Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][C@H:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:4]1.C(Cl)Cl.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C([O-])(O)=O.[Na+]>>[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:1][CH2:2][C@@H:3]2[CH2:7][C@H:6]([NH:8][C:9]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:15])[CH:5]=[CH:4]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C=C[C@H](CO)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2C=C[C@@H](NC(=O)OC(C)(C)C)C2)cc1
Temperature: 0 °C
Yield: 70.9 %

Procedure:
To a stirred solution of tert-butyl (1S,4R)-4-(hydroxymethyl)cyclopent-2-enylcarbamate (Intermediate 6-step 2, about 4.5 g, 21.12 mmol) in DCM (50 ml) triethyl amine (about 9.5 ml, 68.1 mmol) was added at room temperature and cooled to about 0° C. After ten minutes, 4-methylbenzene-1-sulfonyl chloride (about 6.0 g) was added and stirred the reaction at room temperature for about 6 hours and completion of the reaction was monitored by TLC. Reaction mixture was neutralized with saturated NaHCO3 and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure to furnish the title compound (5.5 g) as a light yellow liquid. 1H NMR (300 MHz, CDCl3): 1.45 (s, 9H); 246-2.55 (m, 4H); 2.90-2.91 (m, 1H); 3.95-3.98 (m, 2H); 4.59-4.70 (m, 2H); 5.66-5.77 (m, 2H); 7.34-7.37 (d, J=9 Hz, 2H); 7.77-7.80 (d, J=9 Hz, 2H).
Reaction SMILES: [CH:1]1([C@H:4]([NH:26][CH2:27][CH2:28][C:29](OC)=[O:30])[C:5]([N:7]2[CH2:11][C:10]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[F:19])=[CH:9][C@H:8]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:6])[CH2:3][CH2:2]1.[OH-].[Na+].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1>CC(O)(C)C.CN(C=O)C>[CH:1]1([C@H:4]([NH:26][CH2:27][CH2:28][C:29]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[O:30])[C:5]([N:7]2[CH2:11][C:10]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[F:19])=[CH:9][C@H:8]2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: COC(=O)CCN[C@H](C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1)C1CC1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CC(C)(C)O
Product: O=C(CCN[C@H](C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1)C1CC1)N1CCOCC1
Reaction time: 4 h

Procedure:
A solution of methyl N-{(1S)-1-cyclopropyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethyl}-β-alaninate (40-1, 84 mg, 0.19 mmol, 1 equiv) and sodium hydroxide (1N, 0.57 mL, 0.57 mmol, 3.00 equiv) in t-BuOH (4 mL) was stirred at 23 deg C. for 4 h. The reaction mixture was concentrated and the residue was partitioned between brine adjusted to pH 4 with aqueous 1 N HCL solution and ethyl acetate (2×40 mL). The combined organic layers were dried over sodium sulfate and concentrated. A solution of the residue, morpholine (0.083 mL, 0.95 mmol, 5.0 equiv), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 73 mg, 0.38 mmol, 2.0 equiv), and 1-hydroxy-7-azabenzotriazole (52 mg, 0.38 mmol, 2.0 equiv) in DMF (2 mL) was heated at 50° C. for 20 h. The reaction mixture was partitioned between aqueous saturated sodium bicarbonate solution and ethyl acetate (2×30 mL). The combined organic layers were dried over sodium sulfate and were concentrated. The residue was purified by reverse-phase LC (H2O/CH3CN gradient w/0.1% TFA present) and the desired fractions partitioned between saturated sodium bicarbonate solution and ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to provide N-{(1S)-1-cyclopropyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethyl}-3-morpholin-4-yl-3-oxopropan-1-amine (41-2) as a white foam. LRMS m/z M+H) 496.5 found, 496.2 required.
Reaction SMILES: OC1C2C(=C(O)C=CC=2)N=C(C([NH:15][C@H:16]([C:25]([NH:27][NH:28][C:29](=[O:37])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[OH:36])=[O:26])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=O)C=1.[C:38]([OH:50])(=O)/[CH:39]=[CH:40]/[C:41]1[CH:48]=[CH:47][C:45]([OH:46])=[C:43]([OH:44])[CH:42]=1>>[C:38]([NH:15][C@H:16]([C:25]([NH:27][NH:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[OH:36])=[O:26])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)(=[O:50])/[CH:39]=[CH:40]/[C:41]1[CH:48]=[CH:47][C:45]([OH:46])=[C:43]([OH:44])[CH:42]=1
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)NNC(=O)c1ccccc1O)c1cc(O)c2cccc(O)c2n1
Product: O=C(/C=C/c1ccc(O)c(O)c1)N[C@@H](Cc1ccc(O)cc1)C(=O)NNC(=O)c1ccccc1O
Yield: 24.9 %

