Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[OH:14][C:15]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:16]=1[CH:17]=O>>[OH:14][C:15]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:16]=1[CH2:17][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Product: O=c1cc(N2CCN(Cc3cc([N+](=O)[O-])ccc3O)CC2)nc[nH]1

Procedure:
6-[4-(2-Hydroxy-5-nitro-benzyl)-piperazin-1-yl]-3H -pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 2-hydroxy-5-nitrobenzaldehyde. Mass spectrum (ES) MH+=332.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([CH:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)=[O:11])=[N:4][CH:5]=[CH:6][N:7]=1.C(O)(=O)C.[N:23]1([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C([BH3-])#N.[Na+]>ClCCl>[Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([CH:12]2[CH2:17][CH2:16][CH:15]([N:26]3[CH2:25][CH2:24][N:23]([C:29]([O:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:30])[CH2:28][CH2:27]3)[CH2:14][CH2:13]2)=[O:11])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=C1CCC(C(=O)NCc2nccnc2Cl)CC1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(NCc1nccnc1Cl)C1CCC(N2CCN(C(=O)OCc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 134.6 %

Procedure:
N-((3-chloropyrazin-2-yl)methyl)-4-oxocyclohexanecarboxamide (3.7 mmol, 1 g) was dissolved in dichloromethane (10 mL) and acetic acid (0.1 mL) was added. To this solution benzyl 1-piperazinecarboxylate (11.2 mmol, 2.16 mL) and sodium cyanoborohydride (7.47 mmol, 0.47 g) were added subsequently. The mixture was stirred overnight at room temperature. Reaction was quenched with an aqueous sodium hydrogencarbonate solution and extracted twice with dichloromethane. The combined organic layers were dried over phase separation filter, concentrated under reduced pressure and purified using column chromatography (silica gel; dichloromethane/methanol) to yield 2.35 g of the title compound as a mixture of cis and trans isomers which was used in the next step without further purification.
Reaction SMILES: [CH:1]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4]([OH:11])=[CH:3][C:2]=1[C:12]([F:15])([F:14])[F:13].[OH-].[K+].CN(C)C=O.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(OCC)C.O>[F:15][C:12]([F:13])([F:14])[C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:7]([F:9])([F:8])[F:10])[CH:1]=1)[O:11][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)CBr
Reactant: Oc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
To a stirred solution containing 11.5 g (0.05 mole) of 3,5-ditrifluoromethylphenol, 3.3 g (0.05 mole) of 85% potassium hydroxide, 200 ml of N,N-dimethylformamide and 10 ml of water, 0.055 mole of ethyl bromoacetate was added in one portion. The stirred reaction mixture was heated at 80°-90° C. for 46 hours. After cooling 25° C., 500 ml of water and 500 ml of ethyl ether were added; and stirring was continued for 15 minutes. The separated ether layer was washed with water until neutral to litmus and dried over sodium sulfate. The ether was removed in vacuo at a maximum temperature of 80°-90° C. at 1-2 mm of Hg. A product was obtained with ND25 of 1.4226 with a yield of 85%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:39][C:40]1[CH:41]=[C:42]([CH:46]=[CH:47][CH:48]=1)[C:43]([NH2:45])=[O:44]>>[CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:39][C:40]3[CH:48]=[CH:47][CH:46]=[C:42]([C:43](=[O:44])[NH2:45])[CH:41]=3)=[O:19])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1cccc(N)c1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Cl)ccc3Oc3ccc(OCc4ccccc4)cc3)ncnc2n1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4cccc(C(N)=O)c4)ccc3Oc3ccc(OCc4ccccc4)cc3)ncnc2n1

