Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:23])[N:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:11]=[C:12]([C:14](O)=[O:15])[CH:13]=2)=[CH:4][CH:3]=1.[CH3:24][C:25]1[N:29]=[C:28]([C@H:30]([NH2:32])[CH3:31])[O:27][N:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:23])[N:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:11]=[C:12]([C:14]([NH:32][C@@H:30]([C:28]3[O:27][N:26]=[C:25]([CH3:24])[N:29]=3)[CH3:31])=[O:15])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1noc([C@@H](C)N)n1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2)c(=O)n(-c2ccccn2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1noc([C@@H](C)NC(=O)c2cc(-c3ccc(F)cc3)c(=O)n(-c3ccccn3)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
To a solution of 3-(4-fluorophenyl)-2-oxo-2H-1,2′-bipyridine-5-carboxylic acid (20.0 mg, 0.05 mmol) in DMF (0.5 mL) were added hydrochloride salt of (1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethanamine (13.6 mg, 0.07 mmol), HATU (0.5 M in DMF; 0.16 mL, 0.08 mml) and diisopropylethylamine (36 μL, 0.21 mmol). The mixture was stirred at ambient temperature. After 30 min, the mixture was purified by reverse chromatography (C-18, 95% water/acetonitrile→25% water/acetonitrile with 0.1% trifluoroacetic acid) to give the title compound (20 mg). HRMS 420.1470 (M+1). 1H NMR (400 MHz, CDCl3): δ 8.62 (d, J=4.8 Hz, 1H); 8.53 (d, J=2.5 Hz, 1H); 7.94-7.83 (m, 3H); 7.70 (dd, J=8.3, 5.4 Hz, 2H); 7.41 (t, J=5.8 Hz, 1H); 7.12 (t, J=8.5 Hz, 2H); 6.66 (d, J=7.7 Hz, 1H); 5.60-5.51 (m, 1H); 2.40 (s, 3H); 1.69 (d, J=7.1 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[C:23]([CH3:33])=[CH:24][C:25]([O:31][CH3:32])=[C:26]([CH:30]=1)[C:27](O)=[O:28].[CH3:34][C:35]1[CH:40]=[CH:39][N:38]=[C:37]([C:41]2([NH2:44])[CH2:43][CH2:42]2)[N:36]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:19][CH3:20])=[O:21])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:30]=[C:26]([C:27](=[O:28])[NH:44][C:41]2([C:37]3[N:36]=[C:35]([CH3:34])[CH:40]=[CH:39][N:38]=3)[CH2:43][CH2:42]2)[C:25]([O:31][CH3:32])=[CH:24][C:23]=1[CH3:33]
Reactant: Cc1ccnc(C2(N)CC2)n1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)c(F)c12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5nccc(C)n5)CC4)c(OC)cc3C)c(F)c12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.04 g, 0.089 mmol, 1 eq), 1-(4-methylpyrimidin-2-yl)cyclopropanamine (130 mg, crude), Py-Bop (0.06 g, 0.11 mmol, 1.3 eq) in DMF at ambient temperature under nitrogen was added triethylamine (0.027 g, 0.26 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by preparative HPLC. Yield: 0.022 g (42%). 1H NMR (400 MHz, CD3OD): δ 8.54 (d, J=5.6 Hz, 1H), 7.97-7.94 (m, 2H), 7.90 (s, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.31-7.25 (m, 4H), 7.19 (s, 1H), 4.10 (s, 3H), 2.96 (s, 3H), 2.55 (s, 3H), 2.31 (s, 3H), 1.89-1.86 (m, 2H), 1.59-1.56 (m, 2H). 19F NMR (376.57 MHz, CD3OD): δ −77.65 (TFA), −112.33, −122.77 LCMS: (ES+) m/z=583.2 (M+H)+
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[N:5]([S:7]([NH2:10])(=[O:9])=[O:8])[CH3:6].C[O-].[Na+]>CO>[CH3:14][CH:13]([CH3:15])[CH2:12][CH2:11][CH:4]1[N:5]([CH3:6])[S:7](=[O:9])(=[O:8])[NH:10][C:3]1=[O:2]
Reactant: COC(=O)C(CCC(C)C)N(C)S(N)(=O)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CCC1C(=O)NS(=O)(=O)N1C
Temperature: 25 °C
Reaction time: 18.5 h
Yield: 100.8 %

