Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([CH2:9][CH3:10])[N:6]=[C:5]([NH:11][C:12]2[S:13][C:14]([C:17]#[N:18])=[CH:15][N:16]=2)[CH:4]=1.[Cl-].[CH3:20][NH:21][C:22]([N:24]1[CH2:29][CH2:28][NH2+:27][CH2:26][CH2:25]1)=[O:23].C(N(C(C)C)C(C)C)C>CS(C)=O.O>[C:17]([C:14]1[S:13][C:12]([NH:11][C:5]2[CH:4]=[C:3]([CH2:2][N:27]3[CH2:28][CH2:29][N:24]([C:22]([NH:21][CH3:20])=[O:23])[CH2:25][CH2:26]3)[CH:8]=[C:7]([CH2:9][CH3:10])[N:6]=2)=[N:16][CH:15]=1)#[N:18]
Reactant: CNC(=O)N1CC[NH2+]CC1
Reactant: CCc1cc(CCl)cc(Nc2ncc(C#N)s2)n1
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: CCc1cc(CN2CCN(C(=O)NC)CC2)cc(Nc2ncc(C#N)s2)n1
Reaction time: 24 h

Procedure:
2-{[4-(Chloromethyl)-6-ethylpyridin-2-yl]amino}-1,3-thiazole-5-carbonitrile (0.113 g, 0.41 mmol) was dissolved in 2 mL DMSO. 1-[(Methylamino)carbonyl]piperazin-4-ium chloride (0.146 g, 0.81 mmol) and N-ethyl-N,N-diisopropylamine (0.283 mL, 1.63 mmol) were added and the solution was stirred for 24 hours. The reaction was diluted with water and the resulting precipitate was filtered and washed with water. The precipitate was purified by flash column chromatography (gradient, 5-10% MeOH/CH2Cl2). The fractions containing the desired compound were concentrated to dryness to afford the desired product 12-4.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][CH:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1.[CH3:25][O:26][C:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[CH:29][C:28]=1[OH:42]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][CH:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)=[CH:3][C:2]([C:31]2[CH:30]=[CH:29][C:28]([OH:42])=[C:27]([O:26][CH3:25])[CH:32]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Reactant: CN1CCC(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(NC4CCN(C)CC4)c3c2)ccc1O
Yield: 63.2 %

