Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=2)=[CH:7][NH:6][N:5]=1)([CH3:3])[CH3:2].[C@H:19]1([NH2:28])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]1>CS(C)=O.ClCCl>[C@H:19]1([NH:28][C:11]2[N:10]=[C:9]([C:8]3[C:4]([CH:1]([CH3:3])[CH3:2])=[N:5][NH:6][CH:7]=3)[CH:14]=[CH:13][N:12]=2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]1
Reactant: N[C@@H]1CCc2ccccc21
Reactant: CC(C)c1n[nH]cc1-c1ccnc(S(C)(=O)=O)n1
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)c1n[nH]cc1-c1ccnc(N[C@@H]2CCc3ccccc32)n1
Temperature: 150 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
To a solution of 4-(3-isopropyl-1H-pyrazol-4-yl)-2-methanesulfonyl-pyrimidine (40 mg, 0.15 mmol) in anhydrous DMSO (0.25 mL) is added (R)-indan-1-ylamine (58 uL, 0.45 mmol). The reaction mixture is stirred at 150° C. overnight, diluted with dichloromethane, and washed with water. The organic layer is dried over sodium sulfate and concentrated in vacuo. The crude product is purified by preparative HPLC to provide 20 mg of (R)-indan-1-yl-[4-(3-isopropyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine. (Example 83).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]2[S:9](=[O:10])[CH:8]=[N:7][C:6]=2[CH:11]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23]>CC(C)=O>[C:22]([N:7]1[C:6]2[CH:11]=[C:2]([CH3:1])[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]=2[S:9](=[O:10])[CH2:8]1)(=[O:24])[CH3:23]
Reactant: Cc1cc2c(c([N+](=O)[O-])c1)S(=O)C=N2
Reactant: CC(=O)Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CS(=O)c2c1cc(C)cc2[N+](=O)[O-]
Yield: 82.6 %

Procedure:
6.3 g (0.03 mol) of 5-methyl-7-nitro-benzothiazolone and 3.3 g (0.03 mol) of triethylamine are dissolved in 150 ml of acetone. 2.35 g (0.03 mol) of acetyl chloride are allowed to run in slowly dropwise, with stirring, at an internal temperature of 5°-10° C. The reaction mixture is stirred at room temperature for a further 3 hours and then poured onto ice. 6.3 g (83 % of theory) of 3-acetyl-5-methyl-7-nitro-benzothiazolone are obtained in the form of creamcolored flakes of melting point 141° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[NH:9][C:10]1[O:11][C:12]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:13][N:14]=1.[CH3:21][N:22]([CH3:32])[C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](O)=[O:27].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[CH3:21][N:22]([CH3:32])[C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([NH:9][C:10]2[O:11][C:12]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][N:14]=2)[CH:4]=1)=[O:27]
Reactant: CN(C)c1cccc(C(=O)O)c1
Reactant: Cc1ccc(N)cc1Nc1ncc(-c2cccnc2)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1Nc1ncc(-c2cccnc2)o1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (2-methyl-5-amino-phenyl)-(5-pyridin-3-yl-oxazol-2-yl)-amine (120 mg, 0.451 mmol) and 3-dimethylaminobenzoic acid (86 mg, 0.521 mmol) in DMF (6 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (136 mg, 0.824 mmol), 1-hydroxybenzotriazole (84 mg, 0.622 mmol) and triethylamine (0.98 ml, 0.710 mmol). The mixture was stirred at room temperature for 4 h. After removal of the solvent, the residue was treated with saturated aqueous NaHCO3 (20 mL) and extracted with dichloromethane (3×10 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4 and concentrated. 3-dimethylamino-N-[4-methyl-3-(5-pyridin-3-yl-oxazol-2-ylamino)-phenyl]-benzamide was obtained after silica gel column chromatography (dichloromethane/ethanol:98/2) (113 mg, 58%) as yellow solid.
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N1C=CN=C1.[CH3:16][CH:17]([CH2:20][CH3:21])[CH2:18][OH:19]>CCCCCC>[CH3:1][Si:2]([CH3:9])([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[O:19][CH2:18][CH:17]([CH3:16])[CH2:20][CH3:21]
Reactant: C[Si](C)(Cl)c1ccccc1
Reactant: CCC(C)CO
Agent: c1c[nH]cn1
Solvent: CCCCCC
Product: CCC(C)CO[Si](C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 250 ml, three-necked flask was fitted with a large magnetic, egg-shaped stir bar, a small, pressure-equalizing addition funnel, a thermocouple connected to a THERM-O-WATCH®, a reflux condenser, and an argon inlet. This apparatus was dried in an oven overnight at 125° C., assembled hot, and allowed to cool to room temperature in a stream of argon. The flask was charged with 28.74 grams (0.168 mole, 1.01 equivalents) of dimethylphenylsilyl chloride, 11.69 grams (0.172 mole, 1.03 equivalents) of imidazole, and 100 mls of hexane. 2-Methyl-1-butanol, 14.69 grams (0.167 mole, 1.00 equivalent), was then added dropwise to the resultant slurry. A very mild exotherm was detected. The total feed time was twelve minutes. A fine white precipitate formed almost immediately. The reaction mixture was heated to 40° C. with a heating mantle, controlled by the THERM-O-WATCH®. A more vigorous exotherm was noted as the heat was applied. The heating mantle was removed. After the exotherm had subsided, the reaction mixture was again heated to 40° C. with the heating mantle. The reaction mixture was stirred overnight at 40° C. The progress of the reaction was monitored by gas chromatography (GC). An aliquot of the clear supernatant was injected into the GC. The sample at 15 hours indicated all the starting material had been consumed, with the formation of a single, higher boiling component. The reaction mixture was allowed to cool to room temperature, then it was transferred to a small, dry, Chemglass pressure filter. The filtrate was collected in a dry, 500 ml flask. The filter cake was rinsed with additional hexane (2×100 ml). The solvent was removed on the rotary evaporator, with the bath temperature set at 40° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[SH:9].[OH-].[Na+].Cl[C:13]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:14]=1[CH:15]=[O:16]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9][C:13]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:14]=1[CH:15]=[O:16]
Reactant: Fc1ccc(F)c(S)c1
Reactant: O=Cc1cc(Cl)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=Cc1cc(Cl)ccc1Sc1cc(F)ccc1F
Yield: 73.9 %

