-1H-indol-3-yl)-5,5-dimethylcyclohexane-1,3-dione for 2-(6-fluoro-1H-indol-3-yl)-5,5-dimethylcyclohexane-1,3-dione in step 3a, and 2-amino-4-chlorobenzoic acid for anthranilic acid in step 1a of Example 1, the title compound was prepared and crystallized from toluene; m.p. 248-250° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([N:11]2[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[C:13]([C:20]([OH:22])=O)=[CH:12]2)=[CH:3][CH:2]=1.S(Cl)([Cl:25])=O>>[ClH:25].[Cl:25][C:20]([C:13]1[C:14]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=[CH:2][CH:3]=2)[CH:12]=1)=[O:22]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cn(-c2ccnc3ccccc23)c2ncccc12
Product: Cl
Product: O=C(Cl)c1cn(-c2ccnc3ccccc23)c2ncccc12

Procedure:
50 cm3 of thionyl chloride were added to 3.4 g (11.8 mmol) of 1-(quinolin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid at a temperature in the region of 20° C. under an argon atmosphere. After stirring at reflux for 2 h, the reaction mixture was concentrated to dryness under reduced pressure (2.7 kPa), triturated twice in succession with 30 cm3 of dichloromethane and then concentrated to dryness under reduced pressure (2.7 kPa) to give 11.8 mmol of 3-chlorocarbonyl-1-(quinolin-4-yl)-1H-pyrrolo[2,3-b]pyridine hydrochloride in the form of a yellow powder which was used directly in the following stage.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH2:7][CH:8]([C:14](=O)[CH3:15])[C:9]([O:11]CC)=O)(=[O:3])[CH3:2].Cl.[C:21](=[NH:26])([NH2:25])[CH2:22][CH2:23][CH3:24].C[O-].[Na+].CO>CO>[C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH2:7][C:8]1[C:9](=[O:11])[NH:26][C:21]([CH2:22][CH2:23][CH3:24])=[N:25][C:14]=1[CH3:15])(=[O:3])[CH3:2]
Reactant: CCCC(=N)N
Reactant: CCOC(=O)C(Cc1cccc(C(C)=O)c1)C(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCc1nc(C)c(Cc2cccc(C(C)=O)c2)c(=O)[nH]1
Reaction time: 12 h
Yield: 78 %

Procedure:
To a solution of ethyl 2-(3-acetylbenzyl)-3-oxobutanoate (2.39 g) and butanimidamide hydrochloride (1.68 g) in methanol (20 mL) was added 28% sodium methoxide-methanol solution (5.27 mL), and the mixture was stirred for 12 hr. The reaction mixture was concentrated, and the residue was dissolved in water and diethyl ether. The aqueous layer was separated, and weakly acidified with 1 M hydrochloric acid. The precipitate was collected by filtration and dried under reduced pressure to give the title compound (2.02 g, 78%) as a colorless solid.