Procedure:
A solution of the product from Example 43D and 3-Amino-benzamide was reacted to provide 4-(4-Benzyloxy-phenoxy)-N-(3-carbamoyl-phenyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzamide using the procedure from Example 43E. The material was then deprotected using the procedure from Example 43F to provide the crude title compound which was purified by HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (30 mg, 56%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.35 (d, J=6.62 Hz, 6 H) 3.28 (m, 1 H) 6.78 (m, 2 H) 6.94 (m, 3 H) 7.40 (m, 2 H) 7.60 (d, J=7.72 Hz, 1 H) 7.91 (m, 3 H) 8.02 (dd, J=8.82, 2.21 Hz, 1 H) 8.17 (d, J=2.21 Hz, 1 H) 8.22 (m, 1 H) 8.91 (s, 1 H) 9.00 (d, J=8.46 Hz, 1 H) 9.48 (s, 1 H) 10.37 (s, 1 H) 11.50 (s, 1 H); MS (ESI+) m/z 535 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:28][O:29][CH2:30][CH3:31])[N:14]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][NH:20]C(=O)OC(C)(C)C)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.CCOCC.C>Cl.CCO.CO>[NH2:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=[C:13]1[CH2:28][O:29][CH2:30][CH3:31]
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: CCO
Solvent: CCOCC
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCOCCN
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Tert-butyl 2-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate (14.45 g, 33.6 mmol) was dissolved in 50 mL of 2M HCl in EtOH and the mixture was heated to reflux with stirring. After 3 h, the reaction was cooled to room temperature and treated with ether (100 mL). The HCl salt of the product was collected by vacuum filtration The free base was made by dissolving the hydrochloride salt in 75 mL of water and treating with concentrated NH4OH until pH 12 was reached. The aqueous suspension was extracted with CH2Cl2 (4×50 mL). The combined organic layers were dried over Na2SO4 and concentrated to give a thick orange oil. The oil was dissolved in MeOH (100 mL), treated with 2 g of activated charcoal and heated to reflux. After 2 h, the mixture was filtered through a pad of Celite and rinsed with portions of MeOH. The filtrate was concentrated to yield 1-[2-(2-aminoethoxy)ethyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a sticky orange solid.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([C:19]4([CH2:23][C:24]#[N:25])[CH2:22][NH:21][CH2:20]4)[CH:18]=3)[N:11]3[CH:26]=[CH:27][N:28]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1.C(#N)C.C([O-])([O-])=O.[K+].[K+].Br[C:39]1[N:44]=[CH:43][CH:42]=[CH:41][N:40]=1>CCOC(C)=O>[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([C:19]4([CH2:23][C:24]#[N:25])[CH2:22][N:21]([C:39]5[N:44]=[CH:43][CH:42]=[CH:41][N:40]=5)[CH2:20]4)[CH:18]=3)[N:11]3[CH:26]=[CH:27][N:28]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1
Reactant: Brc1ncccn1
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CNC4)c3)n2)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CN(c5ncccn5)C4)c3)n2)cn1
Temperature: 45 °C
Yield: 20.2 %

Procedure:
To a solution of 2-(3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile hydrochloride (Example 62; 30 mg, 0.069 mmol) in acetonitrile (690 μL, 0.069 mmol) was added K2CO3 (38 mg, 0.28 mmol) and 2-bromopyrimidine (12 mg, 0.076 mmol). The reaction mixture was heated to 45° C. for 3 days. After diluting in EtOAc, the mixture was washed with water and brine. The organic layer was dried with MgSO4, filtered and concentrated in vacuo to a clear colorless oil. The oil was purified by reverse phase HPLC using 0-100% acetonitrile/water gradient to afford 2-(3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-1-(pyrimidin-2-yl)azetidin-3-yl)acetonitrile (6.1 mg, 20% yield) as a white solid. MS (apci) m/z=438.2 (M+H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[C:8]([Cl:27])=[C:9]([C:23]([Cl:26])=[CH:24][CH:25]=1)[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[CH:17]2)[CH3:6])=[O:4].[C:28]1([CH2:34][CH2:35][CH2:36][C:37](O)=[O:38])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O>[Cl:27][C:8]1[C:7]([N:5]([CH3:6])[C:3](=[O:4])[CH2:2][NH:1][C:37](=[O:38])[CH2:36][CH2:35][CH2:34][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:25][CH:24]=[C:23]([Cl:26])[C:9]=1[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[CH:17]2
Reactant: O=C(O)CCCc1ccccc1
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)c2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)CCCc4ccccc4)c3Cl)c2n1
Temperature: 25 °C
Yield: 95.2 %