Procedure:
The solution of 13.1 g of 2,5-difluorothiophenol (I.Cervena et al., Collect. Czech. Chem. Commun. 45, 2688, 1980) in 20 ml hexamethylphosphortriamide is treated with a solution of 3.6 g of sodium hydroxide in 6 ml of water and then with 13.65 g of 2,5-dichlorobenzaldehyde (of Example 6, reference above). Then, the mixture is heated while stirring for 5.5 hours to 100° C. It is then diluted with 150 ml of water and extracted with benzene. The extract is washed with a 5% sodium hydroxide solution and water, dried with magnesium sulfate and evaporated. The residue is crystallized from a mixture of benzene and petroleum ether. There are obtained 16.4 g (74%) 2-(2,5-difluorophenylthio)-5-chlorobenzaldehyde which melts in a pure state at 88°-90° C.
Reaction SMILES: [CH:1]([S:4]([C:7]1[N:11]=[CH:10][NH:9][N:8]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].[CH2:12]([N:15]([CH2:19][CH:20]=[CH2:21])[C:16](Cl)=[O:17])[CH:13]=[CH2:14].O1CCCC1>C(N(CC)CC)C>[CH2:12]([N:15]([CH2:19][CH:20]=[CH2:21])[C:16]([N:9]1[CH:10]=[N:11][C:7]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])=[N:8]1)=[O:17])[CH:13]=[CH2:14]
Reactant: CC(C)S(=O)(=O)c1nc[nH]n1
Reactant: C=CCN(CC=C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCN(CC=C)C(=O)n1cnc(S(=O)(=O)C(C)C)n1