Procedure:
A solution of N-(aminosulfonyl)-2-(3-methylbutyl)sarcosine methyl ester (12.25 g, 48.17 mmol) in methanol (150 ml) was added to a solution of sodium methoxide (Na=2.4 g) in 150 ml of ice-cold methanol. The resulting reaction mixture was stirred at room temperature under nitrogen for 18.5 hours, and then the mixture was treated with 25 g of ion-exchange resin (BIO RAD® 50Wx8; 200-400 mesh) for 40 minutes and filtered. The filtrate was concentrated in vacuo to afford 10.7 g (99.8%) of 4-(3-methylbutyl)-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula IV: R1 =(CH2)2CH(CH3)2 ; R2 =H; R3 =CH3) as a solid, m.p. 212°-214° C.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[C:17]([C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[CH2:23]2)(=[O:19])[CH3:18]>>[C:17]([C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[C:23]2=[CH:7][C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:11]([O:12][CH3:13])=[C:10]([CH:14]([CH3:16])[CH3:15])[CH:9]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Product: COc1c(C(C)C)cc(C=C2C(=O)Nc3ccc(C(C)=O)cc32)cc1C(C)C

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 5-acetyl-2-oxindole to give 0.3 g of 5-Acetyl-3-(3,5-diisopropyl-4-methoxybenzylidene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]CC)=[O:6].[CH2:13](Br)[CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:15]([O:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([OH:7])=[O:6])[CH:14]=[CH2:13]
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCOc1cccc(C(=O)O)c1

Procedure:
The reaction of ethyl 3-hydroxybenzoate and allyl bromide in 2-butanone in the presence of potassium carbonate was performed as described in Example 2 to give 3-Allyloxy-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 12.97 (s, —CO2H); 7.47 (d-like, 1 arom. H); 7.40 (m, 2 arom. H); 7.18 (m, 1 arom. H); 5.99 (m, —CH═CH2); 5.37, 5.23 (2 d-like, CH═CH2); 4.03 (d-like, CH2—CH_CH2). 13C-NMR (100 MHz, d6-DMSO): 167.08 (C═O); 158.12; 133.44; 132.27; 129.67; 121.66; 119.47; 117.47; 114.78; 68.27.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:20]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH3:20])[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1
Reactant: CI
Reactant: O=C(NCc1ccc(Br)cc1)N1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(Cc1ccc(Br)cc1)C(=O)N1CCCC1
Reaction time: 0.25 h
Yield: 103.9 %

Procedure:
N-[(4-bromophenyl)methyl]-1-pyrrolidinecarboxamide (230 mg, 0.81 mmol), was dissolved in dimethylformamide (2 ml) and treated at room temperature with a 60% sodium hydride suspension in mineral oil (33 mg, 0.83 mmol). This mix was stirred for 15 minutes before being treated with iodomethane (116 mg, 0.82 mmol). The resulting mix was stirred at 20° C. for a total of 16.5 hours. The reaction was quenched with water (4 ml) and extracted into ethyl acetate (4 ml). The organic layer was dried over sodium sulphate and the solvent removed under reduced pressure to give the title compound as a colourless oil (250 mg, crude). LC/Mass Spec (ES): Found 297 (ES+), retention time 2.90 mins. C13H1779BrN2O requires 296.
Reaction SMILES: Br[C:2]1[S:6][C:5]2=[N:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1>C(O)C(F)(F)F.ClCCl>[S:6]1[C:2]([NH:18][C:15]2[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)=[N:3][N:4]2[CH:9]=[CH:8][N:7]=[C:5]12
Reactant: COc1ccc(N)cc1
Reactant: Brc1nn2ccnc2s1
Solvent: OCC(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Nc2nn3ccnc3s2)cc1
Temperature: 170 °C
Yield: 29.4 %