Procedure:
N1-[Nα-(tert-butoxycarbonyl)-L-tyrosyl]-N2-(2-hydroxybenzoyl)-hydrazine (349 mg, 0.84 mmol) prepared in example 73, step A was deprotected following the indications of general procedure C and coupled with caffeic acid (230 mg, 1.3 mmol) using general procedure D. The final product was purified by flash chromatography eluting with 40% EtOAc/CH2Cl2 then successively 5% and 10% MeOH/CH2Cl2 to yield 100 mg, 25% of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:16][CH:15]=[N:14][CH:13]=2)=[C:8]([O:17][CH3:18])[CH:7]=1)=[O:4].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH3:18][O:17][C:8]1[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:11]=[CH:10][C:9]=1[C:12]1[O:16][CH:15]=[N:14][CH:13]=1
Reactant: Nc1ccccc1
Reactant: COc1cc(NC(=O)CCl)ccc1-c1cnco1
Solvent: CN(C)C=O
Product: COc1cc(NC(=O)CNc2ccccc2)ccc1-c1cnco1

Procedure:
A solution of 2A (30.0 mg, 0.11 mmol) and aniline (30 μL, 0.33 mmol) in DMF (0.1 mL) was heated at 100° C. for 2.5 h. After the reaction had cooled, the solvent was removed under reduced pressure, and the residue was subjected to preparative HPLC to give 2 as a yellow solid. LC/MS: ret. timeA=3.576 min., MS (M+H)+=324.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]#[N:23])[CH:17]=3)[CH:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.OO.C=CCCCC.C(=O)([O-])[O-:35].[Na+].[Na+]>CO>[F:25][C:2]([F:24])([F:1])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22](=[O:35])[NH2:23])[CH:17]=3)[CH:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cc(-c2ccnc(Nc3cccc(C(F)(F)F)c3)n2)ccn1
Agent: OO
Agent: [Na+]
Solvent: CO
Solvent: C=CCCCC
Product: NC(=O)c1cc(-c2ccnc(Nc3cccc(C(F)(F)F)c3)n2)ccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
100 mg (0.293 mmol) of N-(3-trifluoromethyl-phenyl)-4-(2-cyano-4-pyridyl)-2-pyrimidineamine are suspended in 4 ml of methanol. 1.1 ml of hydrogen peroxide (30%), 0.32 ml of 1-hexene and 22 mg of sodium carbonate are added and the reaction mixture is stirred for 16 hours at RT. The product is isolated by filtration and washed (methanol/water) to give N-(3-trifluoromethyl-phenyl)-4-(2-carbamoyl-4-pyridyl)-2-pyrimidineamine; m.p. 240°-242°, FAB-MS: 360 (M+ +H).
Reaction SMILES: C([NH:5][C:6]1[C:11]([C:12]2[N:13]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=3[F:28])[C:14]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[N:20]=2)=[CH:10][CH:9]=[CH:8][N:7]=1)(C)(C)C.Cl.[OH-].[Na+]>CO>[F:28][C:22]1[C:23]([F:27])=[CH:24][CH:25]=[CH:26][C:21]=1[N:13]1[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[N:20]=[C:12]1[C:11]1[C:6]([NH2:5])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)(C)Nc1ncccc1-c1nc2cnccc2n1-c1cccc(F)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1ncccc1-c1nc2cnccc2n1-c1cccc(F)c1F
Temperature: 0 °C
Yield: 70.5 %

