Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].I.[NH:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[C:36]1[NH:44][CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>>[CH3:33][O:32][C:28]1[CH:27]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:48]2[CH2:47][CH2:46][CH:45]([NH:44][C:36]3[NH:35][C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=4[N:37]=3)[CH2:50][CH2:49]2)([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(Cc3ccccc3)C2)cc(OC)c1OC
Reactant: c1ccc2[nH]c(NC3CCNCC3)nc2c1
Agent: I
Product: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5[nH]4)CC3)(Cc3ccccc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 4.1 using 1-(3,4,5-trimethoxybenzoyl)-3-(phenylmethyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine (0.8 g, 1.67 mmol) and (1H-benzimidazol-2-yl)(piperidin-4-yl)amine hydriodic acid salt (0.8 g, 1.67 mmol). Purify by chromatography on silica gel eluting with 2% triethylamine/30% methanol/ethyl acetate to give the title compound: Rf=0.21 (silica gel, 2% triethylamine/30% methanol/ethyl acetate).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]=[N:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([F:16])[CH:3]=1.C([N-]C(C)C)(C)C.CN([CH:27]=[O:28])C.O>C1COCC1>[Br:1][C:2]1[C:3]([CH:27]=[O:28])=[C:4]([F:16])[C:5]([N:9]=[N:10][N:11]2[CH2:12][CH2:13][CH2:14][CH2:15]2)=[C:6]([F:8])[CH:7]=1
Reactant: CN(C)C=O
Reactant: Fc1cc(Br)cc(F)c1N=NN1CCCC1
Agent: CC(C)[N-]C(C)C
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1c(Br)cc(F)c(N=NN2CCCC2)c1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
In a 200 ml three necked flask fitted with a magnetic stirrer, under inert atmosphere, (4-bromo-2,6-difluoro-phenyl)-pyrrolidin-1-yl-diazene a8 (6.06 g, 0.021 mol.) in THF (50 ml) is added to a solution of diisopropylamide (2 M in THF, 12.5 ml) cooled at −78° C. After 2 h at this temperature, dry DMF (3.2 ml) is added to the green solution. After 1 h, it is poured into water (200 ml), extracted with ether (3×200 ml) and the organic phase is dried over MgSO4, filtered and concentrated in vacuo to give the crude aldehyde a9 (6.62 g, 99%).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:9]=2[C:17]([F:20])([F:19])[F:18])[CH:3]=1.[H][H]>C(O)C.[C].[Pd]>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][C:4]2[CH:3]=[C:2]([CH3:1])[NH:6][N:5]=2)=[C:9]([C:17]([F:20])([F:19])[F:18])[CH:10]=1
Reactant: Cc1cc(Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)n[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(Oc2ccc(N)cc2C(F)(F)F)n[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.7 %

Procedure:
A solution of 5-methyl-3-(4-nitro-2-trifluoromethylphenyloxy)pyrazole (5.3 g, 18.5 mmol) in ethanol (200 ml) was placed in an autoclave, and 10% palladium carbon (2.0 g) was added. An atmosphere in the autoclave was fully replaced with hydrogen gas, and hydrogen gas was filled up to 5 kg/cm2. Then, the reaction solution was stirred at room temperature for 4 hours. After completion of the reaction, the catalyst was separated by filtration using Celite, and the solvent was distilled off from the filtrate under reduced pressure, to give a white solid of 3-(4-amino-2-trifluoromethylphenyloxy)-5-methylpyrazole (3.6 g, yield: 76.1%). mp: 143-145° C.; 1H-NMR (DMSO-d6, DMSO, ppm): δ 2.17 (s, 3H), 5.33 (br s, 2H), 5.44 (s, 1H), 6.78 (dd, J=2.6 and 8.8 Hz, 1H), 6.88 (d, J=2.6 Hz, 1H), 6.95 (d, J=8.8 Hz, 1H), 11.80-11.95 (br s, 1H).
Reaction SMILES: [CH2:1]([C:8]1[O:12][CH:11]=[N:10][C:9]=1[C:13](O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:18])=O>>[CH2:1]([C:8]1[O:12][CH:11]=[N:10][C:9]=1[CH2:13][Cl:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ncoc1Cc1ccccc1
Reactant: O=S(Cl)Cl
Product: ClCc1ncoc1Cc1ccccc1

