Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[O:12][C@H:11]1[N:29]1[CH:37]=[N:36][C:35]2[C:30]1=[N:31][C:32]([I:39])=[N:33][C:34]=2Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:40]([CH:42]([NH2:45])[CH2:43][CH3:44])[CH3:41]>>[C:1]([O:9][C@@H:10]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[O:12][C@H:11]1[N:29]1[CH:37]=[N:36][C:35]2[C:30]1=[N:31][C:32]([I:39])=[N:33][C:34]=2[NH:45][CH:42]([CH2:43][CH3:44])[CH2:40][CH3:41])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(N)CC
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(Cl)nc(I)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NC(CC)CC)nc(I)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1

Procedure:
Prepared from ((2R,3R,4S,5S)-4-(benzoyloxy)-2-(6-chloro-2-iodo-9H-purin-9-yl)-5-[(ethylamino)carbonyl]-tetrahydro-3-furanyl benzoate (Preparation 19) and 1-ethylpropylamine by the same method as Preparation 20. The title compound was obtained as a yellow foam.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:25])=[C:7]([C:9]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:10]=2)[CH:8]=1.C1COCC1.[O:31]1[CH2:35][CH2:34][CH2:33][C@H:32]1[C:36](O)=[O:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:25][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:36]([C@@H:32]2[CH2:33][CH2:34][CH2:35][O:31]2)=[O:37])=[CH:8][C:7]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[N:10]=1
Reactant: O=C(O)[C@@H]1CCCO1
Reactant: NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1)[C@@H]1CCCO1
Yield: 11.3 %

Procedure:
The title compound was prepared according to the procedure described in Example-107 by using 3-(5-(aminomethyl)-2-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one (Intermediate-63, 0.070 g, 0.189 mmol), THF:DMF (5 mL:1 mL), (S)-(−)tetrahydrofuran-2-carboxylic acid (0.032 g, 0.283 mmol), TBTU (0.182 g, 0.567 mmol), and TEA (3.0 mL). The obtained crude was purified by column chromatography on basic alumina by eluting solution of 2% ammonia in 10.0% MeOH:DCM to afford 0.010 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.80 (m, 3H), 2.15 (m, 1H), 3.75 (m, 1H), 3.94 (m, 1H), 4.27-4.32 (m, 3H), 7.42 (d, 1H), 7.60 (d, 2H), 7.85 (d, J=5.4 Hz, 2H), 8.20 (d, J=4.5 Hz, 2H), 8.52 (s, 1H), 12.50 (s, 1H); MS (m/z): 467.08 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[C:15]3[C:10]([C:11](=[O:23])[C:12]([C:20]([OH:22])=[O:21])=[CH:13][N:14]3[CH:17]3[CH2:19][CH2:18]3)=[C:9]([CH3:24])[C:8]=2[F:25])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:26](OC(=O)C)(=[O:28])[CH3:27].Cl>[OH-].[Na+]>[C:26]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:16]=[C:15]3[C:10]([C:11](=[O:23])[C:12]([C:20]([OH:22])=[O:21])=[CH:13][N:14]3[CH:17]3[CH2:18][CH2:19]3)=[C:9]([CH3:24])[C:8]=2[F:25])[CH2:2][CH2:3]1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(F)c(N2CCNCC2)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)N1CCN(c2cc3c(c(C)c2F)c(=O)c(C(=O)O)cn3C2CC2)CC1

Procedure:
To a solution of 7-(l-piperazinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (40 mg) in 5% sodium hydroxide (2 ml) is added acetic anhydride (0.1 ml) at room temperature. After the mixture is made acidic with dilute hydrochloric acid, the resultant is extracted with dichloromethane and the extract is dried over magnesium sulfate. After concentrating, the obtained residue is recrystallized from ethanol to give 7-(4-acetyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (29 mg), as white powder, m.p. 261°-263° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:14][N:15]3[CH:19]=[CH:18][NH:17][C:16]3=[O:20])[CH2:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:14][N:15]3[CH:19]=[CH:18][N:17]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:16]3=[O:20])[CH2:12][CH2:13]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2(Cn3cc[nH]c3=O)CC2)cc1OC
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C2(Cn3ccn(Cc4ccccc4)c3=O)CC2)cc1OC
Temperature: 25 °C
Yield: 51.5 %

