Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.Cl.Cl.[CH3:20][NH:21][C:22](=[O:36])[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[C:25]([CH3:35])[CH:24]=1.[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[CH3:20][NH:21][C:22](=[O:36])[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][N:32]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]5[C:7](=[O:17])[NH:6][C:5]=4[CH:4]=3)[CH2:31][CH2:30]2)=[C:25]([CH3:35])[CH:24]=1
Reactant: O=C1Nc2cc(CO)cnc2N2CCCC[C@@H]12
Reactant: CNC(=O)c1ccc(N2CCNCC2)c(C)c1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)c(C)c1
Temperature: 90 °C
Yield: 14.2 %

Procedure:
(S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one (100 mg, 0.429 mmol), N,3-dimethyl-4-(piperazin-1-yl)benzamide dihydrochloride (131 mg, 0.429 mmol), (cyanomethyl)trimethylphosphonium iodide (167 mg, 0.686 mmol) and N,N-diisopropylethylamine (374 μl, 2.143 mmol) were suspended in propiononitrile (Volume: 1287 μl) and heated in a closed vial at 90° C. for 4 h. The reaction mixture became a dark brown solution. It was cooled to room temperature and purified using HPLC (NH4HCO3 buffered, 20-70% ACN in water). The fractions were concentrated in vacuo and the resulting solid was recrystallized from MeCN (5 mL), filtered off, washed with water (2 mL) and dried in vacuum to afford (S)—N,3-dimethyl-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (27.4 mg, 0.061 mmol, 14.25% yield) as a light beige solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.31-1.57 (m, 3H) 1.64 (d, J=11.87 Hz, 1H) 1.85 (d, J=11.37 Hz, 1H) 2.04 (d, J=11.87 Hz, 1H) 2.25 (s, 3H) 2.51-2.70 (m, 5H) 2.56-2.70 (m, 2H) 2.74 (d, J=4.29 Hz, 3H) 2.87 (br. s., 4H) 3.37-3.45 (m, 2H) 3.84 (dd, J=11.24, 2.40 Hz, 1H) 4.50 (d, J=13.14 Hz, 1H) 6.98 (d, J=1.77 Hz, 1H) 7.01 (d, J=8.34 Hz, 1H) 7.61 (dd, J=8.46, 1.64 Hz, 1H) 7.65 (dd, J=12.25, 1.64 Hz, 2H) 8.23 (q, J=4.13 Hz, 1H) 10.48 (s, 1H); [M+H] calc'd for C25H32N6O2, 449. found, 449.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:12][CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:20]=O.[C:22]1([C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[NH:33][C:32](=[O:37])[CH2:31]3)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1/[CH:20]=[C:31]1\[C:32](=[O:37])[NH:33][C:34]2[C:30]\1=[CH:29][C:28]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:36][CH:35]=2
Reactant: O=C1Cc2cc(-c3ccccc3)ccc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Product: Cc1c(/C=C2\C(=O)Nc3ccc(-c4ccccc4)cc32)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Yield: 62.3 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 28 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 28c obtained from step 3 of Example 28 and 5-phenyl-1,3-dihydro-indol-2-one as starting materials to obtain (Z)-3-methyl-2-(2-oxo-5-phenyl-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-pyrrolidin-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 48 (41 mg, yield 62.3%) as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[F:21])([OH:13])[CH2:9]1)[C:2]1C=CC=C[CH:3]=1.ICCC.N1CCOCC1>CN(C)C=O>[F:21][C:15]1[C:16]([F:20])=[CH:17][CH:18]=[CH:19][C:14]=1[C:10]1([OH:13])[CH2:11][CH2:12][N:8]([CH2:1][CH2:2][CH3:3])[CH2:9]1
Reactant: OC1(c2cccc(F)c2F)CCN(Cc2ccccc2)C1
Solvent: CN(C)C=O
Solvent: CCCI
Solvent: C1COCCN1
Product: CCCN1CCC(O)(c2cccc(F)c2F)C1