Procedure:
Following general procedure F, [6-bromo-4-(1-methylpiperidin-4-ylamino)quinolin-3-yl](cyclopropyl)methanone (47 mg, 0.121 mmol) was reacted with 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (45 mg, 0.182 mmol) to afford the desired product (33 mg, 63%) as a yellow solid: 1H NMR (300 MHz, CD3OD) δ 9.17 (s, 1H), 8.33 (d, J=1.8 Hz, 1H), 8.05 (dd, J=8.7, 1.9 Hz, 1H), 7.92 (d, J=8.7 Hz, 1H), 7.27 (d, J=2.1 Hz, 1H), 7.19 (dd, J=8.2, 2.1 Hz, 1H), 6.94 (d, J=8.2 Hz, 1H), 4.36 (s, 1H), 3.97 (s, 3H), 3.34 (s, 1H), 3.08 (s, 2H), 2.94-2.82 (m, 1H), 2.65 (s, 2H), 2.53 (s, 3H), 2.28 (d, J=13.9 Hz, 2H), 1.89 (d, J=10.3 Hz, 2H), 1.26-1.17 (m, 2H), 1.17-1.08 (m, 2H); ESI MS m/z 432 [C26H29N3O3+H]+; HPLC (AUC), tR=9.78 min.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[Li]CCCC.[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:39]=[C:38]3[C:34]([C:35](I)=[N:36][N:37]3[S:40]([C:43]3[C:48]([CH3:49])=[CH:47][C:46]([CH3:50])=[CH:45][C:44]=3[CH3:51])(=[O:42])=[O:41])=[CH:33][CH:32]=2)=[CH:27][C:26]=1[O:53][CH3:54])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)(O)[O-].[Na+]>[Cl-].[Cl-].[Zn+2].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>[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:39]=[C:38]3[C:34]([C:35]([C:2]4[CH:11]=[CH:10][C:9]5[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=5)[CH:3]=4)=[N:36][N:37]3[S:40]([C:43]3[C:48]([CH3:49])=[CH:47][C:46]([CH3:50])=[CH:45][C:44]=3[CH3:51])(=[O:42])=[O:41])=[CH:33][CH:32]=2)=[CH:27][C:26]=1[O:53][CH3:54])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Brc1ccc2ccccc2c1
Reactant: COc1cc(-c2ccc3c(I)nn(S(=O)(=O)c4c(C)cc(C)cc4C)c3c2)ccc1OCc1ccccc1
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: [Cl-]
Product: COc1cc(-c2ccc3c(-c4ccc5ccccc5c4)nn(S(=O)(=O)c4c(C)cc(C)cc4C)c3c2)ccc1OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
2-Bromonaphthalene (117 mg, 0.564 mmol, 6.0 equiv) was dissolved in TH (0.75 mL) and cooled to −78° C. The mixture was treated with n-BuLi (226 μL, 2.5 M, 6.0 equiv) and was allowed to stir at −78° C. for 30 min. The mixture was then added to freshly dried ZnCl2 solid (139 mg, 0.80 mmol, 8.5 equiv) via cannula and the resulting mix was allowed to warm to 23° C. (during the addition the yellow color disappears). After 30 min at 23° C. the mixture is added to a mixture of 6-(4-benzyloxy-3-methoxy-phenyl)-3-iodo-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-indazole (60 mg, 0.094 mmol, 1 equiv) and Pd(PPh3)4 (6 mg, 0.005 mmol, 0.05 equiv) via cannula The resulting solution was allowed to stir for 16 h. Saturated sodium bicarbonate was added and the mixture was partitioned between saturated sodium bicarbonate (15 mL) and ethyl acetate (15 mL). The organic material was dried over sodium sulfate, decanted and concentrated. Purification by silica gel chromatography (1:9-2:8 ethyl acetate-hexane) gave 6-(4-benzyloxy-3-methoxy-phenyl)-3-naphthalen-2-yl-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-indazole as a solid (42 mg, 70%): Rf sm 0.4, p 0.4 (ethyl acetate-hexane 3:7); 1H NMR (CDCl3) δ 8.44 (s, 1H), 8.41 (s, 1H), 8.12 (d, 1H, J=8 Hz), 8.05-7.00 (m, 17H), 5.30 (s, 2H), 4.02 (s, 3H), 2.80 (s, 3H), 2.34 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C([O:18][C:19](=[O:49])[CH2:20][CH2:21][C:22]1[CH:27]=[C:26]([C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH2:36][C:37]([O:39]CC)=[O:38])=[O:29])[CH:25]=[CH:24][C:23]=1[O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]Br)C>CCCCCC.C(OCC)(=O)C>[C:37]([CH2:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:28]([C:26]1[CH:25]=[CH:24][C:23]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][O:1][C:2]2[CH:12]=[CH:11][C:5]3[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=3[C:3]=2[CH2:13][CH2:14][CH3:15])=[C:22]([CH2:21][CH2:20][C:19]([OH:49])=[O:18])[CH:27]=1)=[O:29])([OH:39])=[O:38]
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Reactant: CCOC(=O)CCc1cc(C(=O)c2ccccc2CC(=O)OCC)ccc1OCCCCCBr
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCCCOc2ccc(C(=O)c3ccccc3CC(=O)O)cc2CCC(=O)O)ccc2c1OCCC2=O
Yield: 23.1 %

