Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[CH2:15][CH2:14][C:13](=[O:19])[NH:12][C:11]=2[N:10]=1)([CH3:7])[CH2:3][CH2:4][CH:5]=O.Cl.[Cl:21][C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.CCN(CC)CC.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Cl:21][C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[N:29]1[CH2:34][CH2:33][N:32]([CH2:5][CH2:4][CH2:3][C:2]([CH3:7])([CH3:1])[O:8][C:9]2[N:10]=[C:11]3[C:16]([CH2:15][CH2:14][C:13](=[O:19])[NH:12]3)=[CH:17][CH:18]=2)[CH2:31][CH2:30]1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: CC(C)(CCC=O)Oc1ccc2c(n1)NC(=O)CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)(CCCN1CCN(c2cccc(Cl)c2Cl)CC1)Oc1ccc2c(n1)NC(=O)CC2
Reaction time: 0.17 h
Yield: 66.2 %

Procedure:
To a solution of 4-methyl-4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-pentanal (335 mg, crude) in DCE (6 mL) was added 2,3-dichlorophenyl-piperazine hydrochloride (335 mg, 1.25 mmol) followed by Et3N (0.35 mL, 2.50 mmol). The mixture was stirred for 10 min and then powdered NaBH(OAc)3 (365 mg, 1.72 mmol) was added. The reaction was stirred at room temperature for 2 h and then quenched with saturated NaHCO3. The mixture was extracted with EtOAc (2×). The organic layer was washed with saturated NaHCO3, H2O and brine, dried over Na2SO4 and concentrated. Purification by liquid chromatography (4% MeOH/CH2Cl2) gave the title compound as a white foam (395 mg, 0.827 mmol, 67% over 2 steps). The foam was dissolved in Et2O and 1 N HCl in Et2O (0.85 mL) was added. The resulting white precipitate was collected by filtration, washed with Et2O and dried to give a white solid (386 mg). MS: APCI: M+1: 477.1 (Exact Mass: 476.17).
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[F:23][C:24]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:28][C:25]=1[C:26]#[N:27].[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[C:4]1[N:27]=[C:26]([C:25]2[CH:28]=[C:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:30]=[CH:31][C:24]=2[F:23])[N:2]([CH3:1])[N:3]=1
Reactant: CN(N=C(Cl)c1c(F)cccc1Cl)S(=O)(=O)c1ccccc1
Reactant: CCCCCCc1ccc(F)c(C#N)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCc1ccc(F)c(-c2nc(-c3c(F)cccc3Cl)nn2C)c1
Temperature: 140 °C
Reaction time: 0.5 h

Procedure:
A mixture of N-methyl-N-(benzenesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (2.17 g), 2-fluoro-5-hexylbenzonitrile (1.23 4), anhydrous aluminum chloride (0.88 g) and o-dichlorobenzene (10 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, the reaction mixture is dissolved in chloroform (200 ml), washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline in this order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 1.11 g of desired compound (refractive index: 1.5608).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([CH3:24])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.C(N(CC)CC)C.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl>[C:32]([OH:39])(=[O:1])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[OH:1][CH2:2][C@@H:3]([CH3:24])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1
Reactant: O=C(Cl)c1ccccc1
Agent: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of (20S)-21-hydroxy-20-methylpregn-4-en-3-one (8.0 g, 24.2 mmole) in dichloromethane (200 mL) was cooled in an ice-water bath and treated sequentially with triethylamine (3.69 mL, 26.6 mmole) and benzoyl chloride (3.09 mL, 26.6 mmole) and stirred for 16 hours at room temperature. After the reaction mixture was diluted with dichloromethane (200 mL), it was extracted with ether, dried over magnesium sulfate and filtered and the filtrate was concentrated to a solid which was purified by flash chromatography to give (20S)-21-hydroxy-20-methylpregn-4-en-3-one benzoate (9.4 g, 89.5%) melting at 193°-195° C. after recrystallization from acetone. IR 1716, 1676, 1614 (m), 1284 cm-1 ; MS (CI) 435 (100%, M+1), 313 (70%, M+1-PhCOOH); 1H NMR (CDCl3) δ 0.77 (3H, s, C18 -Me), 1.04 (d, C22 -Me), 1.19 (s, C19 -Me), 4.05 (1H, dd, 1/2 C2 -CH2), 4.34 (1H, dd, 1/2 C21 -CH2), 5.72 (1H, s, C4 -H), 7.45 (2H, t), 7.56 (1H, t), 8.04 (2H, dd).
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([CH2:9]Cl)=[CH:7][C:6]([C:11]([F:14])([F:13])[F:12])=[CH:5][N:4]=1.[C:15]1([C:21]([NH2:34])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[F:12][C:11]([F:14])([F:13])[C:6]1[CH:7]=[C:8]2[CH2:9][N:34]([C:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:2][C:3]2=[N:4][CH:5]=1
Reactant: NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: FC(F)(F)c1cnc(CCl)c(CCl)c1
Product: FC(F)(F)c1cnc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2