Procedure:
A mixture of 1-[[1-(3,4-dimethoxyphenyl)cyclopropyl]methyl]-1,3-dihydro-2H-imidazol-2-one (1.9 g) in DMF (20 ml) was stirred at RT. Sodium hydride (60%) (0.28 g) was added portionwise over 15 minutes. The mixture was stirred for 30 minutes. A solution of bromomethylbenzene (1.45 g) in DMF (5 ml) was added dropwise over 15 minutes. The reaction mixture was stirred for 1 hour. The solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH 95/5). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from diethyl ether (20 ml). The precipitate was filtered off and dried, yielding 1.3 g (51%) of 1-[[1-(3,4-dimethoxyphenyl)cyclopropyl]methyl]-1,3-dihydro-3-(phenylmethyl)-2H-imidazol-2-one (comp. 21; mp. 110.5° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[NH:6][C:7]3[N:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]([CH:18](OC(C)C)[O:19][CH:20]([CH3:22])[CH3:21])([C:14]([F:17])([F:16])[CH3:15])[C:4]=2[CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[NH:6][C:7]3[N:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]([CH2:18][O:19][CH:20]([CH3:21])[CH3:22])([C:14]([F:16])([F:17])[CH3:15])[C:4]=2[CH:3]=1
Reactant: CC(C)OC(OC(C)C)C1(C(C)(F)F)c2cc(Cl)ccc2Nc2ncccc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)OCC1(C(C)(F)F)c2cc(Cl)ccc2Nc2ncccc21
Reaction time: 14 h
Yield: 80.2 %

Procedure:
Method QQ: To a stirred solution of 7-chloro-5-diisopropoxymethyl-5-(1,1-difluoroethyl)-5,10-dihydrobenzo[b][1,8]naphthyridine (53) (360 mg, 0.876 mmol) in anhydrous methylene chloride (4 mL) at room temperature was added trifluoroacetic acid (8 mL) and triethylsilane (6.0 mL, 36.44 mmol). After 14 h at room temperature, the reaction mixture was concentrated in vacuo, the residue was purified by flash chromatography (30%-40% EtOAc-hexane, gradient elution) afforded 55 (248 mg, 80% yield) as a yellow solid (m.p. 148 -149° C.).
Reaction SMILES: [C:1]1([C:11]2([C:14]([OH:16])=O)[CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:19])=O>>[C:1]1([C:11]2([C:14]([Cl:19])=[O:16])[CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1(c2cccc3ccccc23)CC1
Product: O=C(Cl)C1(c2cccc3ccccc23)CC1

Procedure:
1-(1-Naphthyl)cyclopropane carboxylic acid (6.7 g, prepared in a similar manner to that described in Example H20), was added to thionyl chloride (25 ml) and the mixture heated at 90°-95° C. for 1 hour. Excess thionyl chloride was removed in vacuo to yield 1-(1-naphthyl)cyclopropanecarbonyl chloride (7.1 g) which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15].N1C=CC=CC=1>>[C:14]([O:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)/C=C/c1ccc(O)cc1
Solvent: c1ccncc1
Product: COC(=O)/C=C/c1ccc(OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 26 h
Yield: 93.1 %

Procedure:
To a solution of methyl (2E)-3-(4-hydroxyphenyl)acrylate (5.35 g, 30.0 mmol) in acetic anhydride (45.0 mL, 476 mmol) was added pyridine (4.85 mL, 60.0 mmol), and the mixture was stirred at room temperature for 26 hr. The reaction mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The precipitated crystals were washed with ethyl acetate-hexane to give the title compound (6.15 g, yield 93%) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:47])[N:7]([CH2:27][CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([NH2:38])[CH:36]=2)[NH:31][C:30]=1[C:39]1[CH:44]=[C:43]([CH3:45])[CH:42]=[C:41]([CH3:46])[CH:40]=1)[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([S:19]([CH3:22])(=[O:21])=[O:20])[C:13]=1[S:23]([CH3:26])(=[O:25])=[O:24])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl[C:55](Cl)([O:57]C(=O)OC(Cl)(Cl)Cl)Cl>C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:47])[N:7]([CH2:27][CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([N:38]=[C:55]=[O:57])[CH:36]=2)[NH:31][C:30]=1[C:39]1[CH:40]=[C:41]([CH3:46])[CH:42]=[C:43]([CH3:45])[CH:44]=1)[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([S:19]([CH3:22])(=[O:20])=[O:21])[C:13]=1[S:23]([CH3:26])(=[O:25])=[O:24])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(N)cc3c2CCN(CCCCc2ccc(N)c(S(C)(=O)=O)c2S(C)(=O)=O)C(=O)OC(C)(C)C)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Cc1cc(C)cc(-c2[nH]c3ccc(N=C=O)cc3c2CCN(CCCCc2ccc(N)c(S(C)(=O)=O)c2S(C)(=O)=O)C(=O)OC(C)(C)C)c1
Reaction time: 0.33 h
Yield: 243.8 %