Procedure:
A mixture of 2-bromo-imidazo[2,1-b][1,3,4]thiadiazole (1.0 g, 4.90 mmol) and p-anisidine (19.6 mmol, 2.41 g) in trifluoroethanol (12 mL) was heated under microwave irradiation at 170° C. for 1 hour. On cooling, the mixture was diluted with dichloromethane (10 mL) and purified by column chromatography (Biotage™/Flash, silica, methanol: dichloromethane 0.2:9.8 to 1:9). The residue obtained was triturated with diethylether and few drops of methanol to give imidazo[2,1-b][1,3,4]thiadiazol-2-yl-(4-methoxyphenyl)amine as a white solid (355 mg, 29% yield).
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][C@H:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.Cl.[CH3:22][C:23]1[N:24]=[N:25][N:26]([CH:28]2[CH2:32][CH2:31][NH:30][CH2:29]2)[CH:27]=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[F:1][C:2]1[C:3]([N:30]2[CH2:31][CH2:32][CH:28]([N:26]3[CH:27]=[C:23]([CH3:22])[N:24]=[N:25]3)[CH2:29]2)=[C:4]2[O:9][CH2:8][C@H:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23
Reactant: Cc1cn(C2CCNC2)nn1
Reactant: C[C@H]1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cn(C2CCN(c3c(F)cc4c(=O)c(C(=O)O)cn5c4c3OC[C@@H]5C)C2)nn1

Procedure:
A solution of 70.25 mg (0.25 mmol) of (-)-9,10-difluoro-3(S)-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid and 141 mg (0.75 mmol) of 3-(4-methyl-1,2,3-triazol-1-yl)pyrrolidine hydrochloride in 3 ml of acetonitrile in the presence of 152.24 mg (1 mmol) of DBU was refluxed for 3 days under nitrogen atmosphere. The suspension was then evaporated and water was added to the residue and solid collected and washed with methanol to yield after drying 50 mg of the desired product, m.p. 241°-242° C. 1H NMR (TFA) δ: 9.16 (s, 1H), 8.37 (s, 1H), 7.99 (d, 13.3Hz, 1H), 5.75-5.6 (m, 1H), 5.15-4.1 (m, 7H), 3-2.6 (m, 2H), 2.67 (s , 3H), 1.8 (d, 6.8Hz, 3H). Anal. calcd. for C20H20FN5O4 . 1/2 H2O: C, 56.87; H, 5.01; N, 16.58. Found: C, 57.30; H, 4.77; N, 16.75.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[CH:9].[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]1[N:23]=[C:22]([NH2:24])[N:21]=[C:20]2[C:16]=1[NH:17][CH:18]=[N:19]2.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]1[N:23]=[C:22]([NH2:24])[N:21]=[C:20]2[C:16]=1[N:17]=[CH:18][N:19]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[CH:9]
Reactant: Nc1nc(-c2cccs2)c2[nH]cnc2n1
Reactant: C#CCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCCCCCCn1cnc2c(-c3cccs3)nc(N)nc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.1 %

Procedure:
8-Bromo-1-octyne (2.0 g, 10.6 mmol) prepared in step 1) was added to a dehydrated dimethylformamide (25 mL) solution containing 6-(thien-2-yl)-2-amino purine (1.2 g, 5.5 mmol) and potassium carbonate (2.3 g, 16.5 mmol), followed by stirring at room temperature for 15 hours. The reaction solution was concentrated and was separated between ethyl acetate and water. The organic layer was washed with saturated brine, was dried over anhydrous sodium sulfate, and was purified by medium-pressure preparative column chromatography to yield 6-(thien-2-yl)-9-(7-octynyl)-2-amino purine (1.6 g, 4.9 mmol, 87%).
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][S:11][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:12].Cl[C:14]1[N:19]=[C:18]([NH:20][C@@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]2[NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:17]([Cl:32])=[CH:16][N:15]=1>>[Cl:32][C:17]1[C:18]([NH:20][C@@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]2[NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=[N:19][C:14]([NH:12][C:2]2[CH:3]=[CH:4][C:5]3[S:11][CH2:10][CH2:9][NH:8][CH2:7][C:6]=3[CH:1]=2)=[N:15][CH:16]=1
Reactant: Nc1ccc2c(c1)CNCCS2
Reactant: CS(=O)(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Product: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Nc2ccc3c(c2)CNCCS3)ncc1Cl
Yield: 84.9 %

