Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[N:6][C:5]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1.[OH-].[Na+].O.Cl>CO>[CH3:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:21])=[O:2])=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:18])[F:20])=[CH:13][CH:12]=2)[N:6]=1
Reactant: COC(=O)c1ccc(C)nc1-c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(C(=O)O)c(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
6-Methyl-2-(4-trifluoromethyl-phenyl)nicotinic acid methyl ester (7.26 g) was dissolved in methanol (30 mL). 4M sodium hydroxide (7.2 mL) was added thereto at 0° C. under cooling. The mixture was stirred at 45° C. for 3 hours. Water (30 mL) was added to the mixture at 0° C. under cooling, followed by acidification (pH=3) with 1M hydrochloric acid (about 30 mL) to give the precipitate. The precipitate was filtered and dried to give the title compound as a colorless solid (6.5 g). 1H-NMR (δ, 300 MHz, CDCl3): 2.66 (3H, s), 7.61 (2H, d, J=8.3 Hz), 7.67 (2H, d, J=8.3 Hz), 7.27 (1H, d, J=7.9 Hz), 8.18 (1H, d, J=7.9 Hz)
Reaction SMILES: BrC1C=C2C(=CC=1)C(CC(O)=O)OCC2.O.Cl.Cl.C1(CCN2CCN(C3C=CC=CC=3OC)CC2)C2C(=CC=CC=2)CCO1.[Cl:45][C:46]1[CH:47]=[C:48]([N:53]2[CH2:58][CH2:57][N:56]([C:59](=O)[CH2:60][CH:61]3[C:70]4[C:65](=[CH:66][C:67]([Br:71])=[CH:68][CH:69]=4)[CH2:64][CH2:63][O:62]3)[CH2:55][CH2:54]2)[CH:49]=[CH:50][C:51]=1[Cl:52]>>[Cl:45][C:46]1[CH:47]=[C:48]([N:53]2[CH2:54][CH2:55][N:56]([CH2:59][CH2:60][CH:61]3[C:70]4[C:65](=[CH:66][C:67]([Br:71])=[CH:68][CH:69]=4)[CH2:64][CH2:63][O:62]3)[CH2:57][CH2:58]2)[CH:49]=[CH:50][C:51]=1[Cl:52]
Reactant: O=C(CC1OCCc2cc(Br)ccc21)N1CCN(c2ccc(Cl)c(Cl)c2)CC1
Agent: COc1ccccc1N1CCN(CCC2OCCc3ccccc32)CC1
Agent: Cl
Agent: O=C(O)CC1OCCc2cc(Br)ccc21
Solvent: O
Product: Clc1ccc(N2CCN(CCC3OCCc4cc(Br)ccc43)CC2)cc1Cl

Procedure:
(6-Bromoisochroman-1-yl)acetic acid (EXAMPLE 22, LXVIII) is coupled with 3,4-dichlorophenylpiperazine (XI) and the resulting amide, 1-(3,4-dichlorophenyl)-4-[2-(6-bromoisochroman-1-yl)]acetyl piperazine (LXIII, 1.66 mmol) is reduced following the general procedure of EXAMPLE 50 and making non-critical variations, to give the title compound, HRMS Calcd for C21H23N2O1Br1Cl2 =468.0371, found=418.0363.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:4]([C:17]([OH:19])=[O:18])[CH:3]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>CN(C=O)C.CCOCC>[F:16][C:10]1[CH:11]=[C:12]([I:15])[CH:13]=[CH:14][C:9]=1[NH:8][C:5]1[N:6]=[N:7][C:2]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:3][C:4]=1[C:17]([OH:19])=[O:18]
Reactant: C1COCCN1
Reactant: O=C(O)c1cc(Cl)nnc1Nc1ccc(I)cc1F
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(O)c1cc(N2CCOCC2)nnc1Nc1ccc(I)cc1F
Temperature: 135 °C