Procedure:
To a solution of {2-[5-amino-2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethyl}-[4-(4-amino(dimethanesulfonyl)phenyl)butyl]carbamic acid tert-butyl ester (120 mg in 8 mL dry methylene chloride) at 0° C. was added 0.040 mL pyridine followed by 18.2 mg triphosgene and the mixture stirred at low temperature. After 20 minutes, 0.025 mL triethylamine was added and after another 10 minutes the mixture was applied to a silica gel column for purification by flash chromatography (hexane:ethyl acetate, 2:3) to give the title compound (106 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:15])=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH3:13])=[CH:9][C:8]([F:14])=[CH:7][CH:6]=2.[CH:16](O)=O>>[CH3:13][N:12]1[C:11]2[C:10]3[CH:9]=[C:8]([F:14])[CH:7]=[CH:6][C:5]=3[N:4]=[C:3]([CH3:15])[C:2]=2[N:1]=[CH:16]1
Reactant: O=CO
Reactant: CNc1c(N)c(C)nc2ccc(F)cc12
Product: Cc1nc2ccc(F)cc2c2c1ncn2C

Procedure:
Using the method of Example 137, 3-amino-6-fluoro-2-methyl-4-methylaminoquinoline (from example 44) was reacted with formic acid to provide 1,4-dimethyl-8-fluoro-1H-imidazo[4,5-c]quinoline, m.p. 184°-186° C. Analysis: Calculated for C12H10FN3 : %C, 67.0; %H, 4.7; %N, 19.5; Found: %C, 66.6; %H, 4.4; %N, 19.7.
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH:2]=[CH2:3].[C:7]([NH:15][NH2:16])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[N:10][CH:9]=1>CO>[CH2:1]([NH:4][C:5](=[O:6])[NH:16][NH:15][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[N:10][CH:9]=1)[CH:2]=[CH2:3]
Reactant: C=CCN=C=O
Reactant: NNC(=O)c1cccnc1
Solvent: CO
Product: C=CCNC(=O)NNC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 2.75 h
Yield: 92.4 %

Procedure:
Allyl isocyanate (16.8 g) was added dropwise at ambient temperature to a stirred suspension of nicotinic hydrazide (25 g) in methanol (500 ml), then the mixture was stirred at ambient temperature for 2.75 hours, concentrated in vacuo to 250 ml, then diluted with ether (750 ml). The resulting solid was collected by filtration and dried in vacuo to give 4-allyl-1-nicotinoylsemicarbazide as a colourless solid (37.1 g), m.p. 165-167° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:17](=[O:19])[CH3:18])=[CH:4][C:5]2[C:6]([CH3:16])([CH3:15])[CH2:7][CH:8]([CH3:14])[C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>CCOCC>[CH3:1][C:2]1[C:3]([CH:17]([OH:19])[CH3:18])=[CH:4][C:5]2[C:6]([CH3:16])([CH3:15])[CH2:7][CH:8]([CH3:14])[C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: CC(=O)c1cc2c(cc1C)C(C)(C)C(C)CC2(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: Cc1cc2c(cc1C(C)O)C(C)(C)CC(C)C2(C)C
Temperature: 25 °C
Yield: 101.1 %

Procedure:
A solution of (±)-1-(3,5,5,6,8,8-hexamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)-1-ethanone (10.00 g, 38.7 mmol) in ether (65 ml) was added dropwise during 1 h to a suspension of LiAlH4 (1.48 g, 39.0 mmol) in ether (70 ml) at 0° C. The reaction mixture was left warming up to room temperature and then heated to reflux for 1 day. After cooling to 0° C. more LiAlH4 (0.76 g, 19.5 mmol) was added. After refluxing for another 3 days, the mixture was cooled to 0° C. and water was added dropwise. Extraction of the organic phase with water, drying over Na2SO4 and concentrating gave 10.19 g (99%) of the product.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:12][CH2:11][CH:10]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N>[Ni].CO>[C:1]1([CH2:7][N:8]2[CH2:12][CH2:11][CH:10]([C:13]3[CH:14]=[C:15]([CH2:16][NH2:17])[CH:18]=[CH:19][CH:20]=3)[CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1cccc(C2CCN(Cc3ccccc3)C2)c1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1cccc(C2CCN(Cc3ccccc3)C2)c1
Yield: 83.7 %