Procedure:
To a mixture of 8-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-2-methylquinoline (81 mg), 4-phenylbutyric acid (40 mg) and dimethylformamide (2 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (50 mg) and 1-hydroxybenzotriazole (41 mg). After being stirred for an hour at ambient temperature, the mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (dichloromethane--methanol) to give 8-[2,6-dichloro-3-[N-methyl-N-(4 -phenylbutyrylglycyl)amino]benzyloxy]-2-methylquinoline (105 mg) as a colorless glass.
Reaction SMILES: BrC1C(F)=CC2C3CC(C3)N3C(CC4N(C)N=CC=4)=C(C(OC)=O)N=C3C=2C=1.[Br:29][C:30]1[C:31]([F:56])=[CH:32][C:33]2[O:39][CH2:38][CH2:37][N:36]3[C:40]([CH:47](O)[C:48]4[N:52]([CH3:53])[N:51]=[CH:50][CH:49]=4)=[C:41]([C:43]([O:45][CH3:46])=[O:44])[N:42]=[C:35]3[C:34]=2[CH:55]=1.CS(Cl)(=O)=O.[H][H]>[Pd]>[Br:29][C:30]1[C:31]([F:56])=[CH:32][C:33]2[O:39][CH2:38][CH2:37][N:36]3[C:40]([CH2:47][C:48]4[N:52]([CH3:53])[N:51]=[CH:50][CH:49]=4)=[C:41]([C:43]([O:45][CH3:46])=[O:44])[N:42]=[C:35]3[C:34]=2[CH:55]=1
Reactant: [H][H]
Reactant: COC(=O)c1nc2n(c1C(O)c1ccnn1C)CCOc1cc(F)c(Br)cc1-2
Agent: [Pd]
Agent: COC(=O)c1nc2n(c1Cc1ccnn1C)C1CC(C1)c1cc(F)c(Br)cc1-2
Agent: CS(=O)(=O)Cl
Product: COC(=O)c1nc2n(c1Cc1ccnn1C)CCOc1cc(F)c(Br)cc1-2

Procedure:
Methyl 10-bromo-9-fluoro-3-((1-methyl-1H-pyrazol-5-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylate was prepared similarly to methyl 10-bromo-9-fluoro-3-((1-methyl-1H-pyrazol-5-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate. Methyl 10-bromo-9-fluoro-3-(hydroxy(1-methyl-1H-pyrazol-5-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylate was reacted with methanesulfonyl chloride followed by palladium on carbon and hydrogen to afford 105 mg (85% crude yield) of the titled crude product which was carried forward without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.CS(O[CH2:28][CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[C:33]([O:32][C:31]([NH:30][CH2:29][CH2:28][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([O:15][C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1)=[O:37])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)NCCOS(C)(=O)=O
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)Oc1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C(Cc1ccc(OCCNC(=O)OC(C)(C)C)cc1)Oc1ccc(C)cc1
Yield: 58.9 %