Procedure:
Starting with 0.153 g (0.74 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one, and 0.394 g (0.74 mmol) of 2-[(5-bromopentyl)oxy]-5-[[2-(2-ethoxy-2-oxoethyl)phenyl]carbonyl]benzenepropanoic acid ethyl ester, the title compound (0.103 g, 26.7% overall yield) was obtained as a white solid, mp 105°-108.5° C. (recrystallized from hexane-ethyl acetate), using the procedure of example 22.
Reaction SMILES: C(N(CC)CC)C.[Si]([O:25][CH2:26][C@H:27]1[O:31][C@@H:30]([N:32]2[CH:39]=[C:38]([CH3:40])[C:36](=[O:37])[NH:35][C:33]2=[O:34])[C@H:29]([O:41][CH2:42][CH2:43][O:44][N:45]([CH2:48][CH3:49])[CH2:46][CH3:47])[C@@H:28]1[OH:50])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[CH2:48]([N:45]([CH2:46][CH3:47])[O:44][CH2:43][CH2:42][O:41][C@@H:29]1[C@H:28]([OH:50])[C@@H:27]([CH2:26][OH:25])[O:31][C@H:30]1[N:32]1[CH:39]=[C:38]([CH3:40])[C:36](=[O:37])[NH:35][C:33]1=[O:34])[CH3:49]
Reactant: CCN(CC)OCCO[C@@H]1[C@H](O)[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN(CC)OCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.4 %

Procedure:
A mixture of triethlyamine trihydrogenfluoride (4.39 mL, 26.81 mmol) and triethylamine (1.87 mL, 13.41 mmol) in THF (53.6 mL) was added to 5′-O-tert-butyldiphenylsilyl-2′-O-[2-(N,N-diethylaminooxy)ethyl]-5-methyluridine (3.28 g, 5.36 mmol). The reaction mixture was stirred at room temperature for 18 h. Solvent was removed in vacuo. The residue was placed on a silica gel column and eluted with CH2Cl2/MeOH /NEt3, 89:10:1, to yield the title compound (1.49 g).
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:6].[OH-].[K+].[CH2:16](Cl)[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CS(C)=O.O>[CH2:16]([N:4]1[CH2:3][CH2:2][N:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:5]1=[O:6])/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(NCCCl)Nc1cccnc1
Reactant: ClCC=Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C1N(C/C=C/c2ccccc2)CCN1c1cccnc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.5 %

Procedure:
To a solution of 20 g of N-(2-chloroethyl)-N'-(3-pyridyl) urea dissolved in 200 ml of dimethyl sulfoxide, 13 g of KOH powder was added under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. Further, 3.4 g of KOH powder was added and then 16.8 g of cinnamyl chloride (trans-form) was added under ice-cooling and the mixture was stirred for 20 minutes, followed by stirring at room temperature for 30 minutes. The mixture was diluted with 300 ml of water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, saturated saline water ad dried, and ethyl acetate was distilled off. To the residue was added 100 ml of 70% acetic acid, and the mixture was heated at 90° C. for 10 minutes and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed twice with saturated saline water and twice with water, and dried. After distilling the ethyl acetate off, the residue was recrystallized from ethanol to give 21.96 g of (E)-1-cinnamyl-3-(3-pyridyl)-2-imidazolidinone.
Reaction SMILES: [NH2:1][C:2]1[C:3](Br)=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH3:12])[C:6]=2[CH:13]=1.[CH2:15](B(CC)CC)[CH3:16].C(Cl)Cl.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[NH2:1][C:2]1[C:3]([CH2:15][CH3:16])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH3:12])[C:6]=2[CH:13]=1
Reactant: CCB(CC)CC
Reactant: CN1C(=O)COc2cc(Br)c(N)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1cc2c(cc1N)N(C)C(=O)CO2
Yield: 56.2 %

