Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2](=N)(OCC)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O-]CC.[Na+].[CH3:17][C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:19]=1[C:29]([NH:31][NH2:32])=[O:30]>C(O)C.O1CCOCC1>[CH3:17][C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:19]=1[C:29]1[O:30][C:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[N:32][N:31]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Reactant: CCOC(=N)c1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccccc2)o1
Temperature: 180 °C
Reaction time: 0.25 h
Yield: 58.4 %

Procedure:
To a solution of ethyl benzimidate hydrochloride (376 mg; 2.03 mmol) in ethanol (4 mL) was added at 0° C. sodium ethoxide (2.72 M in ethanol, 355 □L, 0.99 mmol) and stirred for 15 min. The suspension was filtered off and 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was added and stirred for 90 h at 70° C. The reaction mixture was suspended in dioxane (4 mL) and heated in the microwave for 30 min at 180° C. Concentration and then purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 60:40) afforded the title compound (163 mg, 29%) as a white solid. MS: m/e=304.2 [M+H]+.
Reaction SMILES: C1(CC(Cl)=O)C=CC=CC=1.[C:11]1([CH2:17][C:18]([N:20]=[C:21]=[S:22])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[N:31]=[CH:30][CH:29]=[C:28]2[O:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=1.C1(C)C=CC=CC=1>C(O)C>[C:11]1([CH2:17][C:18]([N:20]=[C:21]=[S:22])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[N:31]=[CH:30][CH:29]=[C:28]2[O:37][C:38]1[CH:39]=[CH:40][C:41]([NH:42][C:21]([NH:20][C:18](=[O:19])[CH2:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[S:22])=[CH:43][CH:44]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cc1ccccc1)N=C=S
Agent: O=C(Cl)Cc1ccccc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
2-Phenylethanoyl isothiocyanate was prepared using commercially available 2-phenylethanoyl chloride (80 mg) as a starting compound according to the description of the literature. 2-Phenylethanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (64 mg, yield 80%).
Reaction SMILES: [O:1]=[S:2]1(=[O:20])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][C:10]=1[CH3:19].[OH-].[Li+].O>C(O)C>[O:1]=[S:2]1(=[O:20])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:9]1[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[CH3:19]
Reactant: COC(=O)c1ccc(N2CCCCCS2(=O)=O)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(C(=O)O)ccc1N1CCCCCS1(=O)=O

Procedure:
Prepared analogously to Example 39d from methyl 4-(1,1-dioxo-[1,2]thiazepan-2-yl)-3-methyl-benzoate and lithium hydroxide in a solvent mixture of water and ethanol.
Reaction SMILES: [CH2:1]([N:8]1[C:18](=[O:19])[CH:12]2[CH2:13][C:14](=O)[CH2:15][CH2:16][CH:11]2[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:25]1([NH:31]N)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])O.[Na+]>O.C(OCC)(=O)C.C(O)C>[CH2:1]([N:8]1[C:18](=[O:19])[CH:12]2[CH:11]([CH2:16][CH2:15][C:14]3[NH:31][C:25]4[C:30]([C:13]=32)=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNc1ccccc1
Reactant: O=C1CCC2C(=O)N(Cc3ccccc3)C(=O)C2C1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1C2CCc3[nH]c4ccccc4c3C2C(=O)N1Cc1ccccc1
Temperature: 25 °C
Yield: 29 %