Procedure:
5-Benzyl-4-oxazolecarboxylic acid is converted to 5-benzyl-4-hydroxymethyl xazole by the procedure of Example 135. Treating this hydroxylmethyl compound with thionyl chloride gives 5-benzyl-4-chloromethyloxazole.
Reaction SMILES: [F:1][CH:2]([F:8])[C:3](OCC)=[O:4].[CH3:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([C:18]([CH3:20])=[O:19])[CH:15]=[CH:14][CH:13]=1>>[CH2:10]([O:11][C:12]1[CH:17]=[C:16]([C:18](=[O:19])[CH2:20][C:3](=[O:4])[CH:2]([F:8])[F:1])[CH:15]=[CH:14][CH:13]=1)[CH3:9]
Reactant: CCOC(=O)C(F)F
Reactant: CCOc1cccc(C(C)=O)c1
Product: CCOc1cccc(C(=O)CC(=O)C(F)F)c1
Yield: 112.1 %

Procedure:
Prepared from commercially available ethyl difluoroacetate (16.0 g, 129 mmol) and 3-ethoxyacetophenone (example C.19 step 1) (14.5 g, 88 mmol) as described in example C.1 step 1 to give the title compound (23.90 g, 112%) as a light red oil. MS (ISN) 241.0 [(M−H)−].
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)([CH3:5])[C:3]#[CH:4].[O:16]1C2C=CC=CC=2[O:18][BH:17]1>>[CH3:5][C:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:14])([F:13])[F:15])=[CH:8][CH:7]=1)([CH3:1])/[CH:3]=[CH:4]/[B:17]([OH:18])[OH:16]
Reactant: C#CC(C)(C)c1ccc(C(F)(F)F)cc1
Reactant: B1Oc2ccccc2O1
Product: CC(C)(/C=C/B(O)O)c1ccc(C(F)(F)F)cc1
Temperature: 70 °C
Reaction time: 6 h
Yield: 89.1 %

Procedure:
Under a nitrogen atmosphere, a stirred mixture of 25.2 grams (0.12 mole) of 3-methyl-3-(4-trifluoromethylphenyl)-1-butyne and 12.7 mL (0.12 mole) of 1,3,2-benzodioxaborole was warmed to 70° C. where it stirred for six hours. The reaction mixture was then cooled and poured slowly into 500 mL of ice-water while flushing with nitrogen. The mixture was then allowed to warm to ambient temperature where it stirred for about 18 hours. The mixture was cooled in an ice-bath, and the resultant solid was collected by filtration. The solid was washed with water and then dissolved in diethyl ether. The solution was washed with 100 mL of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate, filtered, and concentrated under reduced pressure to a residual solid. The solid was dried under vacuum without heat, yielding 27.6 grams of trans-3-methyl-3-(4-trifluoromethylphenyl)-1-butenylboronic acid.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[OH:20][CH2:21][CH:22]([NH2:28])[C:23]1[S:24][CH:25]=[CH:26][CH:27]=1.CCN(C(C)C)C(C)C>>[OH:20][CH2:21][CH:22]([NH:28][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1)[C:23]1[S:24][CH:25]=[CH:26][CH:27]=1
Reactant: NC(CO)c1cccs1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NC(CO)c2cccs2)S/C1=C\c1ccc2ncccc2c1

Procedure:
Then similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 2-hydroxy-1-thiophen-2-yl-ethylamine and DIEA to give 2-(2-hydroxy-1-thiophen-2-yl-ethylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 382 (MH+).
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[C:13]([I:19])[C:12]=3[N:11]=[C:10]([CH3:20])[C:9]=2[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2]>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH2:1]([CH:3]([N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[C:13]([I:19])[C:12]=3[N:11]=[C:10]([CH3:20])[C:9]=2[CH:8]=[CH:7]1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)N1CCc2c(C)nc3c(I)cccc3c21
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CCC(CC)n1ccc2c(C)nc3c(I)cccc3c21
Temperature: 40 °C
Yield: 74.9 %

