Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[C:21]1([OH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: Oc1ccccc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 284, Step 2) (0.1 mmol, 32 mg) in 0.7 ml of DM in a 16×100 mm tube was treated with phenol (0.15 mmol, 15 mg), cesium carbonate (0.3 mmol, 95 mg). The mixture was stirred at room temperature overnight and the reactants were filtered and washed with DMF a several times. The solvent was evaporated under vacuum, and the residue was reconstituted in a mixture of ethanol (2 ml) and NaOH (1M, 1 ml), which was stirred at room temperature until temperature until reaction was completed by HPLC-MS. Upon completion, HCl (1M) was added pH=3) and the solvents were eliminated under vacuum. The residue was reconstituted in CH2Cl2/H2O and filtered through a hidrofobic syringer. The organic layer was separated, concentrated and purified by HPLC-MS to afford the title compound as a colorless oil. MS (ES) for C19H22O5 [M+NH4]+: 348.4.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([CH2:16][N:17]2[C:25]3[C:20](=[C:21]([NH:26][C:27]([C:29]4[N:33]5[CH:34]=[CH:35][CH:36]=[CH:37][C:32]5=[N:31][CH:30]=4)=[O:28])[CH:22]=[CH:23][CH:24]=3)[C:19]([CH2:38][CH3:39])=[N:18]2)[CH:13]=[N:12]1)(C(C)(C)C)(C)C>CO.Cl>[CH2:38]([C:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][C:21]=2[NH:26][C:27]([C:29]2[N:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]3=[N:31][CH:30]=2)=[O:28])[N:17]([CH2:16][C:14]2[CH:13]=[N:12][N:11]([CH2:10][CH2:9][OH:8])[CH:15]=2)[N:18]=1)[CH3:39]
Reactant: CCc1nn(Cc2cnn(CCO[Si](C)(C)C(C)(C)C)c2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Agent: Cl
Solvent: CO
Product: CCc1nn(Cc2cnn(CCO)c2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reaction time: 3 h
Yield: 66.5 %

Procedure:
To N-(1-((1-(2-(tert-butyldimethylsilyloxy)ethyl)-1H-pyrazol-4-yl)methyl)-3-ethyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (15 mg, 0.028 mmol) in MeOH (2 mL) was added concentrated hydrochloric acid (5 drops). The reaction was stirred for 3 hours and concentrated. Silica gel chromatography (DCM/MeOH 10:1) gave the desired product (8 mg). MS (ES+APCI) m/z=430 (M+H).
Reaction SMILES: [C:1]([N:5]=[C:6]=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:8][C:9]1[CH:13]=[CH:12][NH:11][N:10]=1>ClCCl>[C:1]([NH:5][C:6]([N:11]1[CH:12]=[CH:13][C:9]([CH3:8])=[N:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc[nH]n1
Reactant: CC(C)(C)N=C=O
Solvent: ClCCl
Product: Cc1ccn(C(=O)NC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
To tert-butyl isocyanate (1.57 mL, 1.34 g, 13.70 mmol) in dichloromethane (30 mL) was added 3-methyl-1H-pyrazole (0.98 mL, 1 g, 12.18 mmol). The mixture was stirred overnight at room temperature and then concentrated under vacuum. The crude material was purified by silica chromatography (eluting with dichloromethane) to give the title compound (2.1 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.CCOCC.C([Li])CCC.[CH3:19][C:20]([CH3:22])=[O:21]>C1COCC1>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:20]([OH:21])([CH3:22])[CH3:19])=[CH:6][CH:7]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(Br)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 48.1 %

Procedure:
2,5-Dibromopyridine 3.05 g (12.5 mmol) was dissolved in 20 mL of THF and 120 mL of anhydrous ether and cooled to −78° C. 5.0 mL n-butyllithium (2.5 M, 12.5 mmol) was slowly dropped through a syringe in 30 min. After being stirred at −78° C. for 30 minutes, acetone (2 ml, 20 mmol) was added. The reaction mixture was warmed up to room temperature during two hours and then quenched by 10 ml water. The mixture was extracted twice using EtOAc. The combined extracts were dried and concentrated. After crystallization using 20% EtOAc in hexane, 1.30 g of white crystals was obtained (48% yield), MS: 215.0, 217.0 (M++1).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[CH:27]=[C:28]([NH:32][C:33](=[N:42][C:43]#[N:44])OOC3C=CC=CC=3)[CH:29]=[C:30]([CH3:31])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[CH3:45][NH:46][CH3:47]>C(O)(C)C>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][N:24]=[N:25][N:26]=3)=[CH:14][CH:15]=2)[C:7]2[CH:27]=[C:28]([NH:32][C:33]([N:46]([CH3:47])[CH3:45])=[N:42][C:43]#[N:44])[CH:29]=[C:30]([CH3:31])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CNC
Reactant: CCCc1nc2c(C)cc(NC(=NC#N)OOc3ccccc3)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Solvent: CC(C)O
Product: CCCc1nc2c(C)cc(NC(=NC#N)N(C)C)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 1c from 4'-[[2-n-propyl-4-methyl-6-(2-phenoxy-3-cyano-isoureido)-1H-benzimidazol -1-yl]-methyl]-2-(1H-tetrazol-5-yl)-biphenyl and dimethylamine in boiling isopropanol.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=1)[C:8]([NH2:10])=O)=[O:4]>C1COCC1>[NH2:10][CH2:8][C:7]1[CH:6]=[C:5]([CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=1)[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)c1cc(C(N)=O)cc([N+](=O)[O-])c1
Solvent: C1CCOC1
Product: COC(=O)c1cc(CN)cc([N+](=O)[O-])c1
Yield: 34.4 %

Procedure:
A mixture of 3-methoxycabonyl-5-nitrobenzamide (1120 mg, 5 mmol) and 1M BH3 in THF (11.5 mL) was refluxed for 90 minutes. The solvent was evaporated and MeOH (15 mL) was added. HCl gas was introduced into the solution and the reaction mixture was refluxed for 70 minutes. The mixture was added saturated NaHCO3 aq. (50 mL) and extracted with CH2Cl2 (5×40 mL). The organic layers were combined, washed with brine and dried over Na2SO4. The dried solution was applied directly to SiO2 column and developed with AcOEt then 1/10=MeOH/AcOEt. The elution was evaporated to give the desired product (361 mg, 34%): 1H NMR (300 MHz, CDCl3) δ 8.696 (s, 1H), 8.403 (s, 1H), 8.320 (s, 1H), 4.051 (s, 2H), 3.961 (s, 3H); 13C NMR (300 MHz, CDCl3) δ 165.0, 148.3, 145.9, 133.7, 131.7, 125.8, 122.8, 52.7, 45.2; HRMS m/e calc'd for C9H10N2O4 : 209.0562, found 209.0565.
Reaction SMILES: C[O:2][C:3](=[O:40])[C@H:4]([OH:39])[C@@H:5]([NH:13][C:14](=[O:38])[C:15]1[CH:20]=[C:19]([C:21]([NH:23][C@@H:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH3:25])=[O:22])[CH:18]=[C:17]([N:32]([CH3:37])[S:33]([CH3:36])(=[O:35])=[O:34])[CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+]>CO>[OH:39][C@H:4]([C@@H:5]([NH:13][C:14](=[O:38])[C:15]1[CH:20]=[C:19]([C:21]([NH:23][C@@H:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH3:25])=[O:22])[CH:18]=[C:17]([N:32]([CH3:37])[S:33]([CH3:36])(=[O:35])=[O:34])[CH:16]=1)[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:3]([OH:40])=[O:2]
Reactant: COC(=O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(C(=O)N[C@H](C)c2ccccc2)cc(N(C)S(C)(=O)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@@H](NC(=O)c1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)C(=O)O)cc(N(C)S(C)(=O)=O)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.4 %

Procedure:
To a 10 ml solution of (2R,3S)-2-hydroxy-3-{[3-[methyl(methylsulfonyl)amino]-5-({[(1R)-1-phenylethyl]amino}carbonyl)-benzoyl]amino}-4-phenylbutanoic acid methylester 775 mg (1.37 mmol) in methanol was added 1N aqueous sodium hydroxide solution 1.64 ml and the mixture was stirred at room temperature for 5 hours. After distilling methanol off, the mixture was washed with ether. The mixture was adjusted with 1N hydrochloric acid to pH 3 under ice-cooling and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium chloride solution and dried on magnesium sulfate, filtered and concentrated to give the title compound 730 mg (1.32 mmol) (yield 96%).