Procedure:
To 7 ml of anhydrous ethanol were added 510 mg of N-benzyl-4-oxocyclohexane-1,2-dicarboximide, 490 mg of concentrated sulfuric acid and 220 mg of phenylhydrazine. The mixture was refluxed for 2 hours and then cooled to room temperature. Thereto were added 30 ml of ethyl acetate and 20 ml of water. The resulting mixture was adjusted to pH 7.5 with an aqueous saturated sodium hydrogencarbonate solution. The organic layer was separated, washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: benzene/ethyl acetate =50/1 to 20/1) to obtain two fractions. The first obtained fraction was concentrated to dryness under reduced pressure, and the residue was recrystallized from isopropyl alcohol to obtain 190 mg (yield: 29%) of N-benzyl-1,2,3,4-tetrahydrocarbazole-3,4-dicarboximide as colorless needles. The later obtained fraction was concentrated to dryness under reduced pressure to remove the solvent, and the residue was recrystallized from isopropyl alcohol to obtain 120 mg (yield: 18%) of N-benzyl-1,2,3,4-tetrahydrocarbazole-2,3-dicarboximide as colorless needles.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:12]([O:14][C:15](=[O:19])[C:16]#[C:17][CH3:18])[CH3:13].N12CCCN=C1CCCCC2>O1CCCC1>[CH2:12]([O:14][C:15](=[O:19])[CH:16]=[C:17]([O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH3:18])[CH3:13]
Reactant: CC#CC(=O)OCC
Reactant: Oc1cccc2ccccc12
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOC(=O)C=C(C)Oc1cccc2ccccc12
Temperature: 130 °C
Reaction time: 8 h
Yield: 50.8 %

Procedure:
A mixture of naphthalen-1-ol (1.28 g, 8.91 mmol) and ethyl-2-butynoate (2.0 g, 17.8 mmol) in tetrahydrofuran (13.7 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (1.33 mL, 8.91 mmol). The reaction was then heated at 130° C. for 1.5 h. At this time, the reaction was cooled to 25° C. and was stirred at 25° C. overnight. At this time, the reaction was concentrated in vacuo. The residue was dissolved in dichloromethane (40 mL) and was washed with a 2N aqueous hydrochloric acid solution (1×100 mL), a 0.5N aqueous sodium hydroxide solution (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL). The organics were then dried over sodium sulfate, filtered, rinsed with dichloromethane and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 5-10% ethyl acetate/hexanes) afforded 3-(naphthalen-1-yloxy)-but-2-enoic acid ethyl ester (1.16 g, 50%) as a clear oil: HR-ES-MS m/z calculated for C16H16O3 [M+H]+ 257.1172, observed 257.1172; 1H NMR (300 MHz, DMSO-d6), δ ppm 1.04 (t, J=7.1 Hz, 3H), 2.60 (s, 3H), 3.93 (q, J=7.1 Hz, 2H), 4.52 (s, 1H), 7.31 (d, J=7.2 Hz, 1H), 7.53-7.65 (m, 3H), 7.78-7.84 (m, 1H), 7.90 (d, J=8.2 Hz, 1H), 7.99-8.07 (m, 1H).
Reaction SMILES: [NH2:1][CH:2]1[CH:6]2[O:7][CH2:8][CH:9]([NH:10][C:11]3[C:16]([Cl:17])=[CH:15][N:14]=[C:13]([NH:18][C:19]4[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=4)[N:12]=3)[CH:5]2[O:4][CH2:3]1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl.CN(C)C1C=CN=CC=1>[Cl:17][C:16]1[C:11]([NH:10][CH:9]2[CH:5]3[O:4][CH2:3][CH:2]([NH:1][S:26]([CH3:25])(=[O:28])=[O:27])[CH:6]3[O:7][CH2:8]2)=[N:12][C:13]([NH:18][C:19]2[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=2)=[N:14][CH:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cn1cc(Nc2ncc(Cl)c(NC3COC4C(N)COC34)n2)cn1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cn1cc(Nc2ncc(Cl)c(NC3COC4C(NS(C)(=O)=O)COC34)n2)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40.7 %

Procedure:
To a solution of N4-(6-aminohexahydrofuro[3,2-b]furan-3-yl)-5-chloro-N2-(1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine (57.0 mg, 0.16 mmol) in dichloromethane (5 mL) were added TEA (26.2 mg, 0.26 mmol) and N,N-dimethylpyridin-4-amine (4.1 mg, 0.03 mmol). The mixture was cooled to 0° C., and methanesulfonyl chloride (28.3 mg, 0.25 mmol) was added to. The mixture was stirred at 0° C. for 30 min, and stirred at room temperature overnight. The solution was concentrated in vacuo, and the residue was purified with a silica gel column chromatography (MeOH/DCM (v/v)=1/30) to afford the target product as an off-white solid (28.0 mg, 40.2%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][C@H:24]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]1>>[CH3:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][NH:2][CH:3]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:19])[CH2:25]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: C[C@H]1CCCNC1
Product: C[C@@H]1CCCN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)C1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (S)-3-methylpiperidine (1.2 equiv) to give 163 (13.8 mg, M+1 395.1)
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([CH:8]1[S:17][CH2:16][S:15][CH2:14][C:9]21[O:13][CH2:12][CH2:11][O:10]2)=[O:7])C>O.C(O)C>[O:10]1[C:9]2([CH2:14][S:15][CH2:16][S:17][CH:8]2[C:6]([OH:7])=[O:5])[O:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)C1SCSCC12OCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1SCSCC12OCCO2
Temperature: 60 °C
Reaction time: 6 h
Yield: 93.7 %