Procedure:
A suspension of 3-[1-(phenylmethyl)-3-pyrrolidinyl]benzonitrile (11.90 g, 45.4 mmol) and Raney nickel (5.0 g) in methanol saturated with ammonia (100 mL) was hydrogenated in a Parr shaker at 3 atm. The resulting suspension was filtered through a pad of Celite and the filtrate concentrated to give an off-green liquid. This crude product was chromatographed (silica gel, chloroform-methanol 2:1) to give the title compound (10.12 g, 84%) as a colorless oil. 1H-NMR (250 MHz, CDCl3): δ=1.68-1.75 (2H, br. s), 1.83-1.97 (1H, m), 2.27-2.41 (1H, m), 2.51 (1H, dd, J=9.0, 8.1 Hz), 2.71 (1H, td, J=8.9, 5.9 Hz), 2.80-2.90 (1H, m), 3.01-3.08 (1H, m), 3.31-3.41 (1H, m), 3.69 (2H, AB quartet, JAB =13.3 Hz), 3.84 (2H, s), 7.11-7.39 (9H, m).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1>>[CH3:1][CH:2]1[CH2:7][CH2:6][C:5]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH2:3]1
Reactant: CC1CCC(=O)CC1
Reactant: C1CCNC1
Product: CC1CC=C(N2CCCC2)CC1
Yield: 99 %

Procedure:
Following the general methods as outlined under Intermediate 1, starting from 4-methylcyclohexanone, and pyrrolidine, the title compound was isolated in 99% yield (96% purity by HPLC). MS(ESI+): 166.4; MS(ESI−): 164.6.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][CH2:13][CH2:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:15]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]1)=[O:16]>Cl.CO>[O:1]=[C:2]1[C:10]2([CH2:14][CH2:13][CH2:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:15]([NH:17][CH2:18][CH:19]1[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)N2C(=O)C3(CCCC3)c3ccccc32)CC1
Agent: Cl
Solvent: CO
Product: O=C(NCC1CCNCC1)N1C(=O)C2(CCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 7 h

Procedure:
tert-Butyl 4-({[(2′-oxospiro[cyclopentane-1,3′-indol]-1′(2′H)-yl)carbonyl]amino}methyl)piperidine-1-carboxylate (750 mg, 1.8 mmol, step 1 of Example 2) was dissolved in 10% HCl in methanol (20 mL) and the mixture was stirred for 7 h at room temperature. Concentrated gave a colorless oil, which was chromatographed on a column of silica gel eluting with CH2Cl2/methanol/NH4OH (12/11/0.1) to give 570 mg (quant.) of the title compound as colorless oil.
Reaction SMILES: [F:1][C:2]1[C:3](I)=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.C[C:11]([N:13](C)C)=O>[C-]#N.[Zn+2].[C-]#N>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:11]#[N:13]
Reactant: CC(=O)N(C)C
Reactant: Cc1cccc(F)c1I
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1cccc(F)c1C#N
Temperature: 80 °C

Procedure:
A 10 L round bottom flask equipped with adapter, thermocouple and stir bar was charged with DMA (6 L) and degassed under vacuum and purged with N2 three times. To the mixture was added palladium tetrakis triphenylphosphine (87.5 g, 72.0 mmol) and the mixture was degassed under vacuum and purged with N2 three times. The reaction was heated to 80° C. for 30 min. 3-Fluoro-2-iodotoluene (575 g, 2.4 mol) and zinc cyanide (171.7 g, 1.46 mol) were added and the mixture was degassed under vacuum and purged with N2 three times. The reaction mixture was heated to 80° C. for 16 h and then allowed to cool to RT. The solution was added to a 2.0 L aqueous solution of 1N NH4OH, which was extracted three times with 1.5 L EtOAc, washed with 2 L brine, dried over Na2SO4, filtered and concentrated. The crude product was treated with mCPBA in cooled DCM and then purified by chromatography (PE/EA=10:1) to get the title compound.
Reaction SMILES: [CH:1]([OH:40])([CH2:21][N:22]([S:24]([C:27]([C:30]([C:33]([C:36]([F:39])([F:38])[F:37])([F:35])[F:34])([F:32])[F:31])([F:29])[F:28])(=[O:26])=[O:25])[CH3:23])[CH2:2][N:3]([S:5]([C:8]([C:11]([C:14]([C:17]([F:20])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12])([F:10])[F:9])(=[O:7])=[O:6])[CH3:4].[N:41]([CH2:44][CH2:45][CH2:46][Si:47]([O:54][CH2:55][CH3:56])([O:51][CH2:52][CH3:53])[O:48][CH2:49][CH3:50])=[C:42]=[O:43]>C(C(C)=O)C>[CH:1]([O:40][C:42]([NH:41][CH2:44][CH2:45][CH2:46][Si:47]([O:48][CH2:49][CH3:50])([O:54][CH2:55][CH3:56])[O:51][CH2:52][CH3:53])=[O:43])([CH2:2][N:3]([S:5]([C:8]([C:11]([C:14]([C:17]([F:20])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12])([F:10])[F:9])(=[O:7])=[O:6])[CH3:4])[CH2:21][N:22]([S:24]([C:27]([C:30]([C:33]([C:36]([F:37])([F:39])[F:38])([F:34])[F:35])([F:31])[F:32])([F:29])[F:28])(=[O:26])=[O:25])[CH3:23]
Reactant: CCO[Si](CCCN=C=O)(OCC)OCC
Reactant: CN(CC(O)CN(C)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CCC(C)=O
Product: CCO[Si](CCCNC(=O)OC(CN(C)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)CN(C)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(OCC)OCC
Temperature: 100 °C