Procedure:
To a stirred solution of N-tert-butyl-3-(1-(2,3-difluorophenyl)-1H-imidazo[4,5-c]pyridin-2-yl)pyridin-2-amine (1.5 g, 3.95 mmol) in methanol (7.0 mL) was added 6N aq. HCl at room temperature and the mixture heated at reflux for 5 hr. After cooling to 0° C., the pH of the solution was adjusted to pH 8-9 with 2N aq. NaOH solution (150 mL). The resulting precipitate was filtered off and dissolved in EtOAc (300 mL). The combined organics were washed with water (3×100 mL), brine (100 mL), and dried (Na2SO4). Filtration and evaporation of solvent in vacuo gave a solid, which was triturated with petroleum ether (3×20 mL) to give 3-(1-(2,3-difluorophenyl)-1H-imidazo[4,5-c]pyridin-2-yl)pyridin-2-amine (0.9 g, 75% yield) as a light yellow solid; LC-MS: 324.0 (M+H).
Reaction SMILES: [CH:1]([O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=1[C:8]([OH:10])=O)([CH2:3][CH3:4])[CH3:2].[N:19]1([C:25]2[S:26][C:27]([C:30]#[N:31])=[CH:28][N:29]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH:1]([O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=1[C:8]([N:22]1[CH2:23][CH2:24][N:19]([C:25]2[S:26][C:27]([C:30]#[N:31])=[CH:28][N:29]=2)[CH2:20][CH2:21]1)=[O:10])([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: N#Cc1cnc(N2CCNCC2)s1
Product: CCC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(C#N)s2)CC1
Yield: 34 %

Procedure:
Prepared in analogy to example 1 (b) from 2-sec-butoxy-5-methanesulfonyl-benzoic acid (Example A10) and 2-piperazin-1-yl-thiazole-5-carbonitrile (Example 6(a)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the tide compound as a white crystalline solid (yield 34%). MS (m/e): 449.4 (M+H+, 100%).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[CH3:5][CH:6]1[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]1>>[CH2:3]([CH:9]1[C:10](=[O:12])[CH2:11][CH:6]([CH3:5])[CH2:7][C:8]1=[O:13])[CH:2]=[CH2:1]
Reactant: CC1CC(=O)CC(=O)C1
Reactant: C=CCBr
Product: C=CCC1C(=O)CC(C)CC1=O

Procedure:
By the procedure of Example 29, allyl bromide is reacted with 5-methyl-1,3-cyclohexanedione to produce 2-allyl-5-methyl-1,3-cyclohexanedione.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[C:21]([CH2:26][CH3:27])[CH:22]=[CH:23][CH:24]=4)[NH:19][N:18]=3)=[CH:15][N:16]=[C:11]2[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C(N)CN>ClCCl.CO.ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[C:21]([CH2:26][CH3:27])[CH:22]=[CH:23][CH:24]=4)[NH:19][N:18]=3)=[CH:15][N:16]=[C:11]2[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1cccc2c(-c3cnc4c(n3)c(C(=O)NC(C)(C)C)cn4COCC[Si](C)(C)C)n[nH]c12
Solvent: ClCCl
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Product: CCc1cccc2c(-c3cnc4[nH]cc(C(=O)NC(C)(C)C)c4n3)n[nH]c12
Temperature: 25 °C
Yield: 48.3 %