Procedure:
1-(1-Ethylpropyl)-6-iodo-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline (450 mg, 1.18 mmol) was dissolved in toluene (10 mL). To the mixture was added activated manganese dioxide (4.95 g), followed by heating at 40° C. overnight. The reaction mixture was filtered through Celite and washed with ethyl acetate. The filtrate was evaporated, and the residue was purified by silica gel column chromatogrpahy (5% ethyl acetate/hexane), to give the title compound (334 mg, 0.884 mmol) as a white oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.CCCCCC.C([Li])CCC.O([Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])S(C(F)(F)F)(=O)=O>C1COCC1>[CH:26]([Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[C:2]1[O:1][CH:5]=[CH:4][N:3]=1)([CH3:28])[CH3:27]
Reactant: c1cocn1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)[Si](c1ncco1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of oxazole (2.1 g) in THF (90 mL) was added dropwise n-butyllithium hexane solution (1.6M, 19.7 mL) at −78° C. The reaction mixture was stirred at 0° C. for 10 min under nitrogen atmosphere, and triisopropylsilyl triflate (8.5 mL) was added thereto. The reaction mixture was stirred at room temperature for 2 hr, and the solvent was evaporated under reduced pressure. To the residue was added ethyl acetate, and the mixture was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (6.7 g).
Reaction SMILES: C(C1C=CC2NC[C@@H](CC3C=CC=CC=3)N(C(=[O:28])CC3C=CC=CC=3)CC=2C=1)#N.[ClH:30].[Br:31][C:32]1[CH:33]=[CH:34][C:35]2[N:41]([CH2:42][C:43]3[N:44]=[CH:45][NH:46][CH:47]=3)[CH2:40][C@@H:39]([CH2:48]C3C=CC=CC=3)[N:38]([S:55]([CH3:58])(=[O:57])=[O:56])[CH2:37][C:36]=2[CH:59]=1>>[ClH:30].[Br:31][C:32]1[CH:33]=[CH:34][C:35]2[N:41]([CH2:42][C:43]3[N:44]=[CH:45][NH:46][CH:47]=3)[CH2:40][CH:39]([CH2:48][OH:28])[N:38]([S:55]([CH3:58])(=[O:57])=[O:56])[CH2:37][C:36]=2[CH:59]=1
Reactant: CS(=O)(=O)N1Cc2cc(Br)ccc2N(Cc2c[nH]cn2)C[C@H]1Cc1ccccc1
Reactant: N#Cc1ccc2c(c1)CN(C(=O)Cc1ccccc1)[C@H](Cc1ccccc1)CN2
Agent: Cl
Product: CS(=O)(=O)N1Cc2cc(Br)ccc2N(Cc2c[nH]cn2)CC1CO
Yield: 12 %

Procedure:
Example 306 was prepared as an offwhite solid in 12% yield from Compound C of Example 305 as described for Compound D of Example 224.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.O.[NH2:26][NH2:27]>C(O)C>[NH:26]([C:2]1[N:7]=[CH:6][C:5]([CH2:8][O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1)[NH2:27]
Reactant: N#Cc1ccccc1-c1ccc(COCc2ccc(Cl)nc2)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: N#Cc1ccccc1-c1ccc(COCc2ccc(NN)nc2)cc1
Yield: 56 %

Procedure:
4′-{[(6-Chloropyridin-3-yl)methoxy]methyl}biphenyl-2-carbonitrile (1.7 g) and hydrazine monohydrate (3 mL) were suspended in ethanol (8 mL), and the suspension was reacted at 150° C. for 2 hours using a microwave reaction apparatus (Biotage Ltd.). The reaction solution was concentrated under reduced pressure, and the obtained residue was then purified by NH-silica gel column chromatography (Moritex Corporation, elution solvent: ethyl acetate) to obtain the title compound (0.90 g) as a yellow oil (yield: 56%).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[CH3:14][CH:15]([CH3:17])[O-:16].[Na+].[Na]>C(O)(C)C>[CH:15]([O:16][C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1)([CH3:17])[CH3:14]
Reactant: CC(C)[O-]
Reactant: Clc1ccc(N2CCNCC2)nn1
Agent: [Na+]
Agent: [Na]
Solvent: CC(C)O
Product: CC(C)Oc1ccc(N2CCNCC2)nn1

Procedure:
3-Chloro-6-piperazinopyridazine (4.0 g) (J. Med. Chem., 5, 541 (1963)) and sodium isopropoxide, prepared by addition of sodium (0.7 g) to dry isopropanol (70 ml), were heated in a bomb at 130°-140° C. for 10 hours. The solvent was evaporated in vacuo, the residue taken up in methylene chloride (300 ml) and the resulting solution washed with water (2×50 ml). The organic extract was dried (Na2SO4) and evaporated in vacuo to give 3-isopropoxy-6-piperazinopyridazine (3.3 g). A sample in ethyl acetate, was converted to the maleate salt by treatment with maleic acid in ethyl acetate. The resulting solid was re-crystallized from ethanol, m.p. 144°-145° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:21]Br)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:31][C:32]([F:48])([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH2:33][O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][NH2:41].C(=O)(O)[O-].[Na+].[I-].[Na+]>CS(C)=O.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:21][NH:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][O:34][CH2:33][C:32]([F:31])([F:48])[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Reactant: NCCCCCCOCC(F)(F)c1ccccc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNCCCCCCOCC(F)(F)c1ccccc1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 140 °C