Procedure:
Preparation according to Example 34: (−)-1-benzyl-3-(2,3-difluorophenyl)pyrrolidin-3-ol (0.40 g, 1.38 mmol), dimethyl formamide (3 mL), iodopropane (1.35 mL, 13.8 mmol) and morpholine (2 mL). Purification by HPLC on Waters OBD C18, 5 μm (MeOH/33 mM NH3, 40:60 to 60:40). Yield: 0.174 g. [α]D=−22.1° (methanol). The amine was converted to the fumaric acid salt and recrystallized from methanol/diethyl ether/diisopropyl ether: M.p. 97-100° C.; MS m/z (relative intensity, 70 eV) 241 (M+, 10), 212, (bp), 182 (34), 84 (53), 57 (14).
Reaction SMILES: C(Cl)(Cl)=O.[Cl:5][C:6]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([O:15][CH3:16])=[C:9]([Cl:17])[C:7]=1[NH2:8].[N-:18]=[C:19]=[O:20].[N:21]1([CH2:27][CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:37]3[CH:42]=[C:41](N)[N:40]=[CH:39][N:38]=3)=[CH:32][CH:31]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C([O-])(O)=O.[Na+]>O1CCOCC1.CN1C(=O)CCC1.C(Cl)Cl>[Cl:5][C:6]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([O:15][CH3:16])=[C:9]([Cl:17])[C:7]=1[NH:8][C:19]([NH:18][C:41]1[CH:42]=[C:37]([NH:36][C:33]2[CH:34]=[CH:35][C:30]([O:29][CH2:28][CH2:27][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:31][CH:32]=2)[N:38]=[CH:39][N:40]=1)=[O:20]
Reactant: Nc1cc(Nc2ccc(OCCN3CCOCC3)cc2)ncn1
Reactant: COc1cc(OC)c(Cl)c(N)c1Cl
Reactant: [N-]=C=O
Agent: O=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(NC(=O)Nc2cc(Nc3ccc(OCCN4CCOCC4)cc3)ncn2)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Phosgene (20% in toluene, 0.8 mL, 1.58 mmol, 2.4 equiv) is added to a solution of 2,6-dichloro-3,5-dimethoxyaniline (175 mg, 0.79 mmol, 1.2 equiv) in dioxane (2.5 mL), under an argon atmosphere. The mixture is heated to reflux, stirred for 1 h, allowed to cool to RT, and concentrated in vacuo. The resulting isocyanate is added to a solution of N-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyrimidine-4,6-diamine (208.5 mg, 0.66 mmol) in NMP (2 mL), at 75° C. and under an argon atmosphere. The reaction mixture is stirred at 75° C. for 2 h, allowed to cool to RT, and is then diluted with DCM and a saturated aqueous solution of NaHCO3. The aqueous layer is separated and extracted with DCM. The organic phase is washed with brine, dried (Na2SO4), filtered and concentrated. Purification of the crude product by silica gel column chromatography (DCM/MeOH+1% NH3aq, 96:4), followed by trituration of the resulting material in MeOH, affords the title compound as a white solid: ESI-MS: 562.9/564.9 [MH]+; tR=2.99 min (purity: 100%, system 1); TLC: Rf=0.36 (DCM/MeOH+1% NH3aq, 93:7).
Reaction SMILES: N.[Br:2][C:3]1[CH:15]=[CH:14][C:6]2[NH:7][C:8](=[O:13])[NH:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[CH3:16]I.O>CO.CN(C=O)C>[Br:2][C:3]1[CH:15]=[CH:14][C:6]2[NH:7][C:8](=[O:13])[N:9]([CH3:16])[S:10](=[O:11])(=[O:12])[C:5]=2[CH:4]=1
Reactant: CI
Reactant: O=C1Nc2ccc(Br)cc2S(=O)(=O)N1
Agent: N
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: CN1C(=O)Nc2ccc(Br)cc2S1(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Gaseous ammonia was passed through a suspension of 7-bromo-2H-benzo[e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide (760 mg, 2.7 mmol) in MeOH (8 mL) until a clear solution was obtained. The solvent was then evaporated and the residue was slurried with MeOH (5 mL) and filtered. The solid obtained was dissolved in DMF (5 mL) and treated with MeI (169 μL, 2.75 mmol). The reaction mixture was stirred at rt for 18 h, poured into water (20 mL) and extracted with EtOAc (3×50 mL). The combined EtOAc layer was dried over Na2SO4, filtered, and concentrated to obtain compound 42a. 1H-NMR (400 MHz, CD3OD) δ (ppm): 7.86 (d, J=2.0 Hz, 1H), 7.60 (dd, J=8.7, 2.1 Hz, 1H), 7.00 (d, J=8.6 Hz, 1H), 3.26 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12]([C:14]2[N:19]=[C:18]([NH:20][C@H:21]([CH3:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:17]([N+:27]([O-])=O)=[CH:16][CH:15]=2)=[C:11]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[N:10]=1.O.O.[Sn](Cl)Cl.[N:42]#[C:43]Br>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12]([C:14]2[N:19]=[C:18]3[N:20]([C@H:21]([CH3:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:43]([NH2:42])=[N:27][C:17]3=[CH:16][CH:15]=2)=[C:11]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[N:10]=1
Reactant: C[C@@H](Nc1nc(-c2[nH]c(-c3c(F)cccc3F)nc2-c2ccc(F)cc2)ccc1[N+](=O)[O-])C(C)(C)C
Reactant: N#CBr
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: C[C@@H](n1c(N)nc2ccc(-c3[nH]c(-c4c(F)cccc4F)nc3-c3ccc(F)cc3)nc21)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
Dissolve {6-[2-(2,6-difluoro-phenyl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-3-nitro-pyridin-2-yl}-(1(R),2,2-trimethyl-propyl)-amine (673 mg, 1.4 mmol) in 100% ethanol (15 mL) and add tin(II) dichloride dihydrate (1.5 g, 6.8 mmol, 5 equiv). Heat the reaction mixture until starting material is consumed. Cool the reaction solution to room temperature, quench slowly with saturated aqueous NaHCO3. Add Celite® to the quenched reaction and filter the suspension on a Celite® pad, washing with water and ethyl acetate. Separate the layers and wash the organic layer with saturated aqueous NaCl. Dry the organic layer with Na2SO4, filter, and concentrated under reduced pressure. Add 10% aqueous ethanol (14 mL) and cyanogen bromide (216 mg, 2.04 mmol, 1.5 equiv) to the residue and stir overnight. Quench with saturated aqueous NaHCO3 (20 mL). Add ethyl acetate and water to dissolve all solids. Wash the organic layer is with saturated aqueous NaCl, dry with Na2SO4, filter, and concentrate under reduced pressure. Subject the residue to medium pressure silica gel chromatography eluting with a gradient of 1.5-3% (2M ammonia in MeOH)/CH2Cl2 to provide 5-[2-(2,6-difluoro-phenyl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-3-(1(R),2,2-trimethyl-propyl)-3H-imidazo[4,5-b]pyridin-2-ylamine as a tan glass (289 mg, 43% yield).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@@H:3]1[C:15]1[N:19]2[C:20]3[CH:26]=[CH:25][N:24](S(C4C=CC(C)=CC=4)(=O)=O)[C:21]=3[N:22]=[CH:23][C:18]2=[CH:17][N:16]=1.[OH-].[Na+]>O1CCOCC1>[C:15]1([C@@H:3]2[C@H:2]([CH3:1])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:4]2)[N:19]2[C:20]3[CH:26]=[CH:25][NH:24][C:21]=3[N:22]=[CH:23][C:18]2=[CH:17][N:16]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2cnc([C@H]4CN(C(=O)OC(C)(C)C)CC[C@H]4C)n23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@@H]1c1ncc2cnc3[nH]ccc3n12
Temperature: 60 °C
Yield: 108.2 %