Procedure:
A mixture of 7.0 g. 3-isopropylsulphonyl-1,2,4-triazole, 7.0 ml. diallylcarbamoyl chloride, 25 ml. dry tetrahydrofuran and 8 ml. dry triethylamine was refluxed for 1 hour under anhydrous conditions. The reaction mixture was worked up as described in Example 1 to give 1-diallylcarbamoyl-3-isopropylsulphonyl-1,2,4-triazole as an oil which was heated under reduced pressure (100° C./0.5 mm.) for 1 hour to remove all traces of volatile material. Refractive index of product nD26 1.5158. Elemental analysis satisfactory.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]#[N:10])=[N:6][CH:7]=1.Br[CH2:12][CH2:13][CH2:14]Br>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:9]#[N:10])[CH2:14][CH2:13][CH2:12]2)=[N:6][CH:7]=1.[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:12][CH2:13][CH2:14][C:8]=2[C:9]#[N:10])[CH:7]=1
Reactant: BrCCCBr
Reactant: N#CCc1ccc(Br)cn1
Product: N#CC1(c2ccc(Br)cn2)CCC1
Product: N#CC1=C2C=CC(Br)=CN2CCC1

Procedure:
The title compound was prepared from (5-bromo-pyridin-2-yl)-acetonitrile and 1,3-dibromopropane following a procedure analogous to that described in Step 1 for Intermediate 34; additionally, 7-bromo-3,4-dihydro-2H-quinolizine-1-carbonitrile was obtained {Yield: 75% of theory; LC (method 1): tR=1.72 min; Mass spectrum (ESI+): m/z=237/239 (Br) [M+H]+}. Yield: 25% of theory; LC (method 1): tR=1.86 min; Mass spectrum (ESI+): m/z=237/239 (Br) [M+H]+.
Reaction SMILES: Br[C:2]1([CH2:10][C:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])=[O:12])[C:6](=[O:7])[O:5][C:4]([CH3:9])([CH3:8])[O:3]1>C(Cl)(Cl)(Cl)Cl.O1CCCC1>[CH3:8][C:4]1([CH3:9])[O:5][C:6](=[O:7])/[C:2](=[CH:10]/[C:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])=[O:12])/[O:3]1
Reactant: CC1(C)OC(=O)C(Br)(CC(=O)O[Si](C)(C)C(C)(C)C)O1
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)OC(=O)/C(=C/C(=O)O[Si](C)(C)C(C)(C)C)O1
Reaction time: 1 h

Procedure:
The solution of crude 4-bromo-2,2-dimethyl-5-oxo-1,3-dioxolane-4-acetic acid, tert-butyldimethylsilyl ester (72.4 mmol) in carbon tetrachloride (˜220 ml) was cooled to 0-5° C. and treated dropwise over 10 min. and under good stirring with a solution of 1,8-diazabcyclo 5,4,0 undec-7-ene (12.1 g, 79.6 mmol) in dry tetrahydrofuran (125 ml). A heavy precipitate was formed which gradually became a granular solid. After 1 h, the solid obtained was filtered and washed with a small amount of tetrahydrofuran. The filtrate was concentrated under reduced pressure to give a light orange oil which was used as such for the next step.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:40])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([OH:31])[N:28]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:47]([O:49][C:50](=[O:53])[CH2:51]Br)[CH3:48]>CN(C=O)C.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:40])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:51][C:50]([O:49][CH2:47][CH3:48])=[O:53])[N:28]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)n(-c3cccc(OC)c3)n2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N2CCN(C(=O)OCC)CC2)nn1-c1cccc(OC)c1
Temperature: 100 °C

Procedure:
To a solution of 100 mg of 4-((S)-4-tert-Butoxycarbonyl-2-{[5-hydroxy-1-(3-methoxy-phenyl)-1H-pyrazole-3-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester in 4 ml of DMF, 116 mg of cesium carbonate and 59 mg of Bromo-acetic acid ethyl ester was added and heated to 100° C. for 3 h. Then, the reaction mixture was diluted with water and filtered through a Chem Elut® cartridge by eluting with ethyl acetate. The solvents were removed under reduced pressure. The crude product was used in the subsequent reaction.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[N:5][CH:4]=1)[CH3:2].C([N-]C(C)C)(C)C.[Li+].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[C:25](=[O:32])[CH2:26][N:27]1[CH:31]=[N:30][CH:29]=[N:28]1>O1CCCC1>[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[C:25]([OH:32])([CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[N:5][CH:4]=1)[CH3:2])[CH2:26][N:27]1[CH:31]=[N:30][CH:29]=[N:28]1
Reactant: O=C(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: CCc1ccnnc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(c1ccnnc1)C(O)(Cn1cncn1)c1ccc(Cl)cc1Cl