Procedure:
In a similar manner to that described in Reference example 25, a reaction was carried out using ethyl 3-(4-hydroxyphenyl)-2-(4-methylphenoxy)propionate (300 mg), which is the-product of Reference example 35(c), t-butyl 2-methanesulfonyloxy-ethylcarbamate (598 mg) and potassium carbonate (691 mg) and the reaction mixture was treated to afford the title compound (261 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:28])[NH:19][C:20]3[CH:25]=[CH:24][C:23](I)=[C:22]([CH3:27])[CH:21]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O.C(OC(C1CCN(C2C=CC(C(=O)NC3C=CC(C4C=CC=CC=4)=C(C)C=3)=CN=2)CC1)=O)C>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:28])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[F:29])=[C:22]([CH3:27])[CH:21]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(I)c(C)c3)cn2)CC1
Reactant: OB(O)c1ccccc1F
Agent: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(-c4ccccc4)c(C)c3)cn2)CC1
Product: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(-c4ccccc4F)c(C)c3)cn2)CC1

Procedure:
5′-(2′-Fluoro-2-methyl-biphenyl-4-ylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester was prepared from 5′-(4-iodo-3-methyl-phenylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4 carboxylic acid ethyl ester and 2-fluorophenyl boronic acid following a method similar to the one described in the synthesis of 5′-(2-methyl-biphenyl-4-ylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester, above. The product was isolated after silica gel column purification with 20-40% EtOAc in hexanes gradient. HRMS m/z calcd for C27H28N3O3F [M+H]+: 462.2188. Found: 462.2186.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[C:4]([CH3:10])[N:3]=1.C(Cl)Cl.[N:14]([S:17]([C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23])(=[O:19])=[O:18])=[C:15]=[O:16]>C(Cl)CCC>[CH3:10][C:4]1[C:5]([CH3:9])=[C:6]([CH3:8])[N:7]=[C:2]([NH:1][C:15]([NH:14][S:17]([C:20]2[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=2[C:22]([O:24][CH3:25])=[O:23])(=[O:19])=[O:18])=[O:16])[N:3]=1
Reactant: Cc1nc(N)nc(C)c1C
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: CCCCCl
Solvent: ClCCl
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)c(C)c(C)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of 1.0 gram (0.0073 mole) of 2-amino-4,5,6-trimethylpyrimidine and 5.0 ml of dried methylene chloride stirring magnetically in a 50 ml RB single neck flask, 2.1 grams of methyl 2-(isocyanatosulfonyl)benzoate was added at room temperature and the mixture stirred at room temperature for 24 hours. Butyl chloride (4 ml) was added with constant stirring and the insoluble product filtered, washed immediately with butyl chloride and dried. (Yield 1.3 grams, m.p. 152°-161°). IR (Nujol): 5.60, 5.75 (C=O), 11.25 11.90 microns; NMR (TFA-d): δ2.30 (s,3H,CH3), 2.65 (s, 6H, 2CH3), 4.00 (s, 3H, CO2CH3), 7.60-8.60 (m, ArH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10]2[O:11][C@:12]3([CH2:20][N:21]=2)[CH:17]2[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]2)[CH2:13]3)=[N:6][C:7]=1[F:8].C1C=C(Cl)C=C(C(OO)=[O:30])C=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10]2[O:11][C@:12]3([CH2:20][N:21]=2)[CH:17]2[CH2:18][CH2:19][N+:14]([O-:30])([CH2:15][CH2:16]2)[CH2:13]3)=[N:6][C:7]=1[F:8]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1nc(NC2=NC[C@@]3(CN4CCC3CC4)O2)ccc1Br
Solvent: ClC(Cl)Cl
Product: [O-][N+]12CCC(CC1)[C@]1(CN=C(Nc3ccc(Br)c(F)n3)O1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.1 %