Procedure:
To a solution of (3R,4R)-tert-butyl 4-methyl-3-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate (40 g, 78 mmol) in 1,4-dioxane (160 mL) was added NaOH (1 N aqueous, 157 mL). The mixture was heated at about 60° C. for about 1 h. The mixture was allowed to cool to ambient temperature. The mixture was partitioned with HCl (4 N aqueous, 50 mL) and extracted with DCM (2×300 mL). The combined organic extracts were washed with brine (400 mL), dried over anhydrous Na2SO4, filtered then concd in vacuo. The product was purified on silica gel (330 g) using 1-5% MeOH in DCM to give (3R,4R)-tert-butyl 3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidine-1-carboxylate (30 g, 99%): LC/MS (Table 1, Method b) Rt=2.00 min; MS m/z: 356 (M+H)+.
Reaction SMILES: [C:1]([CH:3]1[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1)#[N:2].[C:11]([OH:16])(=[O:15])[C:12]([OH:14])=[O:13].C[N:18]1[N:22]=N[C:20]([CH:23]2C3CCN(CC3)C2)=[N:19]1.[N+](=CC)=[N-]>>[C:11]([OH:16])(=[O:15])[C:12]([OH:14])=[O:13].[CH2:20]([N:19]1[N:18]=[N:22][C:1]([CH:3]2[CH:8]3[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]3)[CH2:4]2)=[N:2]1)[CH3:23]
Reactant: N#CC1CN2CCC1CC2
Reactant: Cn1nnc(C2CN3CCC2CC3)n1
Agent: CC=[N+]=[N-]
Agent: O=C(O)C(=O)O
Product: CCn1nnc(C2CN3CCC2CC3)n1