Procedure:
Prepared in analogy to Example A2(b) from 2,3-Bis-chloromethyl-5-trifluoromethyl-pyridine and triphenylmethylamine. White solid. MS (m/e): 431.3 ([MH+, 100%).
Reaction SMILES: C([O:8][C:9](=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1)C1C=CC=CC=1.[C:23]([C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:42])[C:35]2[CH:40]=[CH:39][C:38](Cl)=[N:37][CH:36]=2)=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24].C1(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=NC=2)=O)C=CC=CC=1>>[C:23]([C:27]1[CH:28]=[CH:29][C:30]([NH:33][C:34]([C:35]2[CH:40]=[CH:39][C:38]([N:19]3[CH2:18][CH2:17][N:16]([C:13]4[CH:12]=[CH:11][C:10]([C:9]([OH:8])=[O:22])=[CH:15][CH:14]=4)[CH2:21][CH2:20]3)=[N:37][CH:36]=2)=[O:42])=[CH:31][CH:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: O=C(OCc1ccccc1)c1ccc(N2CCNCC2)cc1
Reactant: CC(C)(C)c1ccc(NC(=O)c2ccc(Cl)nc2)cc1
Agent: O=C(O)c1ccc(N2CCN(c3ccc(C(=O)Nc4ccccc4)cn3)CC2)cc1
Product: CC(C)(C)c1ccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)nc2)cc1

Procedure:
4-{4-[5-(4-tert-Butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid was prepared from 4-piperazin-1-yl-benzoic acid benzyl ester and N-(4-tert-butyl-phenyl)-6-chloro-nicotinamide with a method similar to the one described in the synthesis of 4-[4-(5-phenylcarbamoyl-pyridin-2-yl)-piperazin-1-yl]-benzoic acid above. HRMS m/z calcd for C27H30N4O3 [M+H]+: 459.2391. Found: 459.2390.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:20][C:21](O)=[O:22])[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11].[CH2:24]([NH:26][CH2:27][C:28]1[S:29][CH:30]=[CH:31][N:32]=1)[CH3:25]>>[CH2:24]([N:26]([CH2:27][C:28]1[S:29][CH:30]=[CH:31][N:32]=1)[C:21](=[O:22])[CH2:20][N:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:11])=[O:12])[CH3:25]
Reactant: CCNCc1nccs1
Reactant: COc1ccccc1N(CC(=O)O)S(=O)(=O)c1ccccc1C
Product: CCN(Cc1nccs1)C(=O)CN(c1ccccc1OC)S(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of [(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-acetic acid with ethyl-thiazol-2-ylmethyl-amine
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([CH:12]([CH3:14])[CH3:13])[C@:7]([CH2:16][CH2:17][O:18]S(C1C=CC(C)=CC=1)(=O)=O)([OH:15])[CH2:6][CH2:5]2.FC1C=C2C(=CC=1)[C@H](C(C)C)C(=O)CC2.BrCC([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=O.[Mg]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([CH:12]([CH3:14])[CH3:13])[C@:7]([CH2:16][C:17]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:18])([OH:15])[CH2:6][CH2:5]2
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1ccc(S(=O)(=O)OCC[C@@]2(O)CCc3cc(F)ccc3[C@@H]2C(C)C)cc1
Agent: CC(C)[C@@H]1C(=O)CCc2cc(F)ccc21
Agent: [Mg]
Product: CC(C)[C@H]1c2ccc(F)cc2CC[C@]1(O)CC(=O)OC(C)(C)C