Procedure:
To (R)—N-(5-bromo-6-fluoropyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.064 g, 0.180 mmol) in CHCl3 (15 mL) was added m-CPBA (0.032 g, 0.186 mmol) at room temperature. The reaction stirred at room temperature for 3 hours. TLC showed lower spot and no starting material. The mixture was purified by chromatography (Biotage: 15-20% of 9:1 MeOH:NH4OH in CHCl3; ˜1.1 L) to yield the pure fractions. The fractions were combined and the solvent was removed to yield (S)-2-(5-bromo-6-fluoropyridin-2-ylamino)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]1′-oxide (0.045 g, 0.119 mmol, 65.9% yield) as a yellow powder. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.31-8.76 (m, 1H), 8.00 (br. s., 1H), 6.46-6.96 (m, 1H), 3.73 (d, J=11.0 Hz, 2H), 3.56 (br. s., 1H), 3.37 (br. s., 3H), 2.98-3.27 (m, 2H), 2.11 (br. s., 2H), 1.73-2.00 (m, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C@:17]3([C@@H:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[C@H:20]([C:30](O)=[O:31])[NH:19][C@H:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:71]=[CH:70][C:67]([C:68]#[N:69])=[CH:66][CH:65]=1>>[C:68]([C:67]1[CH:70]=[CH:71][C:64]([NH:63][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:37])([CH3:35])[CH3:36])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[CH:65][CH:66]=1)#[N:69]
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Reactant: N#Cc1ccc(N)cc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C#N)cc2)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in Example 5, chiral (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 136 (0.3 g, 0.52 mmol), was reacted with diisopropylethylamine (0.34 g, 2.7 mmol), diphenylphosphinic chloride (0.35 g, 1.1 mmol), then reacted with 4-aminobenzonitrile (Aldrich) (0.13 g, 1.1 mmol) to give chiral (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-phenyl)-amide as a off white foam (Yield 0.12 g, 41%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@H:10]1[C:14](=[O:15])[CH:13]=[CH:12][C@@H:11]1/[CH:16]=[CH:17]/[C@@H:18]([OH:28])[CH2:19][CH2:20][C:21]1[S:22][C:23]([CH3:27])=[C:24]([Br:26])[CH:25]=1.N1C(C)=CC=CC=1C.[Si:38](OS(C(F)(F)F)(=O)=O)([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39].C([O-])(O)=O.[Na+]>ClCCl>[CH3:1][O:2][C:3](=[O:29])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@H:10]1[C:14](=[O:15])[CH:13]=[CH:12][C@@H:11]1/[CH:16]=[CH:17]/[C@@H:18]([O:28][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH2:19][CH2:20][C:21]1[S:22][C:23]([CH3:27])=[C:24]([Br:26])[CH:25]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: COC(=O)CCC/C=C\C[C@H]1C(=O)C=C[C@@H]1/C=C/[C@@H](O)CCc1cc(Br)c(C)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COC(=O)CCC/C=C\C[C@H]1C(=O)C=C[C@@H]1/C=C/[C@H](CCc1cc(Br)c(C)s1)O[Si](C)(C)C(C)(C)C
Reaction time: 1.5 h
Yield: 90.3 %

Procedure:
A dichloromethane (6 mL) solution of 6 (497 mg, 1.03 mmol) was treated with 2,6-lutidine (143 μL, 1.22 mmol) and TBSOTf (0.26 mL, 1.13 mmol). After 1.5 h, 50 mL saturated NaHCO3 was added and the resulting mixture was extracted with 25 mL CH2Cl2. The CH2Cl2 layer was washed with 50 mL 1 M HCl and 50 mL brine. The CH2Cl2 solution was then dried (Na2SO4), filtered and evaporated. Purification by flash chromatography (8% ethyl acetate/hexanes→10%) gave 7 (553 mg, 0.93 mmol, 90%).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(Cl)[Cl:26].C(=O)([O-])[O-].[Na+].[Na+].[C:35](Cl)([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36]>O>[C:35]([N:15]([C:16]1[CH:17]=[CH:18][C:19]([C:20]([Cl:26])=[O:22])=[CH:23][CH:24]=1)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)([O:37][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:36]
Reactant: O=C(O)c1ccc(NCCCCCCCCC2CCCCC2)cc1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: ClC(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(Cl)c1ccc(N(CCCCCCCCC2CCCCC2)C(=O)OCc2ccccc2)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To 15 g. 4-(8-cyclohexyloctylamino)benzoic acid in 200 ml. warm chloroform is added 15 g. sodium carbonate in 150 ml. water. To the vigorously stirred solution is added 10 g. carbobenzyloxy chloride. After 2 hours stirring at 40° C., the layers are separated, washed three times with 1 N hydrochloric acid, dried, and evaporated to an oil. The oil is dissolved in 300 ml. toluene, treated with 15 ml. thionyl chloride and the solution is refluxed for 5 hours. The solvents are evaporated and the residue is dissolved three times in toluene, evaporating each time to yield a viscous, orange oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([F:9])[C:6]([Cl:10])=[CH:5][C:4]=1[CH2:11]Br.[C:13]1([C:19]([NH2:32])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Cl:10][C:6]1[CH:5]=[C:4]2[C:3](=[CH:8][C:7]=1[F:9])[CH2:2][N:32]([C:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:11]2
Reactant: Fc1cc(CBr)c(CBr)cc1Cl
Reactant: NC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: Fc1cc2c(cc1Cl)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2