Procedure:
This compound was prepared from (±) 3-cyano-1-azabicyclo[2.2.2]octane (EP-A-0 261 763, Description 1) in a similar manner to the compound of Example 2 using an ethereal solution of diazoethane prepared from N-nitroso-N-ethyl urea1,2. The resulting oil was purified by column chromatography using neutral alumina and eluting with 2% MeOH/EtOAc. 1H NMR indicated that the mixture contained a 12:1 ratio of the 2-ethyl isomer to 1-ethyl isomer and this mixture (100 mg, 17%) was crystallised and the title compound E9 recrystallised from methanol/diethyl ether as the oxalate salt (containing 8% of the 1-ethyl isomer).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17]Cl)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CN(C=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: COc1cc2c(Cl)ccnc2cc1OCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ccnc2cc1OCCCN1CCCCC1
Temperature: 70 °C

Procedure:
To a solution of 4-chloro-7-(3-chloropropoxy)-6-methoxyquinoline (3.1 g, 0.0108 mole) NaI (2.4 g, 0.0162 mole), and potassium carbonate (7.5 g, 0.054 mole in DMF (100 mL), was added piperidine (6.4 mL, 0.065 mole). The mixture was heated to 70° C. for 16 h. The mixture was concentrated in vacuo then diluted with H2O (100 mL). The mixture was extracted with EtOAc (3×50 mL) and the organic extracts were washed with H2O and brine. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (7.5% MeOH/CH2Cl2) to yield the title compounds as a light yellow solid. MS (ESI, pos. ion) m/z: 335 (M+1). Mass Calc'd for C18H23ClN2O2: 334.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][C:6]([C:12]([OH:14])=O)=[CH:5]2.[NH2:15][C@@H:16]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:17]([N:19]1[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]1)=[O:18]>>[CH2:26]([C@H:16]([NH:15][C:12]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([F:1])=[CH:10][C:9]=2[F:11])=[O:14])[C:17]([N:19]1[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]1)=[O:18])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CCC(O)CC1
Reactant: O=C(O)c1cc2cc(F)cc(F)c2[nH]1
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CCC(O)CC1)c1cc2cc(F)cc(F)c2[nH]1

Procedure:
From 5,7-difluoro-1H-indole-2-carboxylic acid and (S)-2-amino-1-(4-hydroxy-piperidin-1-yl)-3-phenyl-propan-1-one.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[CH2:15][CH2:14][NH:13]1.Br[CH2:27][C:28](Br)=[O:29].[NH2:31][C@H:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][C@H:33]1[OH:41]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[CH2:15][CH2:14][N:13]1[CH2:27][C:28]([NH:31][C@H:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][C@H:33]1[OH:41])=[O:29]
Reactant: COc1cc2c(cc1OC)C(Cc1ccc3ccccc3c1)NCC2
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Reactant: O=C(Br)CBr
Product: COc1cc2c(cc1OC)C(Cc1ccc3ccccc3c1)N(CC(=O)N[C@H]1c3ccccc3C[C@H]1O)CC2