Procedure:
Following the procedure of 2f, 6,7,8,9-tetrahydro-5-thia-8-aza-benzocyclohepten-2-ylamine (0.07 g, 0.00039 mol) and N-[(1S,2R)-2-(2,5-dichoro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (0.13 g, 0.00039 mol) were reacted giving N-{(1R,2R)-2-[5-chloro-2-(6,7,8,9-tetrahydro-5-thia-8-aza-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide (0.16 g, 85%). MP: 141-3° C.; 1H-NMR (DMSO-d6) 9.30 (s, 1H), 7.93-5 (s, 1H), 7.73-9 (s, 1H), 7.44-6 (d, 1H), 7.33-5 (d, 1H), 7.16-8 (d, 1H), 6.76-8 (d, 1H), 3.91 (s, 1H), 3.84-5 (m, 1H), 3.22-4 (m, 2H), 2.93 (s, 2H), 2.63-4 (m, 2H), 2.00-12 (m, 2H), 1.70 (m, 2H), 1.27-37 (m, 4H); LC/MS (ESI+): 483 (M).
Reaction SMILES: [ClH:1].C(OC([N:9]([CH2:18][CH2:19][C:20]([NH2:22])=[O:21])[CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[CH:12]1([CH2:11][CH2:10][NH:9][CH2:18][CH2:19][C:20]([NH2:22])=[O:21])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N(CCC(N)=O)CCC1CCCCC1
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)CCNCCC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Next, a 4 N solution of hydrogen chloride in 1,4-dioxane (3.1 ml) was added to 3-[N-(t-butoxycarbonyl)-N-(2-cyclohexylethyl)amino]propionamide (0.37 g, 1.2 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, diisopropyl ether was added to the resulting solid, and the solid was filtered off to give 0.30 g (quantitatively) of the titled compound as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.[S:16]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]#[N:23])=[CH:17]1>>[Cl:1][C:2]1[C:11](/[CH:12]=[C:21](/[C:18]2[CH:19]=[CH:20][S:16][CH:17]=2)\[C:22]#[N:23])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1
Reactant: COc1ccc2nc(Cl)c(C=O)cc2c1
Reactant: N#CCc1ccsc1
Product: COc1ccc2nc(Cl)c(/C=C(\C#N)c3ccsc3)cc2c1
Yield: 83.7 %

Procedure:
2-Chloro-6-methoxy-3-quinolinecarboxaldehyde (222 mg) was condensed with 3-thiopheneacetonitrile (123 mg) through Method B (production step 3), to thereby yield the target product (yield: 273 mg, 83%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-])=O)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]>C(O)C.[Pd]>[F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([NH2:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)cc1F
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(C(=O)O)c(F)cc1F
Reaction time: 2 h
Yield: 97.6 %

Procedure:
To a solution of 2,4-difluoro-5-nitrobenzoic acid (0.998 g, 4.91 mmol) in ethanol (50 mL) was added 10% palladium on charcoal (107 mg) and the mixture was hydrogenated at 30 psi. After 2 h, the mixture was degassed, filtered and the filtrate was concentrated in vacuo to afford 2,4-difluoro-5-aminobenzoic acid (0.83 g, 97%) as tan solid. LC/MS (ESI); (M-H)−=172.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.[CH3:10][N:11]1[CH:15]=[C:14]([CH2:16]O)[N:13]=[N:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH:7]=1)[O:8][CH2:16][C:14]1[N:13]=[N:12][N:11]([CH3:10])[CH:15]=1
Reactant: Cn1cc(CO)nn1
Reactant: Oc1cc(Br)ccc1F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cn1cc(COc2cc(Br)ccc2F)nn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.4 %

Procedure:
An ice-cooled solution of 5-bromo-2-fluorophenol (1.91 g, 10 mmol), (1-methyl-1H-[1,2,3]triazol-4-yl)methanol (1.24 g, 11 mmol) and triphenylphosphine (3.93 g, 15 mmol) in tetrahydrofuran (50 ml) was treated dropwise with diisopropyl azodicarboxylate (3.03 g, 15 mmol) over 10 min. The resulting mixture was stirred to ambient temperature over 12 h and then glacial acetic acid (1 ml) was added. The reaction mixture was concentrated in vacuo then partitioned between ethyl acetate and 0.01N sodium hydroxide solution. The organics were washed with water, brine, dried over anhydrous magnesium sulphate and concentrated to give an oil. This oil was purified by chromatography on silica gel, eluting with isohexane on a gradient of ethyl acetate (20-50%). Product-containing fractions were concentrated and the resulting residue triturated with 10% ether in isohexane to furnish 4-(5-bromo-2-fluorophenoxymethyl)-1-methyl-1H-[1,2,3]triazole as a white solid (1.9 g, 66%): δH (360 MHz, d6-DMSO) 4.06 (3H, s), 5.25 (2H, s), 7.10-7.20 (2H, m), 7.55-7.70 (1H, m), 8.19 (1H, s).
Reaction SMILES: [C:1]([CH:4]([C:12](=[O:21])[CH2:13][S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)C(OC(C)(C)C)=O)(=[O:3])[CH3:2]>C(O)(C(F)(F)F)=O>[C:15]1([S:14][CH2:13][C:12](=[O:21])[CH2:4][C:1](=[O:3])[CH3:2])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)C(C(=O)CSc1ccccc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)CC(=O)CSc1ccccc1
Yield: 68.4 %