Procedure:
To a solution of (8-(benzyloxy)-5-((1R)-2-bromo-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)quinolin-2(1H)-one (4.80 g, 9.83 mmol) and Intermediate 9 (3.04 g, 11.8 mmol) in dimethylsulfoxide (13.5 mL) was added sodium bicarbonate (2.49 g, 29.4 mmol) and sodium iodide (2.22 g, 14.8 mmol). The mixture was heated at 140° C. for 2 hours. After cooling, the reaction was diluted with water (40 mL) and extracted with diethyl ether (2×20 mL). The combined organic extracts were washed with water (2×10 mL) and brine (20 mL), dried (Na2SO4), and the solvent removed under reduced pressure. The title compound was obtained (6.40 g, 98%) as oil.
Reaction SMILES: [NH2:1][C@@H:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[H-].[Na+].O=[CH:13][CH2:14][N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[C:24]([O:26][CH3:27])=[O:25])[CH:17]=[CH:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[N:4]12[CH2:9][CH2:8][CH:7]([CH2:6][CH2:5]1)[C@@H:2]([NH:1][CH2:13][CH2:14][N:15]1[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[C:24]([O:26][CH3:27])=[O:25])[CH:17]=[CH:16]1)[CH2:3]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: COC(=O)c1cccc2ccn(CC=O)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1cccc2ccn(CCN[C@H]3CN4CCC3CC4)c12
Reaction time: 1 h
Yield: 84.9 %

Procedure:
To a stirred suspension of (R)-(+)-3-aminoquinuclidine (1.4 g, 7.0 mmol) in methylene chloride (50 mL) was added sodium hydride (562 mg, 14.0 mmol) in portions and the mixture was stirred for 1 h. Acetic acid (0.6 mL) was added dropwise, followed by methyl 1-(2-oxoethyl)-1H-indole-7-carboxylate (1.3 g, 5.9 mmol) from Step B above and the mixture continued to stir at room temperature for 2 h. Sodium triacetoxyborohydride (4.2 g, 19.6 mmol) was added in one portion and stirring was continued overnight at room temperature. The solvent was removed under reduced pressure and the crude material was purified by column chromatography (silica gel, 90:10:1 methylene chloride/methanol/concentrated ammonium hydroxide) to afford (R)-methyl 1-(2-(quinuclidin-3-ylamino)ethyl)-1H-indole-7-carboxylate (1.64 g, 86%) as a brown solid: 1H NMR (500 MHz, CD3OD) δ 7.77 (d, J=4.0 Hz, 1H), 7.62 (d, J=3.8 Hz 1H), 7.30 (d, J=1.5 Hz, 1H), 7.08 (t, J=7.5 Hz, 1H), 6.58 (d, J=1.5 Hz, 1H), 4.50 (t, J=6.5 Hz, 2H), 3.96 (s, 3H), 3.35 (s, 2H), 3.00-2.97 (m, 1H), 2.85-2.58 (m, 7H), 2.21-2.17 (m, 1H), 1.70-1.56 (m, 3H), 1.44-1.42 (m, 1H), 1.27-1.25 (m, 1H); MS (ESI+) m/z 328 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6](I)=[CH:5]2.FC(F)(F)C([O-])=O.[Na+]>CN1CCCC1=O.O.[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[CH:5]2
Reactant: Cn1c(I)cc2cc(Cl)ccc21
Agent: [Cu]I
Agent: O=C([O-])C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cn1ccc2cc(Cl)ccc21
Temperature: 160 °C