Procedure:
prepared by reaction of 1-(Naphthalen-2-yl-methyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with (1S,2R)-1-amino-2-indanol
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1cccc(CBr)c1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Product: Cc1cccc(COc2ccc(Cl)c([N+](=O)[O-])c2)c1

Procedure:
A solution of 4-chloro-3-nitro-phenol was reacted with 1-Bromomethyl-3-methyl-benzene using the conditions described in Example 10C to provide 1-Chloro-4-(3-methyl-benzyloxy)-2-nitro-benzene which was treated sequentially using the procedures from Examples 10D and 10E to provide the title product.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1.CCOC(C)=O.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccccc1
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: N#Cc1ccc(S(=O)(=O)Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
To a solution of 4-cyanobenzene-1-sulfonyl chloride (200 mg, 0.992 mmol) in pyridine (4960 μL) was added aniline (100 μL, 1.091 mmol) and the reaction mixture stirred overnight at rt. The reaction mixture was diluted with EtOAc and water+0.1N HCl. The phases were separated, the aqueous phase extracted and the combined organic layers washed with 0.1N HCl and brine. After drying over magnesium sulfate, the solution was concentrated under vacuum to yield 4-cyano-N-phenyl-benzenesulfonamide 198 mg (0.652 mmol) of yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]3[CH:23]=[C:22]([Sn](CCCC)(CCCC)CCCC)[N:21]=[CH:20]3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:37][C:38]([NH:41][S:42]([C:45]1[S:49][C:48](Br)=[CH:47][CH:46]=1)(=[O:44])=[O:43])([CH3:40])[CH3:39].CCCCCC>C1(C)C=CC=CC=1>[C:38]([NH:41][S:42]([C:45]1[S:49][C:48]([C:22]2[N:21]=[CH:20][N:19]([C:11]3[N:10]=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[CH:14]=[C:13]([C:15]([F:18])([F:16])[F:17])[N:12]=3)[CH:23]=2)=[CH:47][CH:46]=1)(=[O:43])=[O:44])([CH3:40])([CH3:37])[CH3:39]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Br)s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(-c3ccc(Cl)c(Cl)c3)cc(C(F)(F)F)n2)cn1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)cn2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
A stirred mixture of 4-(3,4-dichloro-phenyl)-2-(4-tributylstannanyl-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (Example G.6) (0.46 g, 0.71 mmol), commercially available 5-bromothiophene-2-N-tert-butylsulfonamide (0.23 g, 0.78 mmol), tetrakis(triphenyl-phosphine)palladium (0.049 g, 0.042 mmol) in toluene (8 mL) was heated under reflux conditions for 15 h, hexane (10 mL) was added and the mixture was stirred at RT for 1 h. The precipitate was collected by filtration and dried to yield 5-{1-[4-(3,4-dichloro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.34 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[CH3:7][O:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16]Br)[CH:11]=1>>[CH3:7][O:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][N:4]2[CH:5]=[N:6][C:2]([NH2:1])=[N:3]2)[CH:11]=1
Reactant: Nc1nc[nH]n1
Reactant: COC(=O)c1cccc(CBr)c1
Product: COC(=O)c1cccc(Cn2cnc(N)n2)c1

Procedure:
Prepared in analogy to example 3a) starting with 3-amino-1,2,4-triazole and methyl-3-(bromomethyl)benzoate. The title compound was obtained as a colorless solid (Yield=8%). MS ISP (m/e): 233.1 (100) [(M+H)+].
Reaction SMILES: [F:1][C:2]1([O:19][CH3:20])[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:9]=[C:10]([C:15]([O:17]C)=[O:16])[C:11](=[O:14])[NH:12][N:13]=2)[CH2:3]1.CS(O[CH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:35])(=O)=O>>[C:15]([C:10]1[C:11](=[O:14])[N:12]([CH2:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[N:13]=[C:8]([C:4]2[CH2:3][C:2]([F:1])([O:19][CH3:20])[CH:7]=[CH:6][CH:5]=2)[CH:9]=1)([OH:17])=[O:16]
Reactant: CS(=O)(=O)OCCCc1ccccc1Cl
Reactant: COC(=O)c1cc(C2=CC=CC(F)(OC)C2)n[nH]c1=O
Product: COC1(F)C=CC=C(c2cc(C(=O)O)c(=O)n(CCCc3ccccc3Cl)n2)C1
Yield: 56 %