Procedure:
Treatment of 4-ethylpyridazine (2.16 g) with lithium diisopropylamide (0.02 mole) in dry tetrahydrofuran followed by 1-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (5.12 g) according to the method of Example 9(ii) gave the title compound, diastereoisomeric pair A, (1.24 g), m.p. 174°-177°;
Reaction SMILES: C([C@H](NC(=O)C1C=C(C2C=CC=CC=2)C=C(N2CCCC2=O)C=1)[C@@H](O)C[C@H](C(=O)NCCC(C)(C)C)C)C1C=CC=CC=1.[C@@H:44]([O:48][C:49]1[CH:50]=[C:51]([CH:55]=[C:56]([N:58]2[CH2:62][CH2:61][CH2:60][C:59]2=[O:63])[CH:57]=1)[C:52]([OH:54])=O)([CH2:46][CH3:47])[CH3:45].[CH:64]12[CH2:70][CH:67]([CH2:68][CH2:69]1)[CH2:66][CH:65]2[NH:71][C:72](=[O:87])[C@H:73]([CH3:86])[CH2:74][C@H:75]([OH:85])[C@@H:76]([NH2:84])[CH2:77][C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1>>[CH2:77]([C@H:76]([NH:84][C:52](=[O:54])[C:51]1[CH:55]=[C:56]([N:58]2[CH2:62][CH2:61][CH2:60][C:59]2=[O:63])[CH:57]=[C:49]([O:48][C@H:44]([CH2:46][CH3:47])[CH3:45])[CH:50]=1)[C@@H:75]([OH:85])[CH2:74][C@H:73]([C:72](=[O:87])[NH:71][CH:65]1[CH2:66][CH:67]2[CH2:70][CH:64]1[CH2:69][CH2:68]2)[CH3:86])[C:78]1[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=1
Reactant: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NC1CC2CCC1C2
Reactant: CC[C@H](C)Oc1cc(C(=O)O)cc(N2CCCC2=O)c1
Agent: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(-c2ccccc2)cc(N2CCCC2=O)c1)C(=O)NCCC(C)(C)C
Product: CC[C@H](C)Oc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)C[C@@H](C)C(=O)NC2CC3CCC2C3)cc(N2CCCC2=O)c1

Procedure:
Prepared in an analogous manner to E6 from 3-((S)-sec-butyloxy)-5-(2-oxopyrrolidin-1-yl)benzoic acid (D47) and (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-phenylhexanoic acid (bicyclo[2.2.1]hept-2-yl)amide (D29).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].C([Li])CCC.[C:16]1(=[O:20])[CH2:19][CH2:18][CH2:17]1.[Cl-].[NH4+]>O1CCCC1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[C:16]1([OH:20])[CH2:19][CH2:18][CH2:17]1
Reactant: O=C1CCC1
Reactant: COc1ccc(F)c(F)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(F)c(F)c1C1(O)CCC1
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of 3,4-difluoroanisole (2.47 g) in tetrahydrofuran (50 mL) was added n-butyllithium (2.64 mol/L n-hexane solution, 6.5 mL) at −78° C., and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added a solution of cyclobutanone (1 g) in tetrahydrofuran (20 mL), and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=5/1) to give the title compound (2.69 g).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)/[C:9]1=[O:26])=O)(C)(C)C.[Br:27][C:28]1[CH:29]=[CH:30][C:31]([O:43][CH:44]2[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45]2)=[C:32]([CH:34]=[N:35][C:36]([O:38][Si](C)(C)C)=[CH2:37])[CH:33]=1>C1(C)C=CC=CC=1>[Br:27][C:28]1[CH:29]=[CH:30][C:31]([O:43][CH:44]2[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45]2)=[C:32]([CH:34]2[C:10]3([C:11]4[C:16](=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=4)[NH:8][C:9]3=[O:26])[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[CH2:37][C:36](=[O:38])[NH:35]2)[CH:33]=1
Reactant: C=C(N=Cc1cc(Br)ccc1OC1CCN(C(=O)OC(C)(C)C)C1)O[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)cc2C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)C1