Procedure:
A mixture of 6-amino-7-bromo-4-methyl-4H-benzo[1,4]oxazin-3-one (0.21 g, 0.82 mmol), triethylborane (2.47 ml of 1.0 M solution in hexane, 5.56 mmol), PdCl2dppf.CH2Cl2 (0.067 g, 0.082 mmol) and Cs2CO3 0.81 g, 2.46 mmol) in DMF (6 ml) was heated at 50° C. under argon for 18 hours. The mixture was partitioned between EtOAc and water. The EtOAc layed was dried (MgSO4), filtered, concentrated under reduced pressure and purified with prep-plate TLC (hexanes:EtOAc 1:1) to give 0.095 g of 6-amino-7-ethyl-4-methyl-4H-benzo[1,4]oxazin-3-one as a tan solid, 63%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([CH:19]=1)/[CH:7]=[CH:8]/[C:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]=2[S:11][CH:10]=1.[CH3:21][C:22]1[N:23]=[CH:24][N:25]([C:27]2[CH:28]=[C:29]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=2)[C:30](O)=[O:31])[CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[NH2:18][C:17]1[C:12]2[S:11][CH:10]=[C:9](/[CH:8]=[CH:7]/[C:6]3[CH:19]=[C:2]([NH:1][C:30](=[O:31])[C:29]4[CH:33]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:35]=[C:27]([N:25]5[CH:26]=[C:22]([CH3:21])[N:23]=[CH:24]5)[CH:28]=4)[CH:3]=[CH:4][C:5]=3[CH3:20])[C:13]=2[N:14]=[CH:15][N:16]=1
Reactant: Cc1ccc(N)cc1/C=C/c1csc2c(N)ncnc12
Reactant: Cc1cn(-c2cc(C(=O)O)cc(C(F)(F)F)c2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cn(-c2cc(C(=O)Nc3ccc(C)c(/C=C/c4csc5c(N)ncnc45)c3)cc(C(F)(F)F)c2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
(E)-7-(5-amino-2-methylstyryl)thieno[3,2-d]pyrimidine-4-amine (100 mg, 0.354 mmol) and 3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)benzoic acid (96 mg, 0.354 mmol) were dissolved in DMF (1.5 mL), HATU (404 mg, 1.063 mmol) and TEA (0.248 mL, 1.7728 mmol) were added thereto and stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried with MgSO4, filtered and concentrated. The resulting mixture was purified by silica gel chromatography to obtain the title compound (142 mg, 75% yield).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]=1>C1COCC1.C(=O)([O-])[O-].[Ag+2]>[CH2:1]([O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccnc(O)c1
Reactant: BrCc1ccccc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: Cc1ccnc(OCc2ccccc2)c1
Yield: 94.2 %

Procedure:
A mixture of 13.6 ml (114 mmol, 1.0 eq.) of benzyl bromide and 15.0 g (137 mmol, 1.2 eq.) of 2-hydroxy-4-methylpyridine [CAS No: 13466-41-6] was dissolved in 470 ml of THF. The solution was admixed with 37.9 g (137 mmol, 1.2 eq.) of silver carbonate and the mixture was heated to reflux with exclusion of light overnight. Subsequently, the reaction mixture was filtered through kieselguhr and eluted with ethyl acetate, and the filtrate was concentrated. The crude product was purified by silica gel chromatography (700 g of silica gel, cyclohexane/ethyl acetate 95:5). 21.4 g of the title compound were obtained (94% of theory).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[C:19]([CH3:20])=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=2[CH3:21])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:22][CH:23]([C:28](=O)[CH2:29][CH3:30])[C:24](OC)=[O:25].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:3]([O:12][C:13]2[C:19]([CH3:20])=[C:18]3[C:16](=[CH:15][C:14]=2[CH3:21])[N:17]=[C:28]([CH2:29][CH3:30])[C:23]([CH3:22])=[C:24]3[OH:25])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: CCC(=O)C(C)C(=O)OC
Reactant: Cc1cc(N)cc(C)c1Oc1ncc(C(F)(F)F)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: CCc1nc2cc(C)c(Oc3ncc(C(F)(F)F)cc3Cl)c(C)c2c(O)c1C