Reaction SMILES: C1(C(N2C3C=C(F)C(F)=CC=3N=C2C2C(OC)=NC(OC)=CC=2)C(O)=O)CCCCC1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[N:43]([CH:44]([CH:48]3[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]3)[C:45](O)=[O:46])[C:42]3[CH:54]=[C:55]([F:59])[C:56]([F:58])=[CH:57][C:41]=3[N:40]=2)=[CH:35][CH:34]=1.Cl.N[C@H]1CC[C@H](O)CC1.Cl.[CH2:70]([O:72][C:73](=[O:82])[CH2:74][C@H:75]1[CH2:80][CH2:79][C@H:78]([NH2:81])[CH2:77][CH2:76]1)[CH3:71]>>[CH2:70]([O:72][C:73](=[O:82])[CH2:74][CH:75]1[CH2:76][CH2:77][CH:78]([NH:81][C:45](=[O:46])[CH:44]([N:43]2[C:42]3[CH:54]=[C:55]([F:59])[C:56]([F:58])=[CH:57][C:41]=3[N:40]=[C:39]2[C:36]2[CH:35]=[CH:34][C:33]([Cl:32])=[CH:38][CH:37]=2)[CH:48]2[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]2)[CH2:79][CH2:80]1)[CH3:71]
Reactant: CCOC(=O)C[C@H]1CC[C@H](N)CC1
Reactant: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: COc1ccc(-c2nc3cc(F)c(F)cc3n2C(C(=O)O)C2CCCCC2)c(OC)n1
Agent: Cl
Agent: N[C@H]1CC[C@H](O)CC1
Product: CCOC(=O)CC1CCC(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)CC1

Procedure:
The title compound was prepared in analogy to example 8 replacing cyclohexyl-[2-(2,6-dimethoxy-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-acetic acid with [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid (example 22, intermediate c) and trans-4-amino-cyclohexanol hydrochloride with trans-(4-amino-cyclohexyl)-acetic acid ethyl ester hydrochloride ([CAS RN 76308-26-4]). MS (ES+): 572 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])=O)[CH2:9][CH2:8]2)[CH:2]=1.[Cl-].[CH3:21][O:22][CH2:23][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]([C:7]1([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:9][CH2:8]1)=[CH:21][O:22][CH3:23]
Reactant: O=C(c1ccc(Cl)cc1Cl)C1(c2cccnc2)CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Product: COC=C(c1ccc(Cl)cc1Cl)C1(c2cccnc2)CC1

Procedure:
starting from 2,4-dichlorophenyl 1-(3-pyridyl)-cyclopropyl ketone and methoxymethyltriphenylphosphonium chloride there is obtained 3-[1-(2,4-dichloro-α-methoxymethylenebenzyl)-cyclopropyl]-pyridine as an isomer mixture in the form of a yellow oil;
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[H-].[Na+].Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]([C:27]#[N:28])[N:18]=1>CN1C(=O)CCC1>[C:27]([C:19]1[N:18]=[C:17]([NH:1][C@H:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)[C:26]2[C:21]([CH:20]=1)=[CH:22][CH:23]=[CH:24][CH:25]=2)#[N:28]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: N#Cc1cc2ccccc2c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(C#N)cc3ccccc23)C1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
A mixture of (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (434 mg, 2.333 mmol) in NMP (2.5 mL) at 0° C. was treated with NaH (93 mg, 2.333 mmol) and stirred for 1 hour. Next, 1-chloroisoquinoline-3-carbonitrile (400 mg, 2.121 mmol) was added and the reaction mixture was stirred at RT for 15 minutes and then heated at 140° C. for 15 minutes in a microwave reactor. The crude reaction mixture, which contained the title compound, was used without further purification. ESI-MS m/z [M+H]+ 339.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:13](=[O:14])[N:12]([CH3:15])[C:11](=[O:16])[CH2:10][NH:9]2)[CH:5]=[C:4]([Cl:17])[C:3]=1[CH:18]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:19]#[N:20].[C:28](OC(=O)C)(=[O:30])[CH3:29].CC1C=CC=CC=1>CO>[C:28]([N:9]1[CH2:10][C:11](=[O:16])[N:12]([CH3:15])[C:13](=[O:14])[N:8]1[C:6]1[CH:5]=[C:4]([Cl:17])[C:3]([CH:18]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)[C:19]#[N:20])=[C:2]([Cl:1])[CH:7]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: CN1C(=O)CNN(c2cc(Cl)c(C(C#N)c3ccc(Cl)cc3)c(Cl)c2)C1=O