Procedure:
To a solution of N-tert-butyl-2-(7-ethyl-1H-indazol-3-yl)-5-((2(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (45 mg, 91.3 μmol) in dichloromethane (913 μL) was added trifluoroacetic acid (417 mg, 281 μL, 3.65 mmol) and stirred at room temperature. After 16 h the reaction mixture was concentrated. The residue was dissolved in dichloromethane (913 μL) and ethylenediamine (329 mg, 370 μL, 5.48 mmol) was added and stirred at room temperature. After 1 h the reaction was diluted with 10% methanol/dichloromethane. Purification by chromatography (silica, MeOH/DCM gradient) gave N-tert-butyl-2-(7-ethyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (16 mg, 44.1 μmol, 48%) as a white solid. MS (M+H)+=363.2; 1H NMR (CD3OD) δ: 9.17 (s, 1H), 8.36 (d, J=7.5 Hz, 1H), 8.27 (s, 1H), 7.81 (s, 1H), 7.27 (d, J=7.5 Hz, 1H), 7.18 (t, J=7.5 Hz, 1H), 3.03 (q, J=7.7 Hz, 2H), 1.62 (s, 9H); 1.42 (t, J=7.7 Hz, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:8][C:9]=1[N:10]([C:18]([CH:20]1[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][CH2:21]1)=[O:19])[NH:11]C(=O)C(F)(F)F)=[O:4].[OH-].[Na+].Cl>CCOC(C)=O>[CH3:30][C:29]([CH3:31])([CH3:32])[C:28]#[C:27][C:7]1[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([N:10]([C:18]([CH:20]2[CH2:21][CH2:22][CH:23]([CH3:26])[CH2:24][CH2:25]2)=[O:19])[NH2:11])[CH:8]=1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(NC(=O)C(F)(F)F)C(=O)C1CCC(C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC1CCC(C(=O)N(N)c2cc(C#CC(C)(C)C)sc2C(=O)O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
To a solution of 5-(3,3-dimethyl-but-1-ynyl)-3-[N-(4-methyl-cyclohexanecarbonyl)-N′-(2,2,2-trifluoro-acetyl)-hydrazino]-thiophene-2-carboxylic acid methyl ester (1.6 g, 3.4 mmol) in EtOAc (20 mL) was added NaOH (6.8 mL of 2M aq solution). After 2 h stirring at rt, the reaction was neutralized with 1M HCl aq, extracted with EtOAc, dried over Na2SO4, and concentrated to give 5-(3,3-dimethyl-but-1-ynyl)-3-[N-(4-methyl-cyclohexanecarbonyl)-hydrazino]-thiophene-2-carboxylic acid (1.1 g, 3 mmol) as an off white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13](Cl)[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=1B(O)O>>[CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([C:21]2[CH:22]=[CH:23][C:24]([C:26]([F:29])([F:28])[F:27])=[CH:25][C:20]=2[Cl:19])[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1c(Cl)ccnc1OCc1ccccc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1Cl
Product: O=[N+]([O-])c1c(-c2ccc(C(F)(F)F)cc2Cl)ccnc1OCc1ccccc1
Yield: 79 %

Procedure:
2-Benzyloxy-4-chloro-3-nitro-pyridine (Wilde, et al. WO 99/01454, which is incorporated herein by reference in its entirety) (2.0 g, 7.56 mmol) and 2-chloro-4-trifluoromethylphenylboronic acid (2.31 g, 11.3 mmol) were treated substantially as described in Part A of Example 19a to give 2.44 g (79%) of 2-benzyloxy-4-(2-chloro-4-trifluoromethyl-phenyl)-3-nitro-pyridine: MS (AP) m/z 408.8 [(M+H)+, 72].
Reaction SMILES: O1CCO[CH:2]1[CH:6](C)[CH2:7][NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[C:12]([CH3:17])[CH:11]=1>O>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]2[O:18][C:6]([CH3:2])=[CH:7][N:8]=2)=[CH:11][C:12]=1[CH3:17]
Reactant: Cc1cc(C(=O)NCC(C)C2OCCO2)ccc1Br
Solvent: O
Product: Cc1cnc(-c2ccc(Br)c(C)c2)o1
Temperature: 160 °C
Yield: 89.1 %