Procedure:
In a manner similar to the method described in example 1e, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 5b (0.6 g, 1.5 mmol) was reacted with (R/S)-1-[5-bromo-2-(1-tert-butoxycarbonyl-3-pyrrolidinyloxy)-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene (7.4 mmol) in toluene (30 mL) at 140° C. for 6 h to give racemic(2′R, 3R, 4′S)-2′-[5-bromo-2-(1-tert-butoxycarbonyl-3-pyrrolidinyloxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off white solid (Yield 0.5 g, 48%)
Reaction SMILES: [C:1]1(=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:12][C:13]([NH2:15])=[S:14].[I:16]I>O>[IH:16].[N:12]1[C:1]2[C:10]3[C:5]([CH2:4][CH2:3][C:2]=2[S:14][C:13]=1[NH2:15])=[CH:6][CH:7]=[CH:8][CH:9]=3
Reactant: NC(N)=S
Reactant: O=C1CCCc2ccccc21
Reactant: II
Solvent: O
Product: I
Product: Nc1nc2c(s1)CCc1ccccc1-2
Temperature: 95 °C
Reaction time: 4 h
Yield: 32.2 %

Procedure:
A mixture of 1-tetralone (5.00 mL; 37.6 mmol), thiourea (5.72 g; 75.2 mmol) and iodine (9.54 g; 37.6 mmol) were heated to 95° C. with stirring. After 4 hr., the mixture solidified and was allowed to cool to room temperature. The mixture was diluted with 200 mL of water and the solid material was filtered off and triturated with absolute ethanol. The solid was washed several times with absolute ethanol to provide 4.00 g of 4,5-Dihydro-naphtho[1,2-d]thiazol-2-ylamine hydroiodide 15 as an off white powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[NH2:18][C:19]1[C:24]([O:25][CH3:26])=[CH:23][C:22]([N:27]2[CH2:32][CH2:31][CH:30]([NH:33]C(=O)OC(C)(C)C)[CH2:29][CH2:28]2)=[C:21]([CH3:41])[CH:20]=1>>[NH2:33][CH:30]1[CH2:31][CH2:32][N:27]([C:22]2[C:21]([CH3:41])=[CH:20][C:19]([NH:18][C:2]3[N:7]=[C:6]([C:8]4[C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[NH:10][CH:9]=4)[C:5]([Cl:17])=[CH:4][N:3]=3)=[C:24]([O:25][CH3:26])[CH:23]=2)[CH2:28][CH2:29]1
Reactant: COc1cc(N2CCC(NC(=O)OC(C)(C)C)CC2)c(C)cc1N
Reactant: Clc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Product: COc1cc(N2CCC(N)CC2)c(C)cc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1

Procedure:
Starting materials: 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (INTERMEDIATE 2) tert-butyl 1-(4-amino-5-methoxy-2-methylphenyl)piperidin-4-ylcarbamate (INTERMEDIATE 29).
Reaction SMILES: C([O:8][C:9](=[O:44])[CH:10]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:11][C:12]1[N:13]=[CH:14][N:15]([C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=1)C1C=CC=CC=1.[OH-].[K+].C1COCC1>CO.O>[C:40]([O:39][C:37]([NH:36][CH:10]([CH2:11][C:12]1[N:13]=[CH:14][N:15]([C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:16]=1)[C:9]([OH:44])=[O:8])=[O:38])([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)OC(=O)NC(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)C(=O)OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)C(=O)O
Yield: 94.2 %

