Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:25]=3)=[CH:8][N:9]2[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:5][CH:4]=1.[CH:32]1([C:35](O)=[O:36])[CH2:34][CH2:33]1>CN(C=O)C>[CH:32]1([C:35]([N:29]2[CH2:30][CH2:31][CH:26]([N:24]3[CH:25]=[C:21]([C:7]4[C:6]5[C:10](=[CH:11][C:3]([F:2])=[CH:4][CH:5]=5)[N:9]([S:12]([C:15]5[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=5)(=[O:13])=[O:14])[CH:8]=4)[CH:22]=[N:23]3)[CH2:27][CH2:28]2)=[O:36])[CH2:34][CH2:33]1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(C3CCNCC3)c2)c2ccc(F)cc21
Reactant: O=C(O)C1CC1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(C1CC1)N1CCC(n2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)CC1
Yield: 107.8 %

Procedure:
Following the general method as outlined in Example 83, starting from 6-fluoro-1-(phenylsulfonyl)-3-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-indole hydrochloride (Intermediate 17; 300 mg; 0.65 mmol) and cyclopropanecarboxylic acid (122 mg; 1.42 mmol) in DMF (6 mL), 345 mg of the title compound was obtained as a yellow oil, which was used directly without further purification.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:35]1[S:39][N:38]=[CH:37][N:36]=1)[S:7]([C:10]1[CH:18]=[C:17]2[C:13]([C:14]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=3[C:29]3[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=3)=[CH:15][NH:16]2)=[CH:12][CH:11]=1)(=[O:9])=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:53]([CH3:55])[CH3:54].C(Cl)(=O)C>O.C(#N)C>[CH:53]([N:16]1[C:17]2[C:13](=[CH:12][CH:11]=[C:10]([S:7]([NH:6][C:35]3[S:39][N:38]=[CH:37][N:36]=3)(=[O:8])=[O:9])[CH:18]=2)[C:14]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:21][C:20]=2[C:29]2[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=2)=[CH:15]1)([CH3:55])[CH3:54]
Reactant: CC(C)I
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4-c4ccnn4C)c[nH]c3c2)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)Cl
Solvent: CC#N
Product: CC(C)n1cc(-c2ccc(C(F)(F)F)cc2-c2ccnn2C)c2ccc(S(=O)(=O)Nc3ncns3)cc21
Temperature: 70 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
A vial was charged with N-(2,4-dimethoxybenzyl)-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (Intermediate B) (57.4 mg, 0.088 mmol), cesium carbonate (86 mg, 0.263 mmol), acetonitrile (0.5 mL), and 2-iodopropane (26.3 μl, 0.263 mmol). The vial was sealed and heated to 70° C. for 1 h. The mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was taken up on in MeOH (1 mL), then acetyl chloride (31.2 μl, 0.438 mmol) was added. After stirring for 1 h, the mixture was concentrated in vacuo. The residue was taken up in a solution of 2N ammonia in methanol, and the resulting slurry was concentrated in vacuo. The crude product was purified by chromatography on silica gel (0 to 10% MeOH/DCM) to give 1-isopropyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (38.52 mg, 0.070 mmol, 80% yield) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=8.36 (s, 1 H), 8.00 (d, J=1.5 Hz, 1 H), 7.96-7.89 (m, 2 H), 7.79-7.75 (m, 1H), 7.70 (d, J=8.5 Hz, 1 H), 7.48 (dd, J=1.7, 8.5 Hz, 1 H), 7.44 (d, J=1.9 Hz, 1 H), 7.09 (s, 1 H), 6.42 (d, J=1.9 Hz, 1 H), 4.86 (td, J=6.5, 13.2 Hz, 1 H), 1.33 (d, J=6.6 Hz, 6 H). m/z (ESI) 547.2 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[Br:16][C:17]1[CH:18]=[C:19]2[C@:30]3([CH2:34][O:33][C:32]([NH2:35])=[N:31]3)[C:29]3[C:24](=[CH:25][CH:26]=[C:27](I)[CH:28]=3)[O:23][C:20]2=[N:21][CH:22]=1.O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Br:16][C:17]1[CH:18]=[C:19]2[C@:30]3([CH2:34][O:33][C:32]([NH2:35])=[N:31]3)[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH:28]=3)[O:23][C:20]2=[N:21][CH:22]=1
Reactant: OB(O)c1cccnc1
Reactant: NC1=N[C@@]2(CO1)c1cc(I)ccc1Oc1ncc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3)ccc1Oc1ncc(Br)cc12
Temperature: 80 °C