Procedure:
A solution of 1.52 9 of 4-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-3,5-dimethylaniline, 1.75 g of methyl 2-methyl-3-oxopentanoate, and 0.92 g of p-toluenesulfonic acid dissolved in 49 mL of xylene was heated under reflux for 8 hr. This reaction solution was cooled, and the precipitated crystals were then collected by filtration and were washed with n-hexane and distilled water and were dried to give 2.56 g of 6-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-2-ethyl-4-hydroxy-3,5,7-trimethyl-quinoline. Dimethylacetamide (30 mL) was then added to 1.97 g of the crystals thus obtained, and 0.38 g of 60% sodium hydride and 0.9 g of methyl chloroformate were added thereto at room temperature. The mixture was stirred at room temperature for 2 hr, and ethyl acetate and distilled water were then added. The organic layer was washed with brine and was then concentrated under the reduced pressure. The crude product was purified by column chromatography on silica gel (BW300, manufactured by Fuji Sylysia Chemical Ltd., solvent: n-hexane /ethyl acetate) to give 1.25 g of 4-methoxycarbonyloxy-6-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-2-ethyl-3,5,7-trimethylquinoline (yield 55.6%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15](O)[CH2:16][CH2:17][O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH:22]([C:33]([O:35][CH2:36][CH3:37])=[O:34])([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24].P(C)(C)C.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C1(C)C=CC=CC=1>[CH2:31]([O:30][C:28](=[O:29])[C:22]([C:33]([O:35][CH2:36][CH3:37])=[O:34])([CH:15]1[C:14]2[C:19](=[CH:20][C:11]([S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)(=[O:9])=[O:10])=[CH:12][CH:13]=2)[O:18][CH2:17][CH2:16]1)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:32]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Reactant: O=S(=O)(c1cccc(F)c1)c1ccc2c(c1)OCCC2O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: CP(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(=O)OCC)(C(=O)OCC)C1CCOc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 7-(3-Fluorobenzene-sulfonyl)-chroman-4-ol (3.0 g, 9.7 mmol) in THF (40 ml) and toluene (40 ml) was added HC(COOEt)3 (4.5 g, 19.5 mmol) and then PMe3 (19.5 ml of 1.0M THF solution). The mixture was cooled to −78° C. DIAD (4.0 g, 19.5 mmol) was added dropwise. The mixture was stirred at −78° C. for 1 hour and then at RT for overnight. The next day the TLC showed that the reaction was complete. The solvent was removed and the residue was partitioned between EtOAc and H2O. The EtOAc layer was washed with brine, dried with MgSO4, concentrated and purified with flash column to give 2-Ethoxycarbonyl-2-[7-(3-fluoro-benzenesulfonyl)-chroman-4-yl]-malonicacid diethyl ester: 5.0 g, clear oil. MS: 545 (M+Na)+.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([NH:12][C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=3[N+:20]([O-])=O)=[C:8]([CH:11]=2)[C:9]#[N:10])[CH2:3][CH2:2]1.[Sn](Cl)[Cl:24]>C(O)C.Cl>[ClH:24].[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]3[NH:12][C:13]4[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=4[N:20]=[C:9]([NH2:10])[C:8]=3[CH:11]=2)[CH2:3][CH2:2]1
Reactant: N#Cc1cc(C2CC2)ccc1Nc1cc(F)ccc1[N+](=O)[O-]
Reactant: Cl[Sn]Cl
Agent: Cl
Solvent: CCO
Product: NC1=Nc2ccc(F)cc2Nc2ccc(C3CC3)cc21
Yield: 60.7 %