Procedure:
To mixture of 6-chloro-3-(2-fluoro-4-iodo-phenylamino)-pyridazine-4-carboxylic acid (34 mg, 0.09 mmol) in DMF was added morpholine (37.7 mg, 0.43 mmol). The mixture was heated at 135° C. for 3.5 h. The mixture was diluted with ether and extracted with NaOH (1N). The aqueous layer was acidified by concentrated HCl. The desired product was precipitated and was collected by vacuum filtration. LC/MS [5.51 min; 445 (M+1)].
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:12][O:13][C:14]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[C:15]=1[C:16](O)=[O:17]>>[CH3:12][O:13][C:14]1[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=[C:19]([C:27]([F:28])([F:29])[F:30])[C:15]=1[C:16]([NH:11][C@@H:7]1[CH2:8][CH2:9][CH2:10][C@@H:6]1[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:17]
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)O
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCC[C@@H]1N1CCCC1

Procedure:
The title compound, white solid, MS: m/e=425.2 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2-methoxy-4,6-bis(trifluoromethyl)benzoic acid.
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[CH:3]=[CH:4][C:5]1[N:6]([CH2:23][CH2:24][CH3:25])[C:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:11]=2)=[CH:8][N:9]=1>[Pd].C(O)C>[CH3:1][C:2]([CH3:26])([CH3:27])[CH2:3][CH2:4][C:5]1[N:6]([CH2:23][CH2:24][CH3:25])[C:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:11]=2)=[CH:8][N:9]=1
Reactant: CCCn1c(-c2ccnc(Nc3ccccc3)n2)cnc1C=CC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CCCn1c(-c2ccnc(Nc3ccccc3)n2)cnc1CCC(C)(C)C
Reaction time: 72 h
Yield: 86 %

Procedure:
A mixture of 10% palladium on charcoal catalyst (100 mg), 4-[2-(3,3-dimethylbut-1-en-1-yl)-1-(propyl)imidazol-5-yl]-2-anilinopyrimidine (Method 114; 230 mg, 0.64 mmol) in ethanol (50 ml) was stirred under an atmosphere of hydrogen for 72 hours. The catalyst was removed by filtration through diatomaceous earth, and the filter pad washed with warm MeOH. The solvent removed by evaporation to give the title compound (200 mg, 86%). M/z 364.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]([CH2:11][C:12]([C:40]3[S:44][C:43]([O:45][CH2:46][CH2:47][OH:48])=[N:42][CH:41]=3)=[C:13]2[C:24](=[O:39])[N:25]([CH:36]2[CH2:38][CH2:37]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[C:28]=2[CH3:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:49][C:50]1[CH:55]=[C:54]([F:56])[CH:53]=[C:52]([Cl:57])[C:51]=1O>>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH:10]([CH2:11][C:12]([C:40]3[S:44][C:43]([O:45][CH2:46][CH2:47][O:48][C:51]4[C:50]([Cl:49])=[CH:55][C:54]([F:56])=[CH:53][C:52]=4[Cl:57])=[N:42][CH:41]=3)=[C:13]2[C:24](=[O:39])[N:25]([CH:36]2[CH2:37][CH2:38]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[C:28]=2[CH3:35])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cccc(CN(C(=O)C2=C(c3cnc(OCCO)s3)CC3CN(C(=O)OC(C)(C)C)CC2N3C(=O)OC(C)(C)C)C2CC2)c1C
Reactant: Oc1c(Cl)cc(F)cc1Cl
Product: COc1cccc(CN(C(=O)C2=C(c3cnc(OCCOc4c(Cl)cc(F)cc4Cl)s3)CC3CN(C(=O)OC(C)(C)C)CC2N3C(=O)OC(C)(C)C)C2CC2)c1C

Procedure:
This compound is prepared from compound E9 and 2,6-dichloro-4-fluorophenol, according to the above-described procedure A. LC-MS: tR=1.24 min, ES+: 847.35.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:7]2[C:16]3[CH:15]=[CH:14][N:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)[CH2:2][CH2:3][CH3:4].[H][H]>FC(F)(F)C(O)=O.[Pt]=O>[CH2:1]([C:5]1[N:6]([CH2:19][CH:20]([CH3:21])[CH3:22])[C:7]2[C:16]3[CH2:15][CH2:14][NH:13][CH2:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(N)nc3cnccc3c2n1CC(C)C
Reactant: [H][H]
Agent: O=[Pt]
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2c(N)nc3c(c2n1CC(C)C)CCNC3