Procedure:
To a solution of 0.4 g (0.010 mole) of sodium hydroxide in 15 ml of water and 10 ml of ethanol was added 1.2 g (0.0048 mole) of 6-ethoxycarbonyl-1,4-dioxa-7,9-dithiaspiro[4.5]decane. The reaction mixture was stirred at 60° C. for six hours. After distilling off the ethanol, the mixture was cooled in an ice/water bath. The solution was acidified with concentrated hydrochloric acid, causing a white solid to precipitate. The solid was collected by filtration, washed with water, and dried in a vacuum dessicator, yielding 1.0 g of 1,4-dioxa-7,9-dithiaspiro[4.5]decane-6-carboxylic acid as a whitish solid, m.p. 195°-197° C.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][N:16]=[C:15]([O:18][CH2:19][C:20]([OH:22])=O)[C:14]=3[CH:23]=2)=[CH:6][CH:5]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]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>[N:26]1([C:20](=[O:22])[CH2:19][O:18][C:15]2[C:14]3[CH:23]=[C:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:25])[F:24])=[CH:9][CH:8]=4)[CH:11]=[CH:12][C:13]=3[O:17][N:16]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: C1CCNC1
Reactant: O=C(O)COc1noc2ccc(-c3ccc(OC(F)(F)F)cc3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(COc1noc2ccc(-c3ccc(OC(F)(F)F)cc3)cc12)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.4 %

Procedure:
2-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)acetic acid (50 mg, 0.142 mmol) was dissolved in 3 mL DMF. Pyrrolidine (30 mg, 0.425 mmol) was added followed by addition of HATU (81 mg, 0.212 mmol). The mixture was stirred at ambient temperature overnight, then diluted with 60 mL ethyl acetate, washed with water and brine, and evaporated. The product was purified on 12 g silica gel with 0-100% ethyl acetate in hexane followed by recrystallization from acetonitrile/water to give the title compound (30 mg, 0.073 mmol).
Reaction SMILES: [Cl-].[CH:2]1([CH2:8][NH2+:9][CH2:10][CH2:11]Cl)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[N:21]=[C:22]=[S:23]>>[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[N:21]=[C:22]1[N:9]([CH2:8][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)[CH2:10][CH2:11][S:23]1
Reactant: S=C=Nc1cccc(Cl)c1Cl
Reactant: ClCC[NH2+]CC1CCCCC1
Agent: [Cl-]
Product: Clc1cccc(N=C2SCCN2CC2CCCCC2)c1Cl

Procedure:
2-Hydroxyethylamine was reacted with cyclohexylmethyl bromide according to Method B2a to give N-cyclohexylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclohexylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,3-dichlorophenyl isothiocyanate to give 2-(2,3-dichlorophenylimino)-3-(cyclohexylmethyl)-1,3-thiazolidine.
Reaction SMILES: Br[CH:2]=[CH:3]Br.[Li]CCCC.[CH3:10][O:11][C@H:12]1[CH2:17][CH2:16][C@H:15]2[C@H:18]3[C@H:28]([CH2:29][CH2:30][C@:13]12[CH3:14])[C@:26]1([CH3:27])[C@H:21]([CH2:22][C:23](=[O:31])[CH2:24][CH2:25]1)[CH2:20][CH2:19]3>C1COCC1.C(Cl)Cl>[C:2]([C@@:23]1([OH:31])[CH2:24][CH2:25][C@@:26]2([CH3:27])[C@@H:21]([CH2:20][CH2:19][C@@H:18]3[C@@H:28]2[CH2:29][CH2:30][C@@:13]2([CH3:14])[C@H:15]3[CH2:16][CH2:17][C@@H:12]2[O:11][CH3:10])[CH2:22]1)#[CH:3]
Reactant: BrC=CBr
Reactant: CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: C#C[C@@]1(O)CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](OC)CC[C@@H]32)C1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 4.3 %