Procedure:
A vial charged with pyridin-3-ylboronic acid (0.295 g, 2.401 mmol), palladiumtetrakis (0.126 g, 0.109 mmol), potassium carbonate (1.509 g, 10.92 mmol), and (S)-3-bromo-7-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (1.000 g, 2.183 mmol) was treated with 11 mL dioxane followed by 4.5 mL water. The vial was flushed with argon and was heated to 80° C. for 4 hours. The reaction mixture was diluted with EtOAc and dried over MgSO4. The organics were then concentrated, and the crude residue was purified by column chromatography yielding (S)-3-bromo-7-(pyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1[N:49]=[C:17]2[N:18]([CH2:41][C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=3)[C:19](=[O:40])[C:20]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]4[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=4)=[CH:28][CH:27]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:16]2[N:15]=1>C(OCC)(=O)C>[F:48][C:45]1[CH:46]=[CH:47][C:42]([CH2:41][N:18]2[C:19](=[O:40])[C:20]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[C:38]4[NH:3][C:4](=[O:7])[O:5][N:39]=4)=[CH:30][CH:31]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:16]3[N:15]=[C:14]([CH3:13])[N:49]=[C:17]23)=[CH:43][CH:44]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(Cc2ccc(F)cc2)c2nc(C)nn12
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(Cc2ccc(F)cc2)c2nc(C)nn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 41.5 %

Procedure:
A mixture of hydroxylammonium chloride (1.2 g), sodium hydrogen carbonate (1.9 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[2-methyl-4-(4-fluorobenzyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.56 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.22 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.19 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.26 g, 41%).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])=[CH:6][N:7]=1.O.[NH2:16][NH2:17]>N1C=CC=CC=1>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]1[N:4]=[N:3][C:2]([NH:16][NH2:17])=[N:7][CH:6]=1
Reactant: NN
Reactant: Fc1ccccc1-c1cnc(Cl)nn1
Solvent: O
Solvent: c1ccncc1
Product: NNc1ncc(-c2ccccc2F)nn1
Temperature: 60 °C

Procedure:
A 17.9 g. portion of 3-chloro-6-(o-fluorophenyl)-1,2,4-triazine is dissolved in 120 ml. of pyridine and cooled in an ice bath. An 8.5 g. portion of hydrazine hydrate is added and the mixture is heated at 60° C. for one hour and then cooled, poured into ice water and filtered giving 6-(o-fluorophenyl)-3-hydrazino-1,2,4-triazine as yellow plates.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1N[N:20]=[C:19]([C:22]([OH:24])=O)[CH:18]=1.FC1C=CC=CC=1C(=[O:34])C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[NH2:59][CH2:60][C:61]([N:63]1[CH2:68][CH2:67][CH:66]([NH:69][C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][C:71]=2[Cl:76])[CH2:65][CH2:64]1)=[O:62]>CN(C=O)C.O>[Cl:76][C:71]1[CH:72]=[CH:73][CH:74]=[CH:75][C:70]=1[NH:69][CH:66]1[CH2:67][CH2:68][N:63]([C:61](=[O:62])[CH2:60][NH:59][C:22]([C:19]2[CH:18]=[C:17]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[F:10])[O:34][N:20]=2)=[O:24])[CH2:64][CH2:65]1
Reactant: NCC(=O)N1CCC(Nc2ccccc2Cl)CC1
Reactant: CC(=O)c1ccccc1F
Reactant: O=C(O)c1cc(-c2ccccc2F)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCC(Nc2ccccc2Cl)CC1)c1cc(-c2ccccc2F)on1
Reaction time: 8 h
Yield: 26.6 %