Procedure:
N-[2-(1,3-Dioxolan-2-yl)propyl]-4-bromo-3-methylbenzamide (D74, 2.8 g, 8.9 mmole) was added portionwise over 5 minutes to well stirred polyphosphoric acid (50 g) at 120° C. under argon, then heated at 160° C. for 35 minutes. The reaction mixture was allowed to cool, then treated with water (200 ml) and stirred well to dissolve the glassy mass. The mixture was extracted with ethyl acetate and the extract washed with 10% Na2CO3 solution and water, then dried (Na2SO4) and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 1:1 ether/60-80 petrol to afford the title compound as a pale yellow solid (2.0 g, 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:23])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14]O)=[CH:10][C:9]=2[C:16]2[C:20]([CH3:22])([CH3:21])[CH2:19][CH2:18][CH:17]=2)[CH:7]=1.CN(C=O)C.S(Cl)([Cl:31])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:23])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][Cl:31])=[CH:10][C:9]=2[C:16]2[C:20]([CH3:22])([CH3:21])[CH2:19][CH2:18][CH:17]=2)[CH:7]=1
Reactant: CC1(C)CCC=C1c1cc(CO)ccc1-c1cc(Cl)ccc1F
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)CCC=C1c1cc(CCl)ccc1-c1cc(Cl)ccc1F
Reaction time: 1 h
Yield: 143.2 %

Procedure:
To a stirred solution of 78.9B (0.048 g, 0.1 mmol) in DCM (2.00 mL) at 23° C. was added DMF (0.001 mL) followed by thionyl chloride (0.02 mL, 0.3 mmol). The reaction was stirred for one hour and then concentrated in vacuo. The product was purified on silica gel (0-10% EtOAc in hexanes) to yield 78.9C as a colorless oil (0.05 g, 99% yield).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].C([O:13][C:14]([C:16]1[O:17][C:18]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][C:19]=2[CH:20]=1)=O)C.[NH4+]>O1CCCC1>[Br:25][C:22]1[CH:23]=[CH:24][C:18]2[O:17][C:16]([CH2:14][OH:13])=[CH:20][C:19]=2[CH:21]=1
Reactant: CCOC(=O)c1cc2cc(Br)ccc2o1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cc2cc(Br)ccc2o1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 92.3 %

Procedure:
To a tetrahydrofuran (20 mL) solution of lithium aluminum hydride (706 mg, 18.6 mmol) was added aluminum chloride (2.98 g, 22.3 mmol), which was stirred until the aluminum chloride dissolved in tetrahydrofuran. Then, to the reaction mixture was added 5-bromo-benzofuran-2-carboxylic acid ethyl ester (1.00 g, 3.72 mmol) described in Production Example 56-1-1 at 0° C. followed by stirring at 0° C. for 20 minutes. To the reaction solution was added aqueous ammonium followed by filtering through Celite. The filtrate was concentrated under a reduced pressure and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (780 mg, 92%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:10](CCO[C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH:20]([CH3:22])[CH3:21])[N:16]=[C:17]([CH3:19])[N:18]=1)[N:7]=3.Cl.BrC1C=CC(C(N)=N)=C([F:36])C=1.C(=O)([O-])O.[K+].BrCC(C1N(C(C)C)N=C(C)N=1)=O>C1COCC1.O>[Br:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]2[NH:10][CH:9]=[C:8]([C:14]3[N:15]([CH:20]([CH3:22])[CH3:21])[N:16]=[C:17]([CH3:19])[N:18]=3)[N:7]=2)=[C:4]([F:36])[CH:3]=1
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Reactant: N=C(N)c1ccc(Br)cc1F
Agent: Cc1nc(C(=O)CBr)n(C(C)C)n1
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(-c2c[nH]c(-c3ccc(Br)cc3F)n2)n(C(C)C)n1
Yield: 79 %