Procedure:
A solution of 1,2-dibromoethylene (1.7 mL, 21 mmol) in dry THF (25 mL) was treated with n-BuLi (16.8 mL, 2.5M in THF, 42 mmol) at -65° C. After stirring the mixture at -70° C. for 0.25 hr, a solution of 17β-methoxy-5α-androstan-3-one (2.128 g, 7 mmol) in THF (22 mL) was added and the mixture was stirred at -78° C. for 30 min. The cooling bath was then removed and the mixture was quenched with NH4Cl solution (3 mL). The solvents were removed and the residue was extracted with EtOAc. The organic layer was washed with water, and brine. After drying over anhyd. MgSO4 the solution was filtered and evaporated to yield the crude product. This crude product was then dissolved in a small amount of CH2Cl2 and poured on a column of silica gel. Elution with toluene:acetone mixture (95:5) gave 3β-ethynyl-3-hydroxy-17β-methoxy-5α-androstane (100 mg) as a colorless solid; mp 138-145° C.; TLC Rf (hexane:acetone 7:3)=0.45; and then 3β-ethynyl-3α-hydroxy-17β-methoxy-5α-androstane (1.6 g) as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:15][OH:16])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.O=[Mn]=O>[CH2:1]([O:8][C:9]1[C:10]([CH:15]=[O:16])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ncccc1OCc1ccccc1
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: O=Cc1ncccc1OCc1ccccc1
Temperature: 25 °C
Yield: 72.7 %

Procedure:
A mixture of (3-(benzyloxy)pyridin-2-yl)methanol (7.50 g) and MnO2 (30.00 g) in CHCl3 was heated to reflux for 90 min, and then cooled to rt. The reaction mixture was filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 2:1 (v/v) PE/EA) to give the title compound as a pale yellow solid (5.40 g, 73.00%), HPLC: 93.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 214.6 (M+1); 1H NMR (400 MHz, CDCl3) δ: 5.26 (s, 2H), 7.34-7.47 (m, 7H), 8.41 (t, J=2.5 Hz, 1H), 10.40 (s, 1H) ppm.
Reaction SMILES: C1(C2C=C(C=CC=2)CN)C=CC=CC=1.[CH3:15][C:16]([CH3:38])([CH3:37])[C:17]#[C:18]/[CH:19]=[CH:20]/[CH2:21][N:22]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:26]=1)[CH3:23]>>[CH3:15][C:16]([CH3:38])([CH3:37])[C:17]#[C:18]/[CH:19]=[CH:20]\[CH2:21][N:22]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:26]=1)[CH3:23]
Reactant: CN(C/C=C/C#CC(C)(C)C)Cc1cccc(-c2ccccc2)c1
Agent: NCc1cccc(-c2ccccc2)c1
Product: CN(C/C=C\C#CC(C)(C)C)Cc1cccc(-c2ccccc2)c1

Procedure:
3-Phenylbenzylamine (3.93 g) was processed in a similar manner as in Synthesis Example 5, whereby trans-N-(6,6-dimethyl-2-hepten-4-yn-1-yl)-N-methyl-3-phenylbenzylamine (Compound 7) and cis-N-(6,6-dimethyl-2-hepten-4-yn-1-yl)-N-methyl-3-phenylbenzylamine (Compound 8) were obtained in amounts of 2.73 g (yield: 45%) and 0.72 g (yield: 11.9%), respectively. The followings are their NMR spectrum data:
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][SH:7].[CH2:13]([S:20][CH2:21][C:22](=[CH2:26])[C:23]([OH:25])=[O:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH2:13]([S:20][CH2:21][CH:22]([CH2:26][S:7][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[O:3][CH:2]([F:12])[F:1])[C:23]([OH:25])=[O:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: FC(F)Oc1ccccc1CS
Reactant: C=C(CSCc1ccccc1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: O=C(O)C(CSCc1ccccc1)CSCc1ccccc1OC(F)F
Reaction time: 24 h
Yield: 63 %