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(=O)N1CC(=O)N(C)C(=O)N1c1cc(Cl)c(C(C#N)c2ccc(Cl)cc2)c(Cl)c1
Reaction time: 90 h
Yield: 42.9 %

Procedure:
A mixture of 4 parts of 2,6-dichloro-α-(4-chlorophenyl)-4-(3,4,5,6-tetrahydro-4-methyl-3,5-dioxo-1,2,4-triazin-2(1H)-yl)benzeneacetonitrile, 12 parts of acetic acid anhydride and 36 parts of methylbenzene was stirred for 90 hours at reflux temperature. After cooling, 16 parts of methanol were added. The solvent was evaporated in vacuo. The residue was stirred in water and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from ethanol. The precipitated product was filtered off, washed with 2,2'-oxybispropane and dried, yielding 2.0 parts (42.9%) of 1-acetyl-2-[3,5-dichloro-4-[(4-chlorophenyl)cyanomethyl]phenyl]-1,6-dihydro-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione; mp. 178.1° C. (compound 78).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C.CC(O)=O>[CH3:13][N:14]1[CH2:19][CH2:18][CH:17]([N:10]2[C:11]3[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=3)[CH2:8][CH2:9]2)[CH2:16][CH2:15]1
Reactant: CN1CCC(=O)CC1
Reactant: O=[N+]([O-])c1ccc2c(c1)NCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CN1CCC(N2CCc3ccc([N+](=O)[O-])cc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Nitroindoline (5 g) was dissolved in 200 mL of dichloroethane, N-methyl-4-piperidone (5 g) was added to the mixture, followed by 12 g NaBH(OAc)3 and 1 mL of glacial AcOH. The mixture was stirred at RT overnight. Saturated NaHCO3 solution (200 mL) was added to the reaction mixture and stirred for 1 h. The resulting mixture was separated by separation funnel, the organic layer was extracted once with saturated NaHCO3 solution and once with brine. The resulting organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with 2:1 EtOAc:MeOH to afford an orange oil. MS: 262 (M+1). Calc'd. for C14H19N3O2—261.32.
Reaction SMILES: [Cl:1][N:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([NH:9][C:10]2[CH:11]=[C:12]([S:37]([OH:40])(=[O:39])=[O:38])[C:13]([CH:16]=[CH:17][C:18]3[C:19]([S:33]([OH:36])(=[O:35])=[O:34])=[CH:20][C:21]([NH:24][C:25]4[NH:30][N:29]([Cl:31])[N:28]=[C:27](Cl)[CH:26]=4)=[CH:22][CH:23]=3)=[CH:14][CH:15]=2)[NH:3]1.[NH2:41][C:42]1[C:51]([S:52]([OH:55])(=[O:54])=[O:53])=[CH:50][C:49]2[C:44](=[C:45]([S:60]([OH:63])(=[O:62])=[O:61])[CH:46]=[C:47]([S:56]([OH:59])(=[O:58])=[O:57])[CH:48]=2)[CH:43]=1>>[Cl:1][N:2]1[N:7]=[C:6]([NH:41][C:42]2[C:51]([S:52]([OH:55])(=[O:54])=[O:53])=[CH:50][C:49]3[C:44](=[C:45]([S:60]([OH:63])(=[O:62])=[O:61])[CH:46]=[C:47]([S:56]([OH:59])(=[O:57])=[O:58])[CH:48]=3)[CH:43]=2)[CH:5]=[C:4]([NH:9][C:10]2[CH:11]=[C:12]([S:37]([OH:40])(=[O:39])=[O:38])[C:13]([CH:16]=[CH:17][C:18]3[C:19]([S:33]([OH:36])(=[O:35])=[O:34])=[CH:20][C:21]([NH:24][C:25]4[NH:30][N:29]([Cl:31])[N:28]=[C:27]([NH:41][C:42]5[C:51]([S:52]([OH:55])(=[O:54])=[O:53])=[CH:50][C:49]6[C:44](=[C:45]([S:60]([OH:63])(=[O:62])=[O:61])[CH:46]=[C:47]([S:56]([OH:59])(=[O:57])=[O:58])[CH:48]=6)[CH:43]=5)[CH:26]=4)=[CH:22][CH:23]=3)=[CH:14][CH:15]=2)[NH:3]1