Procedure:
DIPEA (328 mg, 2.5 mmol) to a stirred solution of 5-(2-fluoro-phenyl)-1H-pyrazole-3-carboxylic acid (150 mg, 0.724 mmol) (prepared by the method used for the synthesis of Intermediate 29, starting from 2′fluoroacetophenone) in DMF (5 mL) followed by HOBt (100 mg, 0.76 mmol) and EDCI.HCl (140 mg, 0.76 mmol). After 2 minutes 2-amino-1-[4-(2-chloro-phenylamino)-piperidin-1-yl]-ethanone dihydrochloride (220 mg, 0.724 mmol) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, the precipitate was collected. The solid was purified by recrystallisation from ethyl acetate The residue obtained was again purified by column chromatography (using 60-120 silica gel and 60% EtOAc in hexane as eluent) to afford 88 mg (26.6% Yield) of 5-(2-fluoro-phenyl)-isoxazole-3-carboxylic acid {2-[4-(2-chloro-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 457, 91.47%. 1H NMR (300 MHz, DMSO-d6): δ8.75 (t, 1H), 8.0 (m, 1H), 7.6 (m, 1H), 7.38 (m, 2H), 7.1 (m, 3H), 6.82 (d, 1H), 6.6 (m, 1H), 4.8 (m, 1H), 4.3 (d, 1H), 4.1 (d, 2H), 3.8 (d, 1H), 3.6 (m, 1H), 3.1 (t, 1H), 2.8 (t, 1H), 1.9 (t, 2H), 1.45 (m, 2H).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][OH:12])[CH2:6][CH2:5]1.Cl[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[CH:15]=1.[Cl-].[Na+]>COCCOCCOC.O.C1COCC1>[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[CH:15]=2)[CH2:6][CH2:5]1
Reactant: Nc1cc(Cl)ccn1
Reactant: CN1CCN(CCO)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: COCCOCCOC
Product: CN1CCN(CCOc2ccnc(N)c2)CC1
Temperature: 40 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
Sodium hydride (60% in mineral oil; 43.56 g; 1089 mmol) was added to a 3 L reaction flask under nitrogen. A mechanical stirrer and thermocouple was attached. Dry diglyme (400 mL) was added. A solution of 2-(4-methylpiperazin-1-yl)ethanol (157 g; 1089 mmol) in diglyme (450 mL) was added slowly with stirring. The mixture was stirred with warming to 40° C. for 1 hour. 4-Chloropyridin-2-amine (70.0 g; 544.5 mmol) was added as a solid. The mixture was heated to 80° C. with stirring until effervescence had ceased. The temperature was increased to 157° C. for 16 hours. The mixture was allowed to cool and diluted with water (500 mL). THF (1000 mL) was added followed by sodium chloride (sufficient to saturate the aqueous phase). The phases were separated and the aqueous phase was further extracted with THF (3×800 mL). Additional water was added as required to aid in phase separation. The combined organic phases were dried with sodium sulfate (1000 g) for 16 hours and filtered. The solvent was removed under vacuum to remove the majority of the THF. The solution was filtered through Celite® to remove fine particulates rinsing with diglyme. The diglyme was removed under vacuum (10 mm Hg vacuum, with the bath temperature increased to 60° C.). The residue was placed under high vacuum for 1 hour and then triturated with ether (400 mL). The resulting solids were collected by filtration, washed with ether and dried under vacuum to give the product (100.4 g) as an off white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:9]([C:11]1[CH:30]=[CH:29][C:14]2[N:15]([CH3:28])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].[ClH:38].C(O)C.C(=O)([O-])[O-].[NH4+:46].[NH4+]>ClCCl.C(O)C>[ClH:38].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:9]([C:11]1[CH:30]=[CH:29][C:14]2[N:15]([CH3:28])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:46])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)c1ccccc1F
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1F
Yield: 88 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-fluorophenyl)-N-(2-ethoxycarbonylethyl)amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 88% of theory, C28H29FN6O3 (516.6); Rf value: 0.08 (silica gel; dichloromethane/ethanol=4:1); EKA mass spectrum: (M+H)+=517; (M+H+Na)++=270; (M+2H)++=259.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:10]=[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[C:8](=[O:17])[NH:7][C:6]1=[O:18].[F:19][C:20]([F:34])([F:33])[C:21]1[CH:26]=[CH:25][C:24]([C@:27]23[CH2:32][C@H:31]2[CH2:30][NH:29][CH2:28]3)=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C.O1CCOCC1>CCO>[ClH:1].[ClH:1].[ClH:1].[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:9]2[C:8](=[O:17])[NH:7][C:6](=[O:18])[N:5]([CH2:4][CH2:3][CH2:2][N:29]3[CH2:30][C@H:31]4[C@:27]([C:24]5[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:34])[F:33])=[CH:26][CH:25]=5)([CH2:32]4)[CH2:28]3)[CH:10]=2)[CH:12]=1
Reactant: O=c1[nH]c(=O)n(CCCCl)cc1-c1cccnc1
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCO
Product: Cl
Product: O=c1[nH]c(=O)n(CCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)cc1-c1cccnc1