Procedure:
Alternatively, 8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene may be prepared whereby a mixture of 4-bromo-2-fluoro-benzamidine hydrochloride (5.67 g, 22.3 mmol), potassium hydrogen carbonate (8.95 g, 89.4 mmol), THF (45 mL) and water (10 mL) was heated to reflux and a solution of 2-bromo-1-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-ethanone (5.5 g, 22.3 mmol) in THF (15 mL) added dropwise. The reaction mixture was heated at reflux for 18 h before removal of volatile solvent in vacuo. The resultant suspension was filtered and the residue triturated in hot diethyl ether to give 5-[2-(4-Bromo-2-fluoro-phenyl)-1H-imidazol-4-yl]-1-isopropyl-3-methyl-1H-[1,2,4]triazole as an off-white solid (6.4 g, 79%). 1H NMR 400 MHz (DMSO-d) δ: 7.97 (1 H, t, J=8.30 Hz), 7.81 (1 H, s), 7.76 (1 H, dd, J=10.68, 1.92 Hz), 7.58 (1 H, dd, J=8.42, 1.93 Hz), 5.79 (1 H, br, m), 2.26 (3 H, s), 1.44 (6 H, d, J=6.60 Hz).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])=[CH:22][C:16]2[N:17]=[C:18]([S:20][CH3:21])[NH:19][C:15]=2[CH:14]=1.S(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:12][C:13]1[C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])=[CH:22][C:16]2[N:17]=[C:18]([S:20]([CH3:21])=[O:9])[NH:19][C:15]=2[CH:14]=1
Reactant: CSc1nc2cc(Oc3ccc(Cl)cc3Cl)c(Cl)cc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CS(=O)c1nc2cc(Oc3ccc(Cl)cc3Cl)c(Cl)cc2[nH]1
Reaction time: 15 h
Yield: 71.1 %

Procedure:
A solution of 19.5 g of 90% pure m-chloroperbenzoic acid in 450 ml of chloroform is added dropwise in the course of 30 minutes to a solution, which has been cooled to 0° to 5° C., of 35 g of 5-chloro-6-(2',4'-dichlorophenoxy)-2-methylthio-benzimidazole in 1,750 ml of chloroform, with stirring. The mixture is stirred for a further 3 hours at 0° to 5° C. and then for 15 hours at room temperature and then is freed from the small amount of precipitate which arises. The filtrate, which still contains residues of m-chloroperbenzoic acid, is treated with sodium bisulphite solution, washed with water, dried over calcium chloride, filtered and concentrated in vacuo. After recrystallising the residue from 500 ml of ethyl acetate, and at the same time clarifying the hot solution with active charcoal, and then drying the white crystals at 50° C., 26 g of 5-chloro-6-(2',4'-dichlorophenoxy)-2-methylsulphinyl-benzimidazole with a melting point of 206°-208° C. are obtained, which corresponds to a yield of 69%.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][NH:11][C:10]2[N:15]=[CH:16][C:17](I)=[CH:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)=[O:23]>>[CH3:20][O:21][C:22](=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([C:17]2[CH:16]=[N:15][C:10]3[NH:11][CH2:12][C:13](=[O:14])[N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:9]=3[CH:18]=2)[CH:29]=1
Reactant: O=C1CNc2ncc(I)cc2N1Cc1ccccc1
Reactant: COC(=O)c1cccc(B(O)O)c1
Product: COC(=O)c1cccc(-c2cnc3c(c2)N(Cc2ccccc2)C(=O)CN3)c1
Yield: 70 %