Procedure:
The (1S,2S)-6-fluoro-1-isopropyl-2-[2-(4-toluenesulfonyloxy)ethyl]-1,2,3,4-tetrahydronaphthalene-2-ol, as described in U.S. Pat. No. 4,680,310 (also to Hoffinann-La Roche), is prepared by reacting (S)-6-fluoro-1-isopropyl-3,4-dihydro-1H-naphthalen-2-one with tert-butyl bromoacetate in the presence of activated magnesium to form tert-butyl (1S,2S)-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl)acetate, which is reduced with lithium aluminum hydride to form (1S,2S)-6-fluoro-2-(2-hydroxyethyl)-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-ol, and then reacted with 4-toluenesulfonyl chloride in pyridine to form the (1S,2S)-6-fluoro-1-isopropyl-2-[2-(4-toluenesulfonyloxy)ethyl]-1,2,3,4-tetrahydronaphthalene-2-ol.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)[CH2:10][C:11]([OH:13])=[O:12].N1CCCCC1.N1C=CC=CC=1.Cl>>[C:11]([OH:13])(=[O:12])[CH:10]=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1ccccc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
Benzaldehyde (10 g, 94 mmol), malonic acid (2 eq.), and piperidine (0.1 eq.) were dissolved in pyridine (5 eq.) and stirred at 80° C. for 5 hours. After completion of the reaction, the reaction mixture was cooled down to the room temperature and neutralized with 3M HCl. The white solid thus obtained was filtered out and dried in a vacuum oven to yield cinnamic acid.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH:8]([OH:12])[C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C.CCOC(C)=O>[CH2:19]([O:10][C:9](=[O:11])[CH:8]([OH:12])[CH2:7][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)C(O)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)C(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.4 %

Procedure:
To a solution of DL-Phenyllactic acid (5.0 g, 30.09 mmol) in DMF (30 mL) was added Cs2CO3 (10.79 g, 33.11 mmol) in portions during 10 minutes period at room temperature. The resulting mixture was stirred for 15 min at room temperature, followed by the addition of benzyl bromide (3.57 mL, 30.09 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (300 mL), washed with saturated NaHCO3, water (100×2) and brine, dried (Na2SO4) and filtered. The filtrate was concentrated to give 7.20 g (89%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](F)[CH:6]=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11].[CH3:13][S:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:20]2[CH2:21][CH2:22][N:17]([S:14]([CH3:13])(=[O:16])=[O:15])[CH2:18][CH2:19]2)[CH:6]=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(N2CCN(S(C)(=O)=O)CC2)ccc1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
To 4-fluoro-2-(methyloxy)-1-nitrobenzene (Example 22, step A) (1 g, 5.8 mmol) in 10 mL of DMSO was added, 1-(methylsulfonyl)piperazine (1.15 g, 7.02 mmol), and K2CO3 (2.42 g, 17.5 mmol). The mixture was heated to 80° C. overnight. In the morning, the mixture was poured into 100 mL of H2O, Solid precipitated and was filtered off, washed with H2O and let air dried for a few hours. After drying under high vacuum overnight, the title compound of step A was isolated as a yellow solid. (1.09 g, 3.46 mmol, 60%). MS (ESI): 316 [M+H]+.
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[NH2:7][C@H:8]([C:10]([OH:12])=[O:11])[CH3:9].C(N(CC)CC)C.Cl>C(Cl)Cl>[Br:1][CH:2]([CH3:6])[C:3]([NH:7][C@H:8]([C:10]([OH:12])=[O:11])[CH3:9])=[O:4]
Reactant: C[C@H](N)C(=O)O
Reactant: CC(Br)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Br)C(=O)N[C@@H](C)C(=O)O