Procedure:
A solution of 1-(3-chloro-propyl)-5-pyridin-3-yl-1H-pyrimidine-2,4-dione (Prep43, 92 mg, 0.34 mmol), (1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Prep4, 68 mg, 0.34 mmol), and DIPEA (134 μl, 1 mmol) in absolute EtOH (3 mL) was placed in a microwave oven and irradiated at 130° C. for 3 hours. The solvent was removed under vacuum and the residue was partitioned between water and ethyl acetate. The organic phase was dried (Na2SO4), filtered and evaporated. The residue was purified by preparative LC-MS. After treatment with 4N HCl in dioxane (2 eq), the title compound was obtained (5 mg, 4% yield)
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])([CH3:12])[CH3:11].N1C=CN=C1>ClCCl>[C:10]([Si:14]([CH3:16])([CH3:15])[O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.4 %

Procedure:
4-Hydroxybenzaldehyde (5.14 g, 42.1 mmol) was added to a suspension of tert-butyl-dimethyl-silyl chloride (6.7 g, 44.4 mmol) and imidazole (3.03 g, 44.5 mmol) in dichloromethane (100 ml) under an atmosphere of nitrogen at room temperature. The reaction mixture was stirred at room temperature for 18 hours, and then washed sequentially with 1 M hydrochloric acid (2-fold 50 ml) followed by a saturated aqueous solution of sodium hydrogen carbonate (50 ml). The organic phase was separated, dried over anhydrous magnesium sulphate and the solvent removed in vacuo. The residual yellow oil was passed through a plug of silica gel eluting with 1:1, by volume, dichloromethane:pentane giving 4-(tert-butyl-dimethyl-silanyloxy)-benzaldehyde (7.5 g) as a golden yellow oil.
Reaction SMILES: NC1C([N+]([O-])=O)=C(N2CCN(CC(NC3SC=CN=3)=O)CC2)C(Br)=CN=1.Cl[C:28]1[C:33]([Cl:34])=[CH:32][N:31]=[C:30]([NH2:35])[C:29]=1[N+:36]([O-:38])=[O:37].CCN(C(C)C)C(C)C.[N:48]1[CH:53]=[CH:52][C:51]([CH:54]([N:56]2[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]2)[CH3:55])=[CH:50][CH:49]=1.Cl>CC(O)C>[Cl:34][C:33]1[C:28]([N:59]2[CH2:60][CH2:61][N:56]([CH:54]([C:51]3[CH:50]=[CH:49][N:48]=[CH:53][CH:52]=3)[CH3:55])[CH2:57][CH2:58]2)=[C:29]([N+:36]([O-:38])=[O:37])[C:30]([NH2:35])=[N:31][CH:32]=1
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Reactant: CC(c1ccncc1)N1CCNCC1
Agent: Cl
Agent: Nc1ncc(Br)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(c1ccncc1)N1CCN(c2c(Cl)cnc(N)c2[N+](=O)[O-])CC1
Yield: 73 %