Procedure:
A mixture of 5-chloro-2-iodo-1-methylindole obtained from Example 3 (16.5 g, 56.6 mmole), sodium trifluoroacetate (76.2 g, 56.0 mmole) and copper (I) iodide (10.6 g, 56.0 mmole) in N-methylpyrrolidone is heated at 160° C. for about 8 hours, cooled to room temperature, diluted with water and filtered through diatomaceous earth. The filtrate is extracted with diethyl ether. The extracts are combined, washed with water, dried over MgSO4 and concentrated in vacuo to give a black oil residue. The residue is chromatographed using silica gel and 15:1 hexanes:ethyl acetate to give a yellow oil. The oil is chromatographed a second time using the same eluent and silica gel to give the title product as a yellow oil, 2.92 g (22% overall yield from 5-chloro-1-methylindole), identified by IR, 1HNMR, 13CNMR and 19FNMR analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18](Cl)[C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)[C:6]1=[O:17].C(O)C.COCCN(S(F)(F)[F:38])CCOC>ClCCl>[Cl:1][C:2]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][C:13]([F:38])=[CH:12][CH2:11]2)[C:6]1=[O:17]
Reactant: COc1cc(Cl)c(CC2CCN(C3CCC(=O)CC3)C2=O)c(Cl)c1
Reactant: COCCN(CCOC)S(F)(F)F
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(CC2CCN(C3CC=C(F)CC3)C2=O)c(Cl)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
Dissolve 3-(2,6-Dichloro-4-methoxybenzyl)-1-(4-oxocyclohexyl)-pyrrolidin-2-one (Preparation 17) (2.09 g, 5.4 mmol) in dichloromethane (50 mL) and ethanol (0.06 mL, 1.08 mmol) and cool to 0° C. Add deoxo-fluor (1.69 mL, 9.18 mmol) over several minutes. Stir overnight at room temperature. Add saturated sodium bicarbonate and extract aqueous layer with dichloromethane. Wash the organic layer with brine and dry with Na2SO4, filter and concentrate to dryness. Purify the crude mixture over silica gel (4/1 hexane in ethyl acetate) to give 650 mg (32%) of the title compound: mass spectrum (m/e): 374 (M+1).
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[I:13].C([O-])([O-])=O.[K+].[K+].Cl[CH2:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26].O>CN(C=O)C>[F:14][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[N:8]=[C:7]2[I:13]
Reactant: CN(C)CCCCl
Reactant: FC(F)Oc1ccc2[nH]nc(I)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCCn1nc(I)c2cc(OC(F)F)ccc21
Temperature: 80 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
To a solution of 5-(difluoromethoxy)-3-iodo-1H-indazole (1 g, 3.2 mmol) in DMF (25 mL) was added K2CO3 (1.8 g, 12.8 mmol) and 3-chloro-N,N-dimethylpropan-1-amine (1.1 g, 6.4 mmol), after the addition, the reaction mixture was stirred at 80° C. for 4 hour. After cooling to room temperature, H2O (25 mL) was added and product extracted with ethyl acetate (100 mL). The organic layer was washed with H2O (100 mL), brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure, the residue was purified by column chromatography (silica gel, 200-300 mesh, eluting with dichloromethane/CH3OH=10:1) to give 3-(5-(difluoromethoxy)-3-iodo-1H-indazol-1-yl)-N,N-dimethylpropan-1-amine (1.1 g, 78.5%) as yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.46-7.42 (m, 1H), 7.27-7.17 (m, 2H), 6.87-6.29 (t, 1H, J=73.8 Hz), 4.47-4.41 (m, 2H), 2.24-2.18 (m, 8H), 2.08-2.03 (m, 2H). LCMS: (M+H)+=396.
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][C:7]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([O:16][CH3:17])[C:8]=1[NH2:9].C([O:20][C:21](=O)[C:22]([CH3:37])([CH3:36])[C:23](=[O:35])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])C.Cl>C1C=CC=CC=1>[CH3:37][C:22]([CH3:36])([C:23](=[O:35])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:21]([NH:9][C:8]1[C:10]([O:16][CH3:17])=[CH:11][C:12]([O:14][CH3:15])=[CH:13][C:7]=1[O:6][CH3:5])=[O:20]
Reactant: CCCCCCCCCCCC(=O)C(C)(C)C(=O)OCC
Reactant: COc1cc(OC)c(N)c(OC)c1
Agent: C[Al](C)C
Agent: Cl
Solvent: c1ccccc1
Product: CCCCCCCCCCCC(=O)C(C)(C)C(=O)Nc1c(OC)cc(OC)cc1OC
Temperature: 5 °C
Reaction time: 0.33 h
Yield: 26 %