Procedure:
1-Benzyl-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (370 mg) was reacted with 3-methoxycarbonyl phenyl boronic acid as in General Procedure 4A to give the title compound as a white solid (70% yield). M.p. 211° C., LCMS: m/z=374.17 (M+H+), 1H-NMR (CD3OD, 400 MHz) δ 3.95 (s, 3H), 4.48 (s, 2H), 5.35 (s, 2H), 7.23-7.35 (m, 2H), 7.38-7.40 (m, 2H), 7.50-7.58 (m, 2H), 7.60-7.66 (m, 2H), 7.84 (s, 1H), 7.9-8.1 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[C:4](Cl)[N:3]=1.[CH2:17]([NH2:20])[CH2:18][CH3:19]>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[C:4]([NH:20][CH2:17][CH2:18][CH3:19])[N:3]=1
Reactant: CCCN
Reactant: CCC(CC)n1cnc2c(Cl)nc(Cl)nc21
Solvent: CCCCO
Product: CCCNc1nc(Cl)nc2c1ncn2C(CC)CC
Reaction time: 5 h

Procedure:
The operation is carried out as in Stage 2 of Example 3 from 200 mg of the product obtained in Stage 1 of Example 3 and 4 ml of butanol and using 0.129 ml of propylamine in place of the benzylamine. Agitation is carried out at ambient temperature then the reaction medium is taken to a temperature of 80 to 85° C. for 5 hours, left to return to ambient temperature, followed by evaporating to dryness then impasting in 5 ml of pentane at ambient temperature, separating, washing and drying at a temperature of approximately 50° C. After purification on silica eluting with methylene chloride/ethyl acetate in a proportion of 90/10, 145 mg of expected product is obtained in the form of white crystals.
Reaction SMILES: [H][H].Cl.C([NH:7][C:8]1[C:9]([Cl:18])=[CH:10][CH:11]=[C:12]2[C:17]=1[CH:16]=[N:15][CH:14]=[CH:13]2)(=O)C>CO.[Pt]=O>[ClH:18].[NH2:7][C:8]1[C:9]([Cl:18])=[CH:10][CH:11]=[C:12]2[C:17]=1[CH2:16][NH:15][CH2:14][CH2:13]2
Reactant: [H][H]
Reactant: CC(=O)Nc1c(Cl)ccc2ccncc12
Agent: O=[Pt]
Agent: Cl
Solvent: CO
Product: Nc1c(Cl)ccc2c1CNCC2

Procedure:
Platinum oxide (0.1 g.) in methanol is reduced with hydrogen at atmospheric pressure. 8-Acetamido-7-chloroisoquinoline hydrochloride (1.0 g.) is treated as in Example 11 to give 8-amino-7-chloro-1,2,3,4-tetrahydroisoquinoline hydrochloride.
Reaction SMILES: CO[C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=[CH:5][CH:4]=1.[F:31][C:32]([F:42])([F:41])C1C=CC(C=O)=CC=1.COC1C=CC(C=O)=CC=1>>[F:31][C:32]([F:42])([F:41])[C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=[CH:5][CH:4]=1
Reactant: COc1ccc(CNCCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: COc1ccc(C=O)cc1
Product: O=C(NCCNCc1ccc(C(F)(F)F)cc1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid [2-(4-methoxy-benzylamino)-ethyl]amide using 4-(trifluoromethyl)benzaldehyde lidine instead of 4-methoxy benzaldehyde. LCMS (ESI) 460 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.52 (1H, br. s.) 10.25 (1H, s) 8.05 (1H, t, J=5.66 Hz) 8.01 (1H, d, J=5.47 Hz) 7.77 (1H, d, J=5.27 Hz) 7.58-7.64 (2H, m) 7.50-7.55 (2H, m) 7.46 (1H, d, J=5.42 Hz) 7.30 (1H, d, J=3.17 Hz) 6.79 (1H, d, J=5.52 Hz) 6.43 (1H, dd, J=3.44, 1.93 Hz) 3.77 (2H, s) 3.35 (2H, q, J=6.23 Hz) 2.63 (2H, t, J=6.52 Hz)