Procedure:
A catalytic amount of platinum oxide was added to a solution of 2-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine (0.5 g, 1.68 mol)) in trifluoroacetic acid (20 mL). The reaction mixture was reduced on a Parr apparatus at 50 psi (3.5 Kg/cm2) hydrogen pressure overnight. The reaction mixture was filtered and washed with methanol to remove the catalyst. The filtrate was concentrated under vacuum. The residue was combined with dichloromethane and aqueous sodium bicarbonate was added until the mixture was basic. The dichloromethane layer was separated. The aqueous layer was extracted three times with dichloromethane (100 mL). The dichloromethane extracts were combined, dried over magnesium sulfate and concentrated under vacuum. The resulting residue was recrystallized from toluene then purified by flash chromatography (silica gel eluting with 20% methanol in dichloromethane with a trace of ammonium hydroxide) to provide 6,7,8,9-tetrahydro-2-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine as a solid, m.p. 164-166° C. Analysis: Calculated for C17H27N5+0.5H2O: % C, 65.77; % H, 9.09; % N, 22.56; Found: % C, 65.99; % H, 8.71; % N, 22.23.
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].O[N:17]1[C:21](=[O:22])[CH2:20][CH2:19][C:18]1=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([O:5][N:17]1[C:21](=[O:22])[CH2:20][CH2:19][C:18]1=[O:23])=[O:4]
Reactant: O=C1CCC(=O)N1O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)ON1C(=O)CCC1=O
Yield: 75 %

Procedure:
Condesation of BocProOH (6.46 g.) and N-hydroxysuccinimide (3.5 g.) using dicyclohexylcarbodiimide gave BocProOSu in 75% yield. Condensation of BocProOSu (5.0 g.) and HDPheOH (2.75 g.) by the salt coupling method gave BocPro-DPheOH in 67% yield. Condensation of BocPro-DPheOH (3.98 g.) and HPheOMe hydrochloride salt (2.4 g.) using dicyclohexylcarbodiimide and N-hydroxysuccinimide gave BocPro-DPhe-PheOMe in 74% yield. Hydrazinolysis of Boc-Pro-DPhe-PheOMe (3.14 g.) gave BocPro-DPhe-PheNHNH2 in 79% yield.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:7]([C:8]2[CH:9]=[C:10]([NH:14][C:15]([NH:17][CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)=[O:16])[CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[N:4]1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH:34]=O)=[CH:28][CH:27]=1.C(N(CC)CC)C.C([BH3-])#N>CO.C1(C)C=CC=CC=1>[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH2:34][N:21]2[CH2:22][CH2:23][CH2:24][CH:19]([CH2:18][NH:17][C:15]([NH:14][C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([C:7]4[N:3]([CH3:2])[N:4]=[N:5][N:6]=4)[CH:9]=3)=[O:16])[CH2:20]2)=[CH:28][CH:27]=1
Reactant: Cn1nnnc1-c1cccc(NC(=O)NCC2CCCNC2)c1
Reactant: O=CCCc1ccc(F)cc1
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cn1nnnc1-c1cccc(NC(=O)NCC2CCCN(CCCc3ccc(F)cc3)C2)c1
Temperature: 25 °C
Reaction time: 65 h
Yield: 64.2 %

Procedure:
A mixture of 1-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-3-piperidin-3-ylmethylurea hydrochloride (35 mg, 100 μmol), 3-(4-fluorophenyl)-propionaldehyde (15 mg, 100 μmol), triethylamine (15 μL, 110 μmol), resin-bound cyanoborohydride (prepared according to Ley, S. V., et al., J. Chem. Soc. Perkin Trans. 1, 1998, 2239; 100 mg), toluene (1 mL) and methanol (1 mL) was agitated gently at room temperature for 65 hours. The mixture was filtered, the resin was washed with dichloromethane, and the filtrates were concentrated. The residue was purified by flash chromatography, eluting with 4% methanol in dichloromethane containing 0.4% aqueous ammonium hydroxide, to provide an amorphous white solid (29 mg, 64%). 1H NMR (300 MHz, CDCl3) δ7.88 (s, 1H), 7.79 (d, J=8 Hz, 1H), 7.44 (t, J=8 Hz, 1H), 7.27 (m, 1H), 7.11 (m, 2H), 6.93 (t, J=9 Hz, 2H), 4.18 (s, 3H), 3.2-3.0 (m, 4H), 2.59 (m, 4H), 2.3-1.8 (m, 8H), 1.10 (m, 1H). Mass Spec (ES+) m/z 452.4 (M+H+, 100%).
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]C)=[CH:8][C:7]=1[S:14][CH3:15].N(CCO)CCO>ClCCl>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[S:14][CH3:15]
Reactant: COc1ccc(Cl)c(SC)c1
Agent: BrB(Br)Br
Solvent: OCCNCCO
Solvent: ClCCl
Product: CSc1cc(O)ccc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 80.9 %