Procedure:
Prepared in analogy to Example A2 (b) from 1,2-Bis-bromomethyl-4-chloro-5-fluoro-benzene and triphenylmethylamine. Brown oil.
Reaction SMILES: [CH2:1]([O:10][C:11](=[O:44])[CH:12]([NH:36]C(OC(C)(C)C)=O)[CH2:13][C:14]1[CH:15]=[C:16]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[CH:17]=[C:18]([CH2:20][P:21]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])=[O:22])[CH:19]=1)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:10][C:11](=[O:44])[CH:12]([NH2:36])[CH2:13][C:14]1[CH:15]=[C:16]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)[CH:17]=[C:18]([CH2:20][P:21]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])=[O:22])[CH:19]=1)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOP(=O)(Cc1cc(CC(NC(=O)OC(C)(C)C)C(=O)OCC=Cc2ccccc2)cc(-c2ccc(Cl)cc2)c1)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOP(=O)(Cc1cc(CC(N)C(=O)OCC=Cc2ccccc2)cc(-c2ccc(Cl)cc2)c1)OCC

Procedure:
5.5 g of the product of step c) and 50 ml aqueous trifluoroacetic acid (70%) are stirred at room temperature 20 hours. To the mixture are added CH2Cl2 and dropwise aqueous KHCO3 solution. The organic phase is dried (Na2SO4) and evaporated. The residue is taken up in diethyl ether, filtered and evaporated to dryness, to give the heading compound as an oil.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][Si:6]([CH3:16])([CH3:15])O[Si:8]([CH3:14])([CH3:13])[C:9]([CH3:12])([CH3:11])[CH3:10].[ClH:17]>>[C:9]([Si:8]([CH3:14])([CH3:13])[Cl:17])([CH3:12])([CH3:11])[CH3:10].[CH3:5][Si:6]([CH3:16])([CH3:15])[Cl:3]
Reactant: Cl
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)[Si](C)(C)O[Si](C)(C)C
Product: CC(C)(C)[Si](C)(C)Cl
Product: C[Si](C)(C)Cl
Reaction time: 4 h
Yield: 83.2 %
Yield: 79 %

Procedure:
The reaction system was stirred at room temperature while dropwise adding thionyl chloride through the dropping funnel. In this manner, pentamethyl-t-butyl-disiloxane was reacted with thionyl chloride while dropwise adding the latter and supplying hydrogen chloride gas to the reaction solution. After stirring the reaction solution over 4 hours, it was distilled at 125° C. to give 31.3 g (yield 83.2%) of t-butyldimethylchlorosilane and 21.4 g (yield 79.0%) of trimethylchlorosilane. There was not observed the formation of any viscous oily substance, the distillation temperature during the purification could substantially be decreased and the post-treatment of the reaction vessel was very easy.