Procedure:
69.26 g (404 mmol) of α-bromopropionic acid chloride is added in drops at 0° C. to 30 g (336.7 mmol) of alanine and 102.2 g (1010.2 mmol) of triethylamine in 600 ml of methylene chloride. In this case, the temperature remains between 0° C.-5° C. 1000 ml of 5% aqueous hydrochloric acid is added, and the organic phase is separated. The organic phase is extracted once more with 400 ml of 5% aqueous hydrochloric acid, dried on magnesium sulfate and evaporated to dryness in a vacuum. The residue is recrystallized from acetone/diisopropyl ether.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]=[C:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16])[CH3:7])[CH3:2].[Br:18]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:17])[CH:5]=[C:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16])[CH2:7][Br:18])[CH3:2]
Reactant: CCOC(=O)C=C(C)Oc1ccc(F)cc1F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C=C(CBr)Oc1ccc(F)cc1F
Temperature: 105 °C
Yield: 81.1 %

Procedure:
A solution of 3-(2,4-difluoro-phenoxy)-but-2-enoic acid ethyl ester (1.35 g, 5.57 mmol) in carbon tetrachloride (30.9 mL) was treated with N-bromosuccinimide (1.09 g, 6.13 mmol) and benzoyl peroxide (108 mg, 0.44 mmol). The reaction was then heated to reflux (105° C.) for 5 h. At this time, the reaction was cooled to 25° C. and then was placed in the refrigerator overnight. At this time, the reaction was removed from the refrigerator. The resulting precipitate was removed by filtration and was rinsed with carbon tetrachloride (10 mL). The filtrate was concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 2% ethyl acetate/hexanes) afforded impure 4-bromo-3-(2,4-difluoro-phenoxy)-but-2-enoic acid ethyl ester (1.45 g, 81%) as a clear oil. The material was used without further purification.
Reaction SMILES: C([Si](CC)(CC)[O:4][C@H:5]1[CH2:10][C@H:9]([O:11][Si](CC)(CC)CC)[CH2:8]/[C:7](=[CH:19]/[CH:20]=[C:21]2\[CH2:22][CH2:23][CH2:24][C@@:25]3([CH3:41])[C@H:29]\2[CH2:28][CH2:27][C@@H:26]3[C@@:30]2([CH3:40])[O:34][CH2:33][C@H:32]([CH2:35][C:36]([CH3:39])([OH:38])[CH3:37])[CH2:31]2)/[C:6]1=[CH2:42])C>CC#N.CCN(CC)CC>[OH:38][C:36]([CH3:39])([CH3:37])[CH2:35][C@@H:32]1[CH2:33][O:34][C@@:30]([C@@H:26]2[C@:25]3([CH3:41])[C@H:29](/[C:21](=[CH:20]/[CH:19]=[C:7]4\[C:6](=[CH2:42])[C@@H:5]([OH:4])[CH2:10][C@H:9]([OH:11])[CH2:8]\4)/[CH2:22][CH2:23][CH2:24]3)[CH2:28][CH2:27]2)([CH3:40])[CH2:31]1
Reactant: C=C1/C(=C\C=C2/CCC[C@@]3(C)[C@H]2CC[C@@H]3[C@]2(C)C[C@@H](CC(C)(C)O)CO2)C[C@@H](O[Si](CC)(CC)CC)C[C@@H]1O[Si](CC)(CC)CC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=C1/C(=C\C=C2/CCC[C@@]3(C)[C@H]2CC[C@@H]3[C@]2(C)C[C@H](CC(C)(C)O)CO2)C[C@@H](O)C[C@@H]1O
Reaction time: 0.17 h
Yield: 90 %