Procedure:
Boron tribromide (1M in dichloromethane, 31 ml, 31 mmol) was added dropwise to a solution of 1-chloro-4-methoxy-2-(methylsulfanyl)benzene (2.88 g, 15 mmol) in dichloromethane (80 ml) at 0° C. The mixture was allowed to warm to room temperature, stirred for 72 h then cooled to 0° C. A solution of diethanolamine (10 ml) in dichloromethane (20 ml) was added dropwise (Caution—strong exotherm!) and the mixture was stirred at ambient temperature for 15 min once addition was complete, then partitioned between dichloromethane and 2N hydrochloric acid. The organic phase was washed with water, dried over MgSO4 and the solvent removed under reduced pressure. The residue was purified by flash column chromatography using ethyl acetate:cyclohexane (10:90 to 85:15) as eluant to give 4-chloro-3-(methylsulfanyl)phenol (2.12 g) as a brown oil.
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]([NH:29][C:30]2[C:35]([CH:36]([CH3:38])[CH3:37])=CC(O)=[CH:32][C:31]=2[CH:40]([CH3:42])[CH3:41])=[O:28])[CH2:22][CH2:21]1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17][CH2:18][CH2:19][N:20]1[CH2:21][CH2:22][N:23]([CH2:26][C:27]([NH:29][C:30]2[C:35]([CH:36]([CH3:37])[CH3:38])=[CH:6][C:5]([O:4][C:1](=[O:3])[CH3:2])=[CH:32][C:31]=2[CH:40]([CH3:42])[CH3:41])=[O:28])[CH2:24][CH2:25]1
Reactant: CC(C)c1cc(O)cc(C(C)C)c1NC(=O)CN1CCN(CCSc2nc3ccccc3o2)CC1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)Oc1cc(C(C)C)c(NC(=O)CN2CCN(CCSc3nc4ccccc4o3)CC2)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
Acetic anhydride (2 ml) was dropped into a solution of 2-[4-[2-(benzoxazol-2-ylthio)ethyl]piperazin-1-yl]-N-(2,6-diisopropyl-4-hydroxyphenyl)acetamide (149 mg, 0.3 mmol) in pyridine (1 ml) with ice cooling and the mixture was stirred at room temperature for 3 hours. The reaction solution was neutralized by adding a saturated aqueous solution of sodium bicarbonate thereto and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution successively and dried over sodium sulfate and the solvent was evaporated therefrom. The residue was purified by a silica gel column chromatography (developing solvent, chloroform:methanol=20:1) to provide 166 mg (yield 100%) of the desired compound as colorless needles.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10](Br)[C:9]2[S:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:15][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2].B1([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)C2CCCC1CCC2.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:9]2[S:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:15][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2]
Reactant: c1ccc(CB2C3CCCC2CCC3)cc1
Reactant: CCOC(=O)c1nc(Br)c2sc(-c3ccccc3)nc2c1O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(Cc2ccccc2)c2sc(-c3ccccc3)nc2c1O
Temperature: 25 °C
Yield: 17.9 %