Procedure:
This was prepared using the same procedure as for 2-(4-(2-amino-5-bromo-3-nitropyridin-4-yl)piperazin-1-yl)-N-(thiazol-2-yl)acetamide, but here using 4,5-dichloro-3-nitropyridin-2-amine (22 mg, 0.106 mmol), iPrOH (1 mL), DIPEA (0.2 mL) and 1-(1-(pyridin-4-yl)ethyl)piperazine.3×HCl (1.1 eq, 0.116 mmol, 35 mg). Filtration and washing as previously described gave the product (28 mg, 73%) as a yellow solid; δH (500 MHz, DMSO-d6) 1.30 (d, J=6.7 Hz, 3H, CHCH3), 2.42 (s, br, 2H, piperazine NCH2), 2.53 (s, br, 2H, piperazine NCH2), 3.05 (s, br, 4H, piperazine N(CH2)2), 3.54 (q, J=6.8 Hz, 1H, CHCH3), 6.94 (s, br, 2H, NH2), 7.34 (d, J=6.0 Hz, 2H, pyridine H-2 & H-6), 8.04 (s, 1H, chloropyridine H-6), 8.51 (d, J=6.0 Hz, 2H, pyridine H-3 & H-5);
Reaction SMILES: [CH:1]1([C:4]2[C:15]3[O:14][C:11]4([CH2:13][CH2:12]4)[CH2:10][C:9]([CH3:17])([CH3:16])[C:8]=3[CH:7]=[C:6]([C:18]#[C:19][Si](C)(C)C)[CH:5]=2)[CH2:3][CH2:2]1.CO.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CCCCCC>[CH:1]1([C:4]2[C:15]3[O:14][C:11]4([CH2:13][CH2:12]4)[CH2:10][C:9]([CH3:16])([CH3:17])[C:8]=3[CH:7]=[C:6]([C:18]#[CH:19])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CC1(C)CC2(CC2)Oc2c(C3CC3)cc(C#C[Si](C)(C)C)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: C#Cc1cc(C2CC2)c2c(c1)C(C)(C)CC1(CC1)O2

Procedure:
Following general procedure E, and 8-cyclopropyl-3,4-dihydro-4,4-dimethyl-6-(trimethylsilanyl)ethynylspiro[2H-1-benzopyran-2,1′-cyclopropane] (Intermediate 43, 0.62 g, 1.9 mmol), methanol and potassium carbonate (0.5 g, 3.6 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 1-2% ethyl acetate in hexane as the eluent, the title compound was obtained as an oil (0.5 g, 100%).
Reaction SMILES: CN(C)C(C1C=[CH:9][C:8](Br)=[CH:7][N:6]=1)=O.[Br:13][C:14]1[CH:15]=[N:16][C:17]([C:20]([OH:22])=O)=[N:18][CH:19]=1.Cl.N1CCC1>>[N:6]1([C:20]([C:17]2[N:18]=[CH:19][C:14]([Br:13])=[CH:15][N:16]=2)=[O:22])[CH2:7][CH2:8][CH2:9]1
Reactant: O=C(O)c1ncc(Br)cn1
Reactant: CN(C)C(=O)c1ccc(Br)cn1
Agent: C1CNC1
Agent: Cl
Product: O=C(c1ncc(Br)cn1)N1CCC1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 161a, from 5-bromopyrimidine-2-carboxylic acid (1.60 g, 7.877 mmol) and azetidine hydrochloride (1.11 g, 11.8 mmol) to give a yellow solid (331 mg, 17% yield). 1H NMR (400 MHz, CDCl3) δ 8.92 (s, 2 H) 4.64 (t, J=7.71 Hz, 2 H) 4.29 (t, J=7.83 Hz, 2 H) 2.29-2.41 (m, 2 H); LCMS for C8H8BrN3O m/z 241.00 and 243.00 (M+H)+.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[CH2:25]([O:27][C:28](=[O:37])[C:29]1[CH:34]=[CH:33][N:32]=[C:31]([NH:35]N)[CH:30]=1)[CH3:26]>>[CH2:25]([O:27][C:28](=[O:37])[C:29]1[CH:34]=[CH:33][N:32]=[C:31]([N:35]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:30]=1)[CH3:26]
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Reactant: CCOC(=O)c1ccnc(NN)c1
Product: CCOC(=O)c1ccnc(-n2nccc2-c2nn(-c3cccc(S(C)(=O)=O)c3)ccc2=O)c1