Reactant: Nc1cc2c(S(=O)(=O)O)cc(S(=O)(=O)O)cc2cc1S(=O)(=O)O
Reactant: O=S(=O)(O)c1cc(NC2=CC(Cl)=NN(Cl)N2)ccc1C=Cc1ccc(NC2=CC(Cl)=NN(Cl)N2)cc1S(=O)(=O)O
Product: O=S(=O)(O)c1cc(S(=O)(=O)O)c2cc(NC3=NN(Cl)NC(Nc4ccc(C=Cc5ccc(NC6=CC(Nc7cc8c(S(=O)(=O)O)cc(S(=O)(=O)O)cc8cc7S(=O)(=O)O)=NN(Cl)N6)cc5S(=O)(=O)O)c(S(=O)(=O)O)c4)=C3)c(S(=O)(=O)O)cc2c1

Procedure:
4,4′-Bis-(2,4-dichlorotriazin-6-ylamino)-stilbene-2,2′-disulfonic acid was reacted with 2-aminonaphthalene-3,6,8-trisulfonic acid in a similar manner to Example 5.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([Cl:11])[C:4]=1[Cl:12].O.CO.[C-:16]#[N:17].[Na+]>CS(C)=O>[Cl:12][C:4]1[C:5]([Cl:11])=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=1[CH2:2][C:16]#[N:17]
Reactant: COc1ccc(CBr)c(Cl)c1Cl
Reactant: [C-]#N
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CC#N)c(Cl)c1Cl
Temperature: 40 °C
Reaction time: 5 h
Yield: 97 %

Procedure:
To a mixture of 1-(bromomethyl)-2,3-dichloro-4-methoxybenzene (1.00 g), water (3.00 mL), methanol (6.00 mL), and dimethyl sulfoxide (2.00 mL) was added sodium cyanide (246 mg) at room temperature, followed by stirring at 40° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, and then water was added thereto. The resulting solid was collected by filtration to obtain (2,3-dichloro-4-methoxyphenyl)acetonitrile (776 mg).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:10]([C:11](O)=[O:12])=[C:9]([CH3:14])[O:8][N:7]=1)[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>O1CCCC1.O>[CH2:1]([O:5][C:6]1[C:10]([CH2:11][OH:12])=[C:9]([CH3:14])[O:8][N:7]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: Cc1onc(OCC(C)C)c1C(=O)O
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1onc(OCC(C)C)c1CO
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
To a stirred solution of 3-isobutoxy-5-methyl-isoxazole-4-carboxylic acid (146 mg, 0.73 mmol) and triethylamine (74 mg, 0.73 mmol) in tetrahydrofuran (5 mL) at −10° C. and under argon was added ethyl chloroformate (80 mg, 1.46 mmol). After 30 min, the mixture was filtered and the filter cake washed with tetrahydrofuran (4 mL). The combined filtrates were added to a solution of sodium borohydride (69 mg, 1.83 mmol) in water (2 mL) at 5° C. After 2 h the mixture was concentrated in vacuo, diluted with NaOH (2 N, 4 mL) then dried, filtered and concentrated in vacuo to give the title compound (111 mg, 82%) as a pale yellow oil. MS: m/e=186.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[CH2:21]([O:23][C:24](=[O:39])[C:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)O2)[CH:28]=[N:27][CH:26]=1)[CH3:22]>>[CH2:21]([O:23][C:24](=[O:39])[C:25]1[CH:30]=[C:29]([C:13]2[CH:12]=[N:11][C:7]3[NH:8][CH2:9][CH2:10][N:5]([CH2:4][C:3]4[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:2]=4[F:1])[C:6]=3[CH:14]=2)[CH:28]=[N:27][CH:26]=1)[CH3:22]
Reactant: CCOC(=O)c1cncc(B2OC(C)C(C)(C)O2)c1
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(I)cc32)c1
Product: CCOC(=O)c1cncc(-c2cnc3c(c2)N(Cc2cc(F)ccc2F)CCN3)c1
Yield: 29 %

Procedure:
1-(2,5-Difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (350 mg) was reacted with 5-(4,4,5-trimethyl-[1,3,2]dioxaborolan-2-yl)-nicotinic acid ethyl ester as in General Procedure 4A to give the title compound as a tan solid (29% yield). M.p. 169-172° C., LCMS: m/z=411.03 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.42 (t, J=7.1 Hz, 3H), 3.47-3.52 (m, 2H), 3.62-3.71 (m, 2H), 4.42 (q, J=7.1 Hz, 2H), 4.51 (s, 2H), 4.99 (s, 1H), 6.75 (s, 1H), 6.91-7.02 (m, 2H), 7.03-7.11 (m, 1H), 7.74 (d, J=2.0 Hz, 1H), 8.28 (d, J=2.3 Hz, 1H), 8.79 (d, J=2.3 Hz, 1H), 9.08 (d, J=2.0 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:8]=2[CH:16]=1)([O-])=O.[C:17](OC(=O)C)(=[O:19])[CH3:18].CN(C1C=CC=CN=1)C.O>C(OCC)(=O)C.[Pd]>[NH:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:8]=2[CH:16]=1)[C:17]([CH3:18])=[O:19]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cc2cc([N+](=O)[O-])ccc2o1
Agent: [Pd]
Agent: CN(C)c1ccccn1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc2cc(NC(C)=O)ccc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
Methyl 5-nitrobenzofuran-2-carboxylate (13, 0.5 g, 2.26 mmol, made from 5-nitrobenzofuran-2-carboxylic acid, Trans World Chemicals, Inc.) was dissolved in ethyl acetate (40 mL) and 5% Pd/C (30 mg) was added. The reaction mixture was hydrogenated for 1 h at room temperature at a pressure of 60 lb/inch2. The reaction mixture was filtered and the solvent was removed in vacuo. The residue was dissolved in acetone (10 mL) and was used without further purification. Acetic anhydride (0.86 mL, 9.1 mmol) and dimethylaminopyridine (20 mg) was added. The solution was stirred for 1 h at room temperature. Water (20 mL) was added and the mixture was extracted with ethyl acetate (40 mL×5). The solution was dried using sodium sulfate and solvent was removed in vacuo. A grey powder 9 was obtained (321 mg, 61% yield). An analytical sample was recrystallized in ethyl acetate. mp: 158°-159° C. 1H NMR (DMSO-d6, ppm): 10.03 (s, 1 H, NH), 8.19-8.18 (d, 1 H, J=1.6 Hz, Ar--H), 7.76-7.75 (d, 1 H, J=1.1 Hz, Ar--H), 7.65-7.63 (d, 1 H, J=9.0 Hz, Ar--H), 7.55-7.52 (dd, 2 H, J=2.3, 8.9 Hz, Ar--H), 3.89 (s, 1 H, OCH3), 2.07 (s, 3 H, CH3CO), Anal. (C12H11 NO4), C, H, N.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][C:5](=[O:9])[C:6]=1[CH2:7][CH3:8].[H-].[Na+].[CH3:12][CH:13](Cl)[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1>CN(C)C=O>[CH3:1][C:2]1[NH:3][N:4]([CH:13]([CH3:12])[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[C:5](=[O:9])[C:6]=1[CH2:7][CH3:8]
Reactant: CC(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CCC1=C(C)N=NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1c(C)[nH]n(C(C)c2ccc(Cl)c(Cl)c2)c1=O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
25.2 g of 3-methyl-4-ethylpyrazol-5-one were added in portions to a suspension of 10.0 g (0.22 mol) of sodium hydride in 200 ml of absolute dimethylformamide. After the evolution of H2 had ceased, 41.8 g (0.2 mol) of α-methyl-3,4-dichlorobenzyl chloride were added dropwise to the reaction solution. The mixture was then stirred for 2 hours at 60°C, the solvent was distilled off in vacuo and the residue was taken up in water and acidified with dilute acetic acid. The crude product thereby obtained was recrystallized from ethanol.