Procedure:
A mixture of 4-bromo-7-hydroxy-2-phenyl-thiazolo[5,4-c]pyridine-6-carboxylic acid ethyl ester (351 mg, 0.93 mmole), B-benzyl-9-BBN (4.6 ml, 2.3 mmole, 0.5 M in THF), potassium phosphate (592 mg, 2.79 mmole), (2-(dicyclohexylphosphino)-2′,6′-dimethoxybiphenyl)(76 mg, 0.18 mmole) and palladium acetate (21 mg, 0.09 mmole) in dimethylformamide (1 ml) was refluxed for 20 h before it was cooled to room temperature and partitioned between ethyl acetate and water. The mixture was filtered and the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and dichloromethane to give the title compound as a yellow oil (65 mg). MS: (+) m/z 391.29 (M+H+)
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][N:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[O:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH:13]=[C:12]1B(O)O.[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[O:11]1[C:12]2=[CH:13][CH:14]=[CH:19][C:18]2=[CH:17][CH:16]=[C:15]1[N:6]1[C:7]2=[N:8][CH:9]=[CH:10][CH:2]=[C:3]2[CH:4]=[CH:5]1
Reactant: OB(O)c1cc2ccccc2o1
Reactant: Clc1ccnc2[nH]ccc12
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: c1cc2ccc(-n3ccc4cccnc43)oc-2c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
4-Chloro-7-azaindole (119, 100 mg, 0.66 mmol, prepared as described in Example 70, Scheme 81), 2-Benzofuranboronic acid (212 mg, 1.31 mmol) and Potassium fluoride (127 mg, 2.18 mmol) were stirred in 3 mL of anhydrous dioxane. Tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (10.2 mg, 9.83E-3 mmol) and tri t-butylphosphine (6.6 mg, 0.033 mol) were added and the suspension was stirred at 100° C. for 4 hours in a pressure tube under inert atmosphere. The reaction mixture was cooled to room temperature and was adsorbed onto silica gel and purified by chromatography to provide the compound (120, 56 mg, 36%). MS (ESI) [M+H+]+=235.20.
Reaction SMILES: C(OC([N:6]=[S:7]([C:10]1[CH:11]=[C:12]([CH:34]=[CH:35][CH:36]=1)[CH2:13][O:14][C:15]1[CH:24]=[C:23]2[C:18]([C:19]([NH:25][CH:26]([CH3:28])[CH3:27])=[N:20][CH:21]=[N:22]2)=[CH:17][C:16]=1[C:29]([O:31]CC)=[O:30])([CH3:9])=[O:8])=O)C.[O-]CC.[Na+]>>[CH:26]([NH:25][C:19]1[C:18]2[C:23](=[CH:24][C:15]([O:14][CH2:13][C:12]3[CH:34]=[CH:35][CH:36]=[C:10]([S:7]([CH3:9])(=[NH:6])=[O:8])[CH:11]=3)=[C:16]([C:29]([OH:31])=[O:30])[CH:17]=2)[N:22]=[CH:21][N:20]=1)([CH3:28])[CH3:27]
Reactant: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc3ncnc(NC(C)C)c3cc2C(=O)OCC)c1
Agent: CC[O-]
Agent: [Na+]
Product: CC(C)Nc1ncnc2cc(OCc3cccc(S(C)(=N)=O)c3)c(C(=O)O)cc12
Yield: 35 %

Procedure:
According to GWP 6, ethyl 7-({(RS)-3-[N-(ethoxycarbonyl)-S-methylsulphonimidoyl]-benzyl}oxy)-4-(isopropylamino)quinazoline-6-carboxylate (100 mg, 0.194 mmol) is reacted at 80° C. for 2 hours with sodium ethoxide (59 mg, 0.9 mmol). The reaction mixture is concentrated to dryness. The residue is taken up in ethyl acetate and water and acidified. The organic phase is separated off and subsequently concentrated. After chromatographic purification, the desired product is obtained in 35% yield (28 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].[F:23][C:24]1[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=1[C:26](=O)[CH2:27]Br>O>[F:23][C:24]1[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=1[C:26]1[N:12]=[C:11]([C:9]2[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=2)[S:13][CH:27]=1
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Reactant: O=C(CBr)c1ccccc1F
Solvent: O
Product: O=C(O)c1cc(-c2nc(-c3ccccc3F)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Yield: 18 %

Procedure:
4-[4-(2-Fluoro-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (46 mg, 18%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 2-fluorophenacyl bromide (available from Matrix Scientific) using the procedure described for the preparation of Example 18 except that the entire 4 mL of water was added at the beginning of the hydrolysis step rather than being added in two portions. 1H NMR (300 MHz, DMSO-d6) δ 8.57 (d, J=1.8 Hz, 1H), 8.12-8.30 (m, 4H), 7.61-7.80 (m, 2H), 7.34-7.50 (m, 5H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([CH:9]([N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]=1[NH:21][C:22](=[O:26])[O:23][CH2:24][CH3:25].[O-][Mn](=O)(=O)=O.[K+]>[O-2].[Mn+4].[O-2].ClCCl>[CH:2]([C:3]1[CH:8]=[C:7]([CH:9]([N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:6]=[CH:5][C:4]=1[NH:21][C:22](=[O:26])[O:23][CH2:24][CH3:25])=[O:1]
Reactant: CCOC(=O)Nc1ccc(C(c2ccccc2)n2ccnc2)cc1CO
Agent: O=[Mn](=O)(=O)[O-]
Agent: [Mn+4]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)Nc1ccc(C(c2ccccc2)n2ccnc2)cc1C=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.8 %