Procedure:
Following the procedure of Example 1(6), 6-(3-fluoro-3-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 3-(2-chlorophenyl)-1-propanol methanesulfonate were reacted. Without purification, the reaction product was reacted further following the procedure of Example 1(7) to yield the title compound as a pale yellow solid (yield: 56.0%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][CH2:14][CH2:15][O:16][CH3:17].CC(OC(C)=O)=O.[N+:25]([O-])([OH:27])=[O:26]>CC(O)=O>[CH3:1][O:2][C:3]1[C:4]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:5][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:11]([N+:25]([O-:27])=[O:26])[CH:12]=1
Reactant: O=[N+]([O-])O
Reactant: COCCOc1cc(C(=O)OC)ccc1OC
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: COCCOc1cc(C(=O)OC)c([N+](=O)[O-])cc1OC
Temperature: 50 °C
Yield: 56 %

Procedure:
According to the procedure described in Example 6A Step 2, to a solution of methyl 4-methoxy-3-(2-methoxyethoxyl)benzoate (5.6 g, 23.3 mmol) and Ac2O (12 mL) in AcOH (60 mL) was dropped fuming nitric acid (90%, 4 mL). The reaction was heated at 50° C. for 3 hours, and the residue was purified by silica gel chromatography with 0-15% EtOAc/hexane as eluants to afford methyl 4-methoxy-5-(2-methoxyethoxy)-2-nitrobenzoate as a solid (3.67 g, 56%). 1H NMR (300 MHz, DMSO-d6) δ 7.64 (s, 1H), 7.34 (s, 1H), 4.26 (m, 2H), 3.91 (s, 3H), 3.82 (s, 3H), 3.68 (m, 2H), 3.33 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][CH2:12][NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1>CC(O)C>[CH3:28][O:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][C:23]=1[O:29][CH3:30])[N:20]=[CH:19][N:18]=[C:17]2[N:13]1[C:14]2[C:10](=[CH:9][CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:15]=2)[CH2:11][CH2:12]1
Reactant: c1ccc(-c2ccc3c(c2)NCC3)cc1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Solvent: CC(C)O
Product: COc1cc2ncnc(N3CCc4ccc(-c5ccccc5)cc43)c2cc1OC
Yield: 61 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 61% yield from 6-phenyl-indoline (1.1 eq.), and 4-chloro-6,7- dimethoxy-quinazoline (1.0 eq) in i-PrOH. (M.P. 175°-177° C.; GC-MS: 383 (M+); anal. RP18-HPLC RT: 6.03min.).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:5]=[C:6]2[C:10]=1[N:9]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:8]=[CH:7]2.[C:22]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[CH3:22][O:1][C:2]1[CH:3]=[C:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:5]=[C:6]2[C:10]=1[N:9]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:8]=[CH:7]2
Reactant: CCOC(=O)c1cc(O)c2c(cnn2C2CCCCO2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCOC(=O)c1cc(OC)c2c(cnn2C2CCCCO2)c1
Temperature: 25 °C
Yield: 92 %

Procedure:
To a solution of ethyl 7-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxylate (1.45 g, 5.0 mmol) in acetone (20 mL) containing K2CO3 (760 mg, 5.50 mmol) was added iodomethane (781 mg, 0.34 mL, 5.5 mmo). The mixture was heated at reflux under N2 overnight. The mixture was cooled to room temperature, filtered, evaporated and partitioned between EtOAc and water. The aqueous phase was extracted with additional EtOAc. The combined organic extracts were washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated to provide crude product. The crude material was purified by chromatography (Isco, 0-40% EtOAc/heptane) to provide material which was dried under high vacuum overnight to afford ethyl 7-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxylate (1.40 g, 92%).