Procedure:
1-(Phenyltlhio)pentane-2,4-dione Stir 1,1-dimethylethyl 2-acetyl-3-oxo-4-(phenylthio)butanoate (1.11 g, 3.60 mmol) in TFA (3 mL) for 20 h at RT. Quench with water (10 mL), and extract using diethyl ether (10 mL). Wash organic layer with water (3×10 mL), dry (MgSO4), concentrate and purify (silica gel chromatography, eluting with 100:0 to 80:20 2-methylpentane:EtOAc) to give the title compound as an orange oil (513 mg, 69%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:26][C:10]3=[CH:11][C:12]4[C:13]([CH2:24][CH3:25])([CH2:22][CH3:23])[C:14](=[O:21])[N:15]([CH:18]([CH3:20])[CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH3:27][C:28]1([C:31](O)=[O:32])[CH2:30][CH2:29]1>>[CH2:24]([C:13]1([CH2:22][CH3:23])[C:12]2[CH:11]=[C:10]3[NH:26][C:7]([C:3]4[C:2]([NH:1][C:31]([C:28]5([CH3:27])[CH2:30][CH2:29]5)=[O:32])=[CH:6][NH:5][N:4]=4)=[N:8][C:9]3=[CH:17][C:16]=2[N:15]([CH:18]([CH3:20])[CH3:19])[C:14]1=[O:21])[CH3:25]
Reactant: CC1(C(=O)O)CC1
Reactant: CCC1(CC)C(=O)N(C(C)C)c2cc3nc(-c4n[nH]cc4N)[nH]c3cc21
Product: CCC1(CC)C(=O)N(C(C)C)c2cc3nc(-c4n[nH]cc4NC(=O)C4(C)CC4)[nH]c3cc21

Procedure:
Methyl-cyclopropanecarboxylic acid[3-(7,7-diethyl-5-isopropyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-amide was prepared using 2-(4-Amino-1H-pyrazol-3-yl)-7,7-diethyl-5-isopropyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (150 mg, 0.43 mmol) and 1-methyl-cyclopropane-carboxylic acid (51 mg, 0.43 mmol). 17 mg (9%) %) of the title compound were obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:29]=[CH:30][C:31]([NH:34][CH2:35][C:36]([O:38]CC)=[O:37])=[N:32][CH:33]=4)=[C:14](/[CH:16]=[CH:17]/[C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.[Li+].[OH-]>C1COCC1.O>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:29]=[CH:30][C:31]([NH:34][CH2:35][C:36]([OH:38])=[O:37])=[N:32][CH:33]=4)=[C:14](/[CH:16]=[CH:17]/[C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)CNc1ccc(-c2c(/C=C/c3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CNc1ccc(-c2c(/C=C/c3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of compound 45a (0.13 g, 0.24 mmol) in THF (3 mL) and water (2 mL) was added LiOH (30 mg, 1.25 mmol). The resulting solution was stirred at rt for 4 h, and concentrated under reduced pressure to remove volatile solvent. The pH of the resulting solution was adjusted to ˜4 with 1N HCl solution. The solids formed were collected by filtration. The crude solid was further purified by flash column chromatography on silica gel (1%-10% MeOH/DCM) to obtain the title compound 17 as a red solid. 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 8.53 (d, J=8.7 Hz, 1H), 8.31-8.16 (m, 6H), 8.06-8.03 (m, 2H), 7.94-7.78 (m, 3H), 7.65 (t, J=7.5 Hz, 1H), 7.16 (d, J=9.3 Hz, 1H), 6.47 (d, J=5.7 Hz, 1H), 4.19-4.02 (m, 4H), 3.94-3.80 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C28H25N7O3: 508.2 (M+H). Found: 508.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([S:21]([CH:24]=[CH2:25])(=[O:23])=[O:22])[CH2:17][C:16]2=[O:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:27][C:28]1[CH:29]=[C:30]([OH:36])[C:31](=[CH:34][CH:35]=1)[CH:32]=O.CC(C)([O-])C.[K+]>C(O)(C)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH2:25][O:36][C:30]4[CH:29]=[C:28]([Cl:27])[CH:35]=[CH:34][C:31]=4[CH:32]=3)(=[O:22])=[O:23])[CH2:17][C:16]2=[O:26])[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: C=CS(=O)(=O)N1CCN(CC2CCN(C(=O)OC(C)(C)C)CC2)C(=O)C1
Reactant: O=Cc1ccc(Cl)cc1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)C3=Cc4ccc(Cl)cc4OC3)CC2=O)CC1
Yield: 34.3 %