Procedure:
To a solution of 5.9 parts of intermediate 61, namely ethyl [2-(hydroxymethyl)-4-[(1H-imidazol-1-yl)phenylmethyl]phenyl]carbamate, in 798 parts of dichloromethane were added 21.5 parts of manganese(IV)oxide and a catalytic amount of KMnO4. After stirring for 18 hours at room temperature, the reaction mixture was filtered over diatomaceous earth and the filtrate was evaporated. The residue was co-evaporated with methylbenzene and was further purified by column chromatography (silica gel; CHCl3 /CH3OH 95:5). The eluent of the desired fraction was evaporated and the residue was taken up in ethyl acetate. This solution was concentrated and left to crystallize. The crystallized product was filtered off, stirred in 2,2'-oxybispropane and dried in vacuo, yielding 2.85 parts (48.8%) of ethyl [2-formyl-4-[(1H-imidazol-1-yl)phenylmethyl]phenyl]carbamate; mp. 107.0° C. (interm. 62).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:30])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=3)=[CH:17][C:16]=2[NH:31][C:32]2[C:33]3[CH:41]=[CH:40][C:39]([CH:42]([CH3:44])[CH3:43])=[N:38][C:34]=3[N:35]=[CH:36][N:37]=2)=[CH:10][CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([Br:29])=[CH:27][CH:28]=3)=[O:30])=[CH:17][C:16]=2[NH:31][C:32]2[C:33]3[CH:41]=[CH:40][C:39]([CH:42]([CH3:44])[CH3:43])=[N:38][C:34]=3[N:35]=[CH:36][N:37]=2)=[CH:10][CH:9]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(Br)cc4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(Br)cc4)ccc3Sc3ccc(N)cc3)ncnc2n1
Yield: 60.8 %

Procedure:
The product of Example 13D (106 mg, 0.1546 mmol) was treated with trifluoroacetic acid (3 mL) in methylene chloride (3 mL) at room temperature for 30 minutes. The solvents were removed by rotary evaporation and the residual oil taken up in ethyl acetate (75 mL) and washed with saturated aqueous sodium bicarbonate (50 mL), water, and brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel flash chromatography with 5% methanol/methylene chloride provided the title compound as a light yellow solid (55 mg, 61%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J=6.99 Hz, 6 H) 3.13-3.31 (m, 1 H) 5.60 (s, 2 H) 6.63 (d, J=8.82 Hz, 2 H) 6.88 (d, J=8.46 Hz, 1 H) 7.14 (d, J=8.46 Hz, 2 H) 7.52 (d, J=8.82 Hz, 2 H) 7.64 (d, J=8.46 Hz, 1 H) 7.73 (d, J=8.82 Hz, 2 H) 7.78 (dd, J=8.27, 1.65 Hz, 1 H) 7.94 (d, J=1.47 Hz, 1 H) 8.59 (s, 1 H) 8.88 (d, J=8.82 Hz, 1 H) 10.16 (s, 1 H) 10.28 (s, 1 H); MS (ESI+) m/z 585/587 (M+H)+, MS (ESI−) m/z 583/585 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[Cl:11]N1C(=O)CCC1=O.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[Cl:11][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[N+:8]([O-:10])=[O:9]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=[N+]([O-])c1cccc(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(F)c1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 9.3 %

Procedure:
To a −78° C. solution of 3-fluoronitrobenzene (2 g, 14.2 mmol) in THF (30 mL) was added N-chlorosuccinimide (5.69 g, 42.6 mmol) in THF (20 mL), NaHMDS (1 M in THF, 28.4 mL, 28.4 mmol) was then added dropwise to maintain an internal temperature below −75° C. The resulting mixture was stirred for 30 min at −78° C. Then it was partitioned between 5% of HCl and ethyl acetate. The combined organic layer is dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (20% Ethyl acetate Hexane) gave the desired product(231 mg, 9.2%). EI-MS m/z 176.5 (M+).