Procedure:
To a flask containing 10 mL benzene which had been flushed with nitrogen, trimethylaluminum (2.0M hexane solution, 0.003 mol, 1.14 eq) was added dropwise and cooled to 5° C. A solution of 2,4,6-trimethoxyaniline (0.653 g, 0.003 mol) in 1.5 mL benzene was added dropwise (exotherm to 10° C.) and stirred for 20 minutes at 5° C. The ice bath was removed and the contents were allowed to gradually warm to room temperature over a 45-minute period. A solution of 2,2-dimethyl-3-oxo-tetradecanoic acid ethyl ester (1.0 g, 0.003 mol) in 1.5 mL benzene was added dropwise and the resulting reaction mixture was heated to reflux for 16 hours (M. F. Lipton, et al, Org. Syn. Coll. Vol. 2, 492). After cooling to room temperature, the mixture was hydrolyzed slowly with 2% HCl solution (5 mi) and stirred for 20 minutes. The layers were then separated and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), and concentrated in vacuo (30° C.) to yield a residue which was washed with hot hexanes, cooled, filtered, and oven-dried to yield 0.340 g (0.78 mmol, 26%) of the title compound, mp 92°-94° C.
Reaction SMILES: N=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[NH:8][C:9]([N:11]1C=CN=C1)=[S:10].Cl[CH2:17][C:18]1[N:19]=[C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][N:21]2[CH:29]=1>C(O)CC>[N:11]1[C:9]([S:10][CH2:17][C:18]2[N:19]=[C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][N:21]3[CH:29]=2)=[N:8][N:3]2[CH:2]=[CH:7][CH:6]=[CH:5][C:4]=12
Reactant: N=c1ccccn1NC(=S)n1ccnc1
Reactant: ClCc1cn2c(n1)-c1ccccc1C2
Solvent: CCCO
Product: c1ccc2c(c1)Cn1cc(CSc3nc4ccccn4n3)nc1-2
Yield: 62.4 %

Procedure:
An adaptation of the method described in WO 96801826 was used, Imidazole-1-carbothioic acid (2-imino-2H-pyridin-1-yl)-amide (200 mg, 1.37 mmol) and 2-Chloromethyl-5H-imidazo[2,1-a]isoindole (300 mg, 1.46 mmol) were dissolved in 1-propanol (25 mL) and the mixture was heated to reflux for 2 hours. The solvent was removed under reduced pressure and the residue dissolved in dichloromethane. The solution was washed with water and the organic layer was dried over Na2SO4 and concentrated. The residue was purified by chromatography on silica gel to afford the title compound (273 mg, 62%) as a yellow solid. LC-MS: m/z=321.1 (MH+), tR=1.40 min, method B.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Br)[CH2:9][CH2:10][CH2:11]Br)=[CH:4][CH:3]=1.[C:14]([O:18][C:19]([N:21]1[CH2:25][C:24](=[O:26])[N:23]([C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=2)[C:22]1=[S:35])=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([N:21]1[C@@:25]2([CH2:11][CH2:10][CH2:9][C@H:8]2[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[C:24](=[O:26])[N:23]([C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=2)[C:22]1=[S:35])=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CC(=O)N(c2cc(Cl)cc(Cl)c2)C1=S
Reactant: BrCCCC(Br)c1ccc(Br)cc1
Product: CC(C)(C)OC(=O)N1C(=S)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CCC[C@H]2c1ccc(Br)cc1

Procedure:
Using the same procedure as in Example 1 starting from 1-bromo-4-(1,4-dibromobutyl)benzene (423 mg, 1.1 mmol) (Preparation 4) and 3-(3,5-dichlorophenyl)-4-oxo-2-thioxoimidazolidine-1-carboxylic acid tert-butyl ester (361 mg, 1 mmol) (Preparation 9), (5R*,6S*)-6-(4-bromophenyl)-3-(3,5-dichlorophenyl)-4-oxo-2-thioxo-1,3-diazaspiro[4.4]nonane-1-carboxylic acid tert-butyl ester was obtained (54 mg) as a white solid. 1H NMR (CDCl3): 7.49 (2H, d, J=8.4 Hz), 7.33 (1H, m), 7.09 (2H, d, J=8.4 Hz), 6.22 (2H, m), 4.17 (1H, dd, J1=13.2 Hz, J2=5.4 Hz), 2.35–2.6 (3H, m), 2–2.35 (3H, m), 1.69 (9H, s).