Procedure:
Heat a solution of 5-cyclopropyl-2-(5-fluoro-2-nitro-phenylamino)-benzonitrile (0.447 g, 1.50 mmol) in ethanol (7 ml) to 60° C. Add a solution of tin (II) chloride (0.855 g, 4.51 mmol) in 5.0 N hydrochloric acid (7 ml) and heat the resulting mixture to reflux for 16 hours. Cool the reaction to room temperature, add 25 ml of 5.0 N hydrochloric acid and place the mixture in a freezer for 16 hours. Collect by filtration the precipitated product from the solution. Wash solid with 5.0 N hydrochloric acid to obtain 0.277 g of the title compound (0.91 mmol, 61% yield) as a yellow amorphous solid: Mass Spectrum (m/e): 268(M+1).
Reaction SMILES: [CH3:1][C:2]([CH:4]=[N+]=[N-])=[CH2:3].[F:7][C@:8]12[C@@H:28]([OH:29])[CH2:27][C@@:26]3([CH3:30])[C@@H:18]([CH2:19][C@@H:20]([OH:32])[C@:21]3([OH:31])[C:22](=[O:25])[CH2:23][OH:24])[C@@H:17]1[CH2:16][CH2:15][C:14]1[C@:9]2([CH3:34])[CH2:10][CH2:11][C:12](=[O:33])[CH:13]=1>CCOCC.CO>[F:7][C@:8]12[C@@H:28]([OH:29])[CH2:27][C@@:26]3([CH3:30])[C@@H:18]([CH2:19][C@@H:20]([O:32][CH2:3][C:2]([CH3:4])=[CH2:1])[C@:21]3([OH:31])[C:22](=[O:25])[CH2:23][OH:24])[C@@H:17]1[CH2:16][CH2:15][C:14]1[C@:9]2([CH3:34])[CH2:10][CH2:11][C:12](=[O:33])[CH:13]=1
Reactant: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3C[C@@H](O)[C@](O)(C(=O)CO)[C@@]3(C)C[C@H](O)[C@@]12F
Reactant: C=C(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: C=C(C)CO[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CO
Temperature: 0 °C

Procedure:
A solution of 2-methyl-3-diazo-1-propene in 250 ml of ether (prepared from 0.2 mole of N-(2-methyl-2-propenyl)ethyl carbamate by the method of J. L. Brewbaker and H. Hart, J. Am. Chem. Soc., 91, 711 (1969) is diluted with 300 ml of methanol and cooled to 0°C. A total of 6.5 g of 9-fluoro-11β ,16α ,17,21-tetrahydroxypregn-4-ene-3,20-dione, 16,17-cycloborate is added in portions until the initial red color fades and nitrogen evolution ceases. The solvent is evaporated in vacuo and the residue dissolved in chloroform and chromatographed on a 100 g - silica gel column. Elution with chloroform and chloroform-ethyl acetate gives TLC homogeneous material which crystallizes from acetone-hexane to give 3.73 g of 9-fluoro-11β ,17,21-trihydroxy-16α-[(2-methyl-2-propenyl)oxy]pregn-4-ene-3,20-dione, melting point 213°-215°C, softening at 198°-200°C.
Reaction SMILES: [Cl:1]C1C=C(C=CC=1)C([O-])=O.O[N+:12]1[CH:17]=[CH:16][CH:15]=[C:14]2[CH:18]=[CH:19][NH:20][C:13]=12>O=P(Cl)(Cl)Cl>[Cl:1][C:15]1[CH:16]=[CH:17][N:12]=[C:13]2[NH:20][CH:19]=[CH:18][C:14]=12
Reactant: O=C([O-])c1cccc(Cl)c1
Reactant: O[n+]1cccc2cc[nH]c21
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ccnc2[nH]ccc12
Temperature: 90 °C
Yield: 57.8 %