Procedure:
A solution of 2-difluoromethoxybenzyl mercaptan (0.534 g, 2.81 mmol), 2-benzylsulfanylmethyl-acrylic acid (0.585 g, 2.81 mmol) and 4-dimethylaminopyridine (36 mg, 0.3 mmol) in DMF (1.5 ml) was stirred at room temperature for 20 hours. An additional amount of 2-difluoromethoxybenzyl mercaptan (0.201 g) was added to the reaction mixture and stirring was continued for another 24 hours. The reaction mixture was poured into dilute, cold, aqueous HCl and the product extracted with ethyl acetate. The extracts were washed with saturated aqueous sodium chloride and then dried over magnesium sulfate. The solvent was removed by rotary evaporation at reduced pressure and the residue was chromatographed on silica gel eluting with ethyl acetate/hexane to give 2-Benzylsulfanylmethyl-3-[2-(1,1-difluoro-methoxy)-benzylsulfanyl]-propionic acid (0.706 g).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.[C:12]([CH:16]1[CH2:20][CH2:19][N:18]([C:21]2[N:26]=[C:25]([NH2:27])[CH:24]=[CH:23][CH:22]=2)[CH2:17]1)([CH3:15])([CH3:14])[CH3:13].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:12]([CH:16]1[CH2:20][CH2:19][N:18]([C:21]2[N:26]=[C:25]([NH:27][C:2]3[C:3]4[N:4]([CH:9]=[CH:10][N:11]=4)[N:5]=[C:6]([Cl:8])[CH:7]=3)[CH:24]=[CH:23][CH:22]=2)[CH2:17]1)([CH3:15])([CH3:13])[CH3:14]
Reactant: Clc1cc(Br)c2nccn2n1
Reactant: CC(C)(C)C1CCN(c2cccc(N)n2)C1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)C1CCN(c2cccc(Nc3cc(Cl)nn4ccnc34)n2)C1
Reaction time: 15 h
Yield: 43.7 %

Procedure:
A mixture of 8-bromo-6-chloroimidazo[1,2-b]pyridazine (573 mg, 2.47 mmol), 6-(3-tert-butylpyrrolidin-1-yl)pyridin-2-amine (540 mg, 2.47 mmol), Pd2(dba)3 (142 mg, 0.25 mmol), BINAP (307 mg, 0.50 mmol), Cs2CO3 (2.4 g, 7.41 mmol) and dioxane (20 mL) was heated to reflux with stirring for 15 h under N2. The solvent was removed in vacuo and the resulting mixture was purified by chromatography (silica gel, 200-300 mesh, dichloromethane:MeOH=50:1) to give N-(6-(3-tert-butylpyrrolidin-1-yl)pyridin-2-yl)-6-chloroimidazo[1,2-b]pyridazin-8-amine (400 mg, crude) as a brown oil. LC-MS: [M+H]+, 371.1, tR=2.23 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH2:10][NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[CH:29]=[CH:30][CH:31]=[CH:32][C:33](Cl)=[O:34]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][CH2:10][N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[C:33](=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][C:23]2[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:22]=2[Cl:21])=[CH:6][CH:7]=1
Reactant: O=C(Cl)C=CC=Cc1ccc(Cl)cc1Cl
Reactant: Fc1ccc(CNCC=Cc2ccc(Cl)cc2)cc1F
Product: O=C(C=CC=Cc1ccc(Cl)cc1Cl)N(CC=Cc1ccc(Cl)cc1)Cc1ccc(F)c(F)c1