Procedure:
2-tert-Butoxycarbonylamino-3-(1-trityl-1H-imidazol-4-yl)-propionic acid benzyl ester (6 g, 10.22 mmol) in MeOH (20 mL) was added potassium hydroxide (1.14 g, 20.44 mmol) in water (10 mL). THF (25 mL) was added to homogenise the solution. The solution was stirred for 1 hour and the solvents removed. Water was added and extracted with Et2O. The aqueous layer was acidified with dilute aqueous HCl and extracted with Et2O. The Et2O was washed with water, brine, dried over MgSO4 and filtered. The solvent was removed to give the title compound (4.792 g, 94%). ESMS 498 (M+H+) Mpt 101.5-103.6° C. 1H NMR (CDCl3) δ 1.35 (9H, s), 3.25 (1H, dd, J=5.37, 14.9), 3.39 (1H, dd, J=4.83, 14.9), 4.46-4.52 (1H, m), 5.66, (1H, d, J=5.91), 6.83 (1H, s), 7.07-7.10 (3H, m), 7.26-7.30 (8H, m), 7.42-7.45 (4H, m), 8.13 (1H, s). 13C NMR (CDCl3) δ 28.26, 29.00, 53.07, 76.14, 78.98, 120.88, 128.21, 128.32, 129.63, 133.68, 137.22, 141.52, 154.90, 173.60.
Reaction SMILES: [C:1]1([CH2:7][NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:25]([C:27]([CH3:29])=[O:28])=[CH2:26].N#N>CO>[O:28]=[C:27]([CH3:29])[CH2:25][CH2:26][N:17]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:8]([CH2:26][CH2:25][C:27](=[O:28])[CH3:29])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(CNCCCCCCCCNCc2ccccc2)cc1
Reactant: C=CC(C)=O
Agent: N#N
Solvent: CO
Product: CC(=O)CCN(CCCCCCCCN(CCC(C)=O)Cc1ccccc1)Cc1ccccc1
Reaction time: 16 h

Procedure:
Dissolve the product obtained in Step A in 1400 ml of methanol and introduce 21.6 of methyl vinyl ketone on a stream of N2 gas. Stir for 16 hours to yield the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[N:29]([O-])=O.[Na+]>CC(O)=O.O>[NH2:29][C:19]1[C:18]2[C:22](=[CH:23][CH:24]=[C:16]([NH:15][C:13]([C:10]3([C:8]4[CH:7]=[CH:6][C:5]5[O:1][CH2:2][O:3][C:4]=5[CH:9]=4)[CH2:12][CH2:11]3)=[O:14])[CH:17]=2)[NH:21][C:20]=1[C:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)c1[nH]c2ccc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cc2c1N
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1H-indol-5-yl)cyclopropane carboxamide (50 mg, 0.13 mmol) was dissolved in AcOH (2 mL) and warmed to 45° C. To the mixture was added a solution of NaNO2 (9 mg) in H2O (0.03 mL). The mixture was allowed to stir for 30 min at 45° C. before the precipitate was collected and washed with Et2O. This material was used in the next step without further purification. To the crude material, 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-3-nitroso-1H-indol-5-yl)cyclopropanecarboxamide, was added AcOH (2 mL) and Zn dust (5 mg). The mixture was allowed to stir for 1 h at ambient temperature. EtOAc and H2O were added to the mixture. The layers were separated and the organic layer was washed with sat. aq. NaHCO3, dried over MgSO4, and concentrated in vacuo. The residue was taken up in DMF (1 mL) and was purified using prep-HPLC. LCMS: m/z 392.3; retention time of 2.18 min.
Reaction SMILES: [F:1][CH:2]([F:10])[C:3]1[O:7][C:6]([CH2:8]O)=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(P([N:56]=[N+:57]=[N-:58])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1.ClCCl>[N:56]([CH2:8][C:6]1[O:7][C:3]([CH:2]([F:10])[F:1])=[CH:4][CH:5]=1)=[N+:57]=[N-:58]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: OCc1ccc(C(F)F)o1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: [N-]=[N+]=NCc1ccc(C(F)F)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77 %

Procedure:
To a solution of (5-(difluoromethyl)furan-2-yl)methanol (0.55 g, 3.72 mmol), triphenylphosphine (1.07 g, 4.09 mmol) and diethylazodicarboxylate (0.64 mL, 4.09 mmol) in anhydrous tetrahydrofuran (20 mL) was added diphenylphosphorylazide (0.88 mL, 4.09 mmol). The reaction mixture was stirred at ambient temperature for 18 hours, diluted with dichloromethane (40 mL) and washed with water and brine. The organic solution was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with ethyl acetate/hexane (1/9) to afford 2-(azidomethyl)-5-(difluoromethyl)furan as a yellow oil in 77% yield (0.50 g): 1H NMR (300 MHz, CDCl3) δ 6.61 (d, J=3.3 Hz, 1H), 6.58 (t, J=54.3 Hz, 1H), 6.37 (d, J=3.3 Hz, 1H), 4.30 (s, 2H); MS (ES+) m/z 172.2 (M+1).