Procedure:
HF-Py (0.4 mL) was added to a solution of compound 16 (134 mg, 0.2 mmol) in CH3CN (2.5 mL) and Et3N (1.5 mL). After 10 min, the reaction was quenched by the addition of saturated NaHCO3 (5 mL). The mixture was extracted with Et2O (2×20 mL). The combined organic phase was washed with saturated NaCl (25 mL) and H2O (25 mL), dried, filtered and concentrated in vacuum. The residue was purified by flash chromatography (SiO2, 1.5×9.5 cm, 50% EtOAc-hexanes) to give compound A (80 mg, 88%, white solid, mp: 128° C.).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][S:10][CH2:9][CH2:8][NH:7]1)=[O:5])[CH3:2].CN(C1C=CC=CN=1)C.[N+:21]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28])([O-:23])=[O:22].Cl>C(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][S:10][CH2:9][CH2:8][N:7]1[C:27](=[O:28])[C:26]1[CH:30]=[CH:31][CH:32]=[C:24]([N+:21]([O-:23])=[O:22])[CH:25]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)C1CSCCN1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CSCCN1C(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
To a solution of thiomorpholin-3-ylcarboxylic acid ethyl ester (5.05 g) in methylene chloride (120 mL) were added dimethylaminopyridine (352 mg), triethylamine (4.9 mL) and 3-nitrobenzoyl chloride (5.62 g) in ice bath and then the mixture was stirred at room temperature overnight. 2N hydrochloric acid was added to the reaction mixture, which was extracted with methylene chloride. The extract was wash with a saturated aqueous sodium hydrogen carbonate solution and brine sequentially, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1) to give the title compound (5.91 g) having the following physical data.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:27][CH:28]3[CH2:33][CH2:32][CH:31]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:30][CH2:29]3)[CH:9]=[C:10]([N:11]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]2=[N:4][CH:3]=1.[CH:42]1(B(O)O)[CH2:44][CH2:43]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CCO>C1(C)C=CC=CC=1.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>[CH:42]1([C:2]2[N:6]3[N:7]=[C:8]([NH:27][CH:28]4[CH2:33][CH2:32][CH:31]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:30][CH2:29]4)[CH:9]=[C:10]([N:11]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:5]3=[N:4][CH:3]=2)[CH2:44][CH2:43]1
Reactant: COc1ccc(CN(c2ccccc2)c2cc(NC3CCC(NC(=O)OC(C)(C)C)CC3)nn3c(Br)cnc23)cc1
Reactant: OB(O)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(CN(c2ccccc2)c2cc(NC3CCC(NC(=O)OC(C)(C)C)CC3)nn3c(C4CC4)cnc23)cc1
Temperature: 120 °C
Yield: 15.4 %

Procedure:
tert-Butyl 4-(3-bromo-8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexylcarbamate (30 mg, 0.048 mmol) from (1a) and cyclopropylboronic acid (10 mg, 0.090 mmol) in toluene were purged with argon for 15 min, then aq. K3PO4 (2M, 0.06 mL), EtOH (0.04 mL) and tetrakis(triphenylphosphine)palladium(0) were added sequentially. The mixture was heated at 120° C. for 20 h. After cooling to room temperature, the mixture was partitioned between EtOAc (20 mL) and water (5 mL) and the organic layer was washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by reverse phase preparative HPLC to provide tert-butyl 4-(3-cyclopropyl-8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexylcarbamate as a cream colored oil (4.3 mg, 15%) LCMS [M+H]+ 583.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[F:7][C:8]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[S:13][C:12]=2[C:11]([OH:23])=[CH:10][CH:9]=1.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CO>[CH2:24]([O:23][C:11]1[C:12]2[S:13][C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20](=[O:22])[C:21]=2[C:8]([F:7])=[CH:9][CH:10]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=c1c2ccccc2sc2c(O)ccc(F)c12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=c1c2ccccc2sc2c(OCc3ccccc3)ccc(F)c12
Temperature: 25 °C
Yield: 66.2 %