Procedure:
The cis-diaryl compounds were prepared as shown above. To a solution of 4-chlorocinnamaldehyde (1.45 g, 8.70 mmol) in 100 mL of dichloroethane was added 3,4-difluorobenzylamine followed by sodium triacetoxyborohydride (3.7 g, 17.5 mmol, 2 eq.). The mixture was stirred overnight at room temperature, washed with aq. NaHCO3, brine, dried over MgSO4, filtered, concentrated and chromatographed with 40% ethyl acetate-hexanes to provide 0.84 g of [3-(4-chloro-phenyl)-allyl]-(3,4-difluoro-benzyl)-amine. The [3-(4-chloro-phenyl)-allyl]-(3,4-difluoro-benzyl)-amine was coupled with 5-(2,4-dichloro-phenyl)-penta-2,4-dienoyl chloride to provide 5-(2,4-dichloro-phenyl)-penta-2,4-dienoic acid [3-(4-chloro-phenyl)-allyl]-(3,4-difluoro-benzyl)-amide. When 5-(2,4-dichloro-phenyl)-penta-2,4-dienoic acid [3-(4-chloro-phenyl)-allyl]-(3,4-difluoro-benzyl)-amide was subjected to the Diels-Alder reaction conditions shown above, it gave 60 as the major product. Epimerization of the trans-lactam gave 61 and reduction of the double bond of 61 gave 62.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]2[CH:20]=[CH:19][S:18][C:17]=2[C:21]([O:23]C)=[O:22])(=[O:14])=[O:13])=[CH:8][CH:7]=1)([CH3:5])[CH2:3][CH3:4].[OH-].[Na+]>CO>[CH3:5][C:2]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]2[CH:20]=[CH:19][S:18][C:17]=2[C:21]([OH:23])=[O:22])(=[O:13])=[O:14])=[CH:8][CH:7]=1)([CH3:1])[CH2:3][CH3:4]
Reactant: CCC(C)(C)c1ccc(S(=O)(=O)Nc2ccsc2C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(C)(C)c1ccc(S(=O)(=O)Nc2ccsc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 64 (210 mg; 0.14 mmol) in methanol (2 mL) was added aqueous sodium hydroxide (2 mL; 2N) and the resulting mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure and the resulting residue was dissolved in water, acidified to pH 2 with aqueous hydrochloric acid (2N), and extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The desired product was obtained from dichloromethane and hexanes as a yellow solid (75 mg).
Reaction SMILES: ON1[C:6]2C=CC=C[C:5]=2N=N1.C(N(CC)CC)C.[OH:18][NH:19][C:20](=[NH:47])[C:21]1[CH:26]=[CH:25][C:24]([C@@H:27]([N:29]2[CH2:34][CH2:33][C@:32]([CH2:41][C:42]([OH:45])([CH3:44])[CH3:43])([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:31][C:30]2=[O:46])[CH3:28])=[CH:23][CH:22]=1.C(N=C=NCCCN(C)C)C>C(O)C.C(OCC)(=O)C.CN(C)C=O.C(O)(=O)C>[OH:45][C:42]([CH3:44])([CH3:43])[CH2:41][C@@:32]1([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[O:31][C:30](=[O:46])[N:29]([C@H:27]([C:24]2[CH:23]=[CH:22][C:21]([C:20]3[N:47]=[C:5]([CH3:6])[O:18][N:19]=3)=[CH:26][CH:25]=2)[CH3:28])[CH2:34][CH2:33]1
Reactant: C[C@@H](c1ccc(C(=N)NO)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)no1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
1-Hydroxybenzotriazole (74 mg), triethylamine (0.11 mL), N-hydroxy-4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-benzamidine (150 mg), and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (140 mg) were added in the given order to a solution of acetic acid (21 μL) and dimethylformamide (3 mL) at room temperature. The resulting mixture was stirred at 70° C. for 1 h and then at room temperature overnight. Ethyl acetate was added and the resulting mixture was washed with water and brine and dried (Na2SO4). The solvent was removed and the residue was purified by chromatography on silica gel (CH2Cl2/MeOH 98:2->94:6) to afford the intermediate which was taken up in ethanol (2 mL) and stirred with microwave irradiation at 120° C. for 30 min. After cooling to room temperature, the solvent was evaporated and the residue was purified by chromatography on silica gel (CH2Cl2/MeOH 97:3) to afford the title compound.