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and 2-hydrazino-isonicotinic acid ethyl ester according to example 43 gave the desired product. MS: M=466.0 (M+H)+
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10]Br.[O:13]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[O:13]([C:20]1[CH:21]=[CH:22][C:23]([CH2:24][N:25]2[CH2:10][C:5]3[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:3]2=[O:12])=[CH:26][CH:27]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: NCc1ccc(Oc2ccccc2)cc1
Reactant: COC(=O)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1c2ccccc2CN1Cc1ccc(Oc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 60.2 %

Procedure:
A mixture of 2-bromomethyl-benzoic acid methyl ester (0.115 g, 0.5 mmol), 4-phenoxy-benzylamine (0.106 mL, 0.6 mmol), and K2CO3 (0.207 g, 1.5 mmol) in toluene (3 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-(4-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.095 g, 61%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.28 (s, 2H), 4.79 (s, 2H), 6.98-7.54 (m, 12H), 7.89 (d, 1H). GC-MS: m/z 315 (M)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([NH2:20])[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]([F:35])([F:34])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](O)=[O:32])=[CH:26][CH:25]=1>>[C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([NH:20][C:31](=[O:32])[CH2:30][C:27]2[CH:26]=[CH:25][C:24]([C:23]([F:34])([F:22])[F:35])=[CH:29][CH:28]=2)[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)NCc1nn(N)c(=O)c2ccccc12
Product: CC(C)(C)OC(=O)NCc1nn(NC(=O)Cc2ccc(C(F)(F)F)cc2)c(=O)c2ccccc12

Procedure:
The product of Example 41B and 2-[4-(trifluoromethyl)phenyl]acetic acid were treated using a method similar to that described in Example 56 to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 11.67 (s, 1H), 8.32 (dd, J=7.8, 1.4, 1H), 8.11 (d, J=8.0, 1H), 8.04-7.95 (m, 1H), 7.95-7.86 (m, 1H), 7.76-7.69 (m, 2H), 7.63-7.57 (m, 2H), 7.44-7.37 (m, 1H), 4.48-4.41 (m, 2H), 3.79 (bs, 2H), 1.37 (s, 9H); MS (ESI−) M/Z 475 (M−H)−.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[N:11]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.CCN(C(C)C)C(C)C>CN(C)C(=O)C>[C:20]([O:19][C:17]([N:11]1[CH2:16][CH2:15][N:14]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=2)[CH2:13][CH2:12]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)cn2)CC1
Temperature: 130 °C
Reaction time: 72 h

Procedure:
6-Chloronicotinic acid was dissolved in N,N-dimethylacetamide (10 ml), and tert-butyl piperazine-1-carboxylate (1.2 g) and DIPEA (1.6 g) were added thereto, followed by stirring at 130° C. for 3 days. The reaction mixture was concentrated under reduced pressure, and to the obtained residue was added a 1 M aqueous NaOH solution, followed by washing with CHCl3. The pH of the aqueous layer was adjusted to around 6 to 7 by the addition of 1 M hydrochloric acid, followed by extraction with CHCl3. The organic layer was dried over Na2SO4 and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain 6-[4-(tert-butoxycarbonyl)piperazin-1-yl]nicotinic acid (934 mg).