Procedure:
To a solution of the obtained 1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-4-vinylsulfonyl-2-piperazinone (3.99 g) and 4-chlorosalicylaldehyde (1.61 g) in tert-butanol (35 ml) was added potassium t-butoxide (446 mg), and the mixture was refluxed for 4 days. The reaction solution was concentrated, and the residue was partitioned with ethyl acetate/water. The organic layer was washed with brine, dried and concentrated, and the residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:4) to give colorless solid of 1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-4-(7-chloro-2H-benzopyran-3-sulfonyl)-2-piperazinone (1.856 g).
Reaction SMILES: C[N:2](/[CH:4]=[C:5]1/[CH2:6][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][C:9]/1=[O:10])C.O.[NH2:19]N>C1(C)C=CC=CC=1>[OH:10][C:9]12[CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH:5]1[CH:4]=[N:2][NH:19]2
Reactant: NN
Reactant: CN(C)/C=C1/CN(C(=O)OC(C)(C)C)CC1=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC2C=NNC2(O)C1
Temperature: 5 °C
Reaction time: 10 h

Procedure:
To a solution of tert-butyl (3Z)-3-[(dimethylamino)methylene]-4-oxopyrrolidine-1-carboxylate (58.2 kg, 242 mol) in toluene (251 kg) at 35-45° C. was added hydrazine hydrate (14.6 kg, 290 mol) via drop-wise addition over 2 h. The mixture was then stirred for 10 h at this temperature. The batch was then cooled to 0-10° C. and the slurry stirred for 6 h. This slurry was then filtered and the cake washed with n-heptane. The solids were then dried under vacuum overnight at 35-50° C. to give tert-butyl 6a-hydroxy-3a,4,6,6a-tetrahydropyrrol[3,4-c]pyrazole-5(1H)-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:7]([NH:6][C:4]([C:3]1[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=1[NH:1][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:5])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)CBr
Reactant: Nc1ccccc1C(=O)NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1ccccc1C(=O)NCc1ccccc1
Temperature: 100 °C
Reaction time: 17 h
Yield: 24.8 %

Procedure:
A mixture of 2-amino-N-benzylbenzamide (400 mg), ethyl bromoacetate (295 mg) and potassium carbonate (244 mg) in N,N-dimethylformamide (10 ml) was stirred at 100° C. for 17 hours. After cooling, the reaction mixture was poured into ice-cold water and extracted with diethyl ether. The extract was washed with water and dried. Removal of the solvent gave a residue, which was chromatographed on silica gel. Elution with chloroform gave ethyl 2-[2-(N-benzylcarbamoyl)anilino]-acetate (137 mg).
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:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19]Br)[CH:14]=1>>[Br:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[CH2:19][O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: BrCc1cccc(Br)c1
Product: O=[N+]([O-])c1cc(OCc2cccc(Br)c2)ccc1Cl

Procedure:
A solution of 4-chloro-3-nitro-phenol was reacted with 1-bromo-3-bromomethyl-benzene using the conditions described in Example 237C to provide 4-(3-Bromo-benzyloxy)-1-chloro-2-nitro-benzene which was treated sequentially using the procedures from Examples 237D and 237E to provide 4-[2-Amino-4-(3-bromo-benzyloxy)-phenylsulfanyl]-phenol.