Procedure:
K2CO3 (21.0 g, 150 mmol) was added to a stirred suspension of 1-Fluoro-4-hydroxy-thioxanthen-9-one (18.47 g, 75.0 mmol) in methanol (100 mL) followed by benzylbromide (16 mL, 75.0 mmol) which was added in slow stream via syringe. The resulting mixture was then heated to reflux for 90 minutes and then cooled to room temperature before it was poured onto crushed ice (0.5 L). The resulting precipitate was filtered off and dried (P2O5) to give the title compound as a yellow solid (16.7 g, 66.1%) m/z (LC-MS, ESP): 337 [M+H]+, R/T=5.22 mins
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:38].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl.C(OCC)(=O)C>[NH2:38][C:9]1[C:8]2[N:17]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]([CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCOCc1nc2cnc3ccccc3c2n1CCCC(=O)OCC
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCCC(=O)OCC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of ethyl 4-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butanoate (15.4 g, 45.1 mmol) in dichloromethane (150 mL) at 0° C. was added mCPBA (approximately 77% purity, 19.7 g, 87.9 mmol) in portions. The reaction mixture was stirred at room temperature for 1.5 hours, then concentrated ammonium hydroxide (50 mL) was added. p-Toluenesulfonyl chloride was added in portions to the mixture, which was stirred for 1 hour then filtered. The filtrate was transferred to a separatory funnel, saturated aqueous sodium bicarbonate (50 mL) was added and the layers were separated. The aqueous layer was extracted with dichloromethane (2×50 mL). The organic layers were combined, washed with 5% aqueous sodium hydroxide (2×75 mL), dried over potassium carbonate, filtered, and concentrated under reduced pressure to yield a brown solid that was slurried in ethyl acetate (50 mL) and filtered. The filtrate was concentrated under reduced pressure and the solid was recrystallized from ethanol/water four times, then was dissolved in dichloromethane (100 mL). The solution was washed with saturated aqueous sodium bicarbonate (2×50 mL), then was concentrated under reduced pressure to yield a solid that was recrystallized from ethanol/water three times. The crystals were dried in a vacuum oven at 70° C. to provide ethyl 4-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butanoate as pale yellow crystals, mp 129-131° C.
Reaction SMILES: [C:1]([C:5]1[C:16]([O:17][CH3:18])=[CH:15][C:8]([CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([O:35][C:36]1[C:41](Br)=[CH:40][CH:39]=[C:38]([CH3:43])[N:37]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>CO.C(Cl)Cl.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>[CH2:28]([O:35][C:36]1[C:41]([C:7]2[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:16]([O:17][CH3:18])=[CH:15][C:8]=2[CH2:9][NH:10][S:11]([CH3:14])(=[O:12])=[O:13])=[CH:40][CH:39]=[C:38]([CH3:43])[N:37]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COc1cc(CNS(C)(=O)=O)c(B2OC(C)(C)C(C)(C)O2)cc1C(C)(C)C
Reactant: Cc1ccc(Br)c(OCc2ccccc2)n1
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: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(CNS(C)(=O)=O)c(-c2ccc(C)nc2OCc2ccccc2)cc1C(C)(C)C
Yield: 27.9 %

Procedure:
step 2—A sealed tube containing 72 (51 mg, 0.13 mmol), 2-benzyloxy-3-bromo-6-methyl-pyridine (51 mg, 0.19 mmol), Na2CO3 (40 mg, 0.38 mmol) and Pd(PPh3)4 (15 mg, 0.013 mmol) in a mixture of MeOH (3 mL) and DCM (1 mL) was irradiated in a microwave synthesizer at 125° C. for 30 min. The reaction mixture was diluted with DCM, filtered through a pad of CELITE, and the filtrate was concentrated. The crude residue was purified on a preparative SiO2 TLC plate developed with 5% MeOH/DCM to afford 17 mg (28%) of N-[2-(2-benzyloxy-6-methyl-pyridin-3-yl)-4-tert-butyl-5-methoxy-benzyl]-methanesulfonamide (74).