Procedure:
POCl3 (10 mL) was added to 7-hydroxy-1H-pyrrolo[2,3-b]pyridin-7-ium 3-chlorobenzoate (1.0 g, 3.4 mmol). The resulting mixture was heated to 90° C. for 18 hours. The mixture was then cooled to room temperature and concentrated. The resulting residue was diluted with acetonitrile (“ACN”; 3 mL) and water (3 mL). The pH was adjusted with 50% NaOH to a pH of 9. The resulting solid was filtered and washed with water. The solid was then washed with DCM to give 4-chloro-1H-pyrrolo[2,3-b]pyridine (0.30 g, 57% yield).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]#[N:8].CN(C)[CH:11]=[CH:12][C:13]([C:15]1[CH:16]=[CH:17][C:18]([F:27])=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[CH:20]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[F:27][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[N:6]3[N:5]=[CH:4][C:3]([C:7]#[N:8])=[C:2]3[N:1]=[CH:11][CH:12]=2)=[CH:20][C:19]=1[N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23]
Reactant: N#Cc1cn[nH]c1N
Reactant: CN(C)C=CC(=O)c1ccc(F)c(N(C)S(C)(=O)=O)c1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CN(c1cc(-c2ccnc3c(C#N)cnn23)ccc1F)S(C)(=O)=O
Yield: 71.1 %

Procedure:
A mixture of 0.036 g (0.33 mmol) of 5-amino-1H-pyrazole-4-carbonitrile and 0.1 g (0.33 mmol) of N-[5-(3-dimethylamino-acryloyl)-2-fluoro-phenyl]-N-methyl-methanesulfonamide in 10 mL of glacial acetic acid was refluxed for 2.5 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 15 mL of dichloromethane and 10 mL of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 mL of dichloromethane. The organic layers were washed with 10 mL of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 81 mg of N-{2-fluoro-5-[3-cyano-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-methanesulfonamide as a solid (yield 70%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5](Br)=[CH:6][CH:7]=1.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1B(O)O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.COCCOC>[NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5]([C:15]2[C:14]([F:13])=[CH:19][CH:18]=[CH:17][C:16]=2[F:20])=[CH:6][CH:7]=1
Reactant: OB(O)c1c(F)cccc1F
Reactant: COC(=O)c1nc(Br)ccc1N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: COCCOC
Solvent: ClCCl
Product: COC(=O)c1nc(-c2c(F)cccc2F)ccc1N
Yield: 47 %

Procedure:
A solution of methyl 3-amino-6-bromopicolinate (1.0 equiv.), 2,6-difluorophenyl-boronic acid (3.0 equiv), and Pd(dppf)Cl2-DCM (0.1 equiv.) in 3:1 DME/2M Na2CO3 (0.5 M) was subjected to microwave irradiation at 120° C. for 15 min intervals. The reaction was filtered and washed with EtOAc. The organic was partitioned with H2O (25 mL), was further washed with NaCl(sat.) (25 mL), was dried over MgSO4, and the volatiles were removed in vacuo. The residue was diluted in EtOAc and passed through a silica gel plug and the volatiles were removed in vacuo yielding methyl 3-amino-6-(2,6-difluorophenyl)picolinate (47%). LCMS (m/z): 265.1 (MH+); LC Rt=2.70 min
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].CS([C:18]1[NH:19][CH:20]=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24])=O>C(O)C>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:18]2[NH:19][CH:20]=[CH:21][C:22]=2[N+:23]([O-:25])=[O:24])=[CH:7][CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: CS(=O)c1[nH]ccc1[N+](=O)[O-]
Solvent: CCO
Product: CN(C)Cc1ccc(CSCCNc2[nH]ccc2[N+](=O)[O-])o1

Procedure:
A solution of 2-(5-dimethylaminomethyl-2-furylmethylthio)ethylamine (3 g, 0.014 mol) and 2-methylsulphinyl-3-nitropyrrole (2 g, 0.011 mol) in ethanol (50 ml) was refluxed for 7 days, and it was then evaporated to dryness. The residue was purified by elution from a column of silica gel with ethyl acetate-petroleum ether (b.p. 60°-80°)(4:1) to give 2-[2-(5-dimethylaminomethyl-2-furylmethylthio)ethylamino]-3-nitropyrrole, m.p. 67°-67°.