Procedure:
Next, [C4F9SO2N(CH3)CH2]2CHOC(O)NH(CH2)3Si(OCH2CH3)3 was prepared as follows. A three-necked round bottom 500 ml flask fitted with a stirrer, heating mantle, condenser, nitrogen inlet, Dean-Stark trap and thermometer was charged with about 204.6 grams of the [C4F9SO2N(CH3)CH2]2CHOH (0.3 mol), and about 250 grams methyl ethyl ketone. The mixture was heated for about 1 hour at about 100° C. and about 50 grams of material was removed using the Dean-Stark trap. The mixture was cooled to about 30° C., and about 74.4 grams of OCN(CH2)3Si(OCH2CH3)3 (0.3 mol), and three drops of stannous octanoate were added. The resulting mixture was heated at about 75° C. under nitrogen for about 16 hours.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[C:2]1[C:14]([O:16][CH3:17])=[O:15].C([O-])([O-])=O.[Cs+].[Cs+].[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1>CN(C=O)C>[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[C:2]2[C:14]([O:16][CH3:17])=[O:15])=[CH:27][CH:26]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: COC(=O)c1[nH]c2ccccc2c1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(C(=O)OC)n(Cc2ccc(F)cc2)c2ccccc12
Temperature: 90 °C
Reaction time: 2 h
Yield: 34.5 %

Procedure:
A 300 mL RBF was charged with N,N-Dimethylacetamide (DMA) (144 ml) and Acetic Acid (48.1 ml) was degassed with O2 for 5 min. To this was added aniline (2.94 ml, 32.2 mmol), dimethyl but-2-ynedioate (3.96 ml, 32.2 mmol), and Pd(OAc)2 (0.723 g, 3.22 mmol) and the reaction was heated to 115° C. under an atmosphere of O2. After 18 h, the reaction was cooled to ambient temperature, filtered through a pad of celite, diluted with EtOAc and washed with H2O. The organic was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by ISCO (0-50% EtOAc-hexanes: 120 g SiO2) to afford dimethyl 1H-indole-2,3-dicarboxylate (3 g, 12.86 mmol, 39.9% yield) as a yellow solid. The indole was dissolved in DMF (50 mL), treated with Cs2CO3 (6.30 g, 19.33 mmol), 4-Fluorobenzyl chloride (1.929 ml, 16.11 mmol) and KI (5.35 g, 32.2 mmol) and heated to 90° C. After 2 h, the reaction mixture was cooled to ambient temperature and partitioned between EtOAc and sat. aq. NH4Cl. The organic layer was washed with water (5×), brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified on ISCO (0-100% EtOAc-hexanes) to afford dimethyl 1-(4-fluorobenzyl)-1H-indole-2,3-dicarboxylate (3.79 g, 11.10 mmol, 34.5% yield) as a yellow solid. LCMS (m/z) ES+=342 (M+1).
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]2[N:13]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])(=[O:16])=[O:15])[CH:12]=[C:11]([CH2:25][N:26](C)[C:27](=O)OC(C)(C)C)[CH:10]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].C(OCC)(=O)C.[ClH:41]>C(OCC)(=O)C.CC(O)C>[ClH:41].[F:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[S:14]([N:13]1[CH:12]=[C:11]([CH2:25][NH:26][CH3:27])[CH:10]=[C:9]1[C:8]1[C:3]([C:1]#[N:2])=[N:4][CH:5]=[CH:6][CH:7]=1)(=[O:16])=[O:15]
Reactant: CN(Cc1cc(-c2cccnc2C#N)n(S(=O)(=O)c2ccc(F)cc2F)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cc(-c2cccnc2C#N)n(S(=O)(=O)c2ccc(F)cc2F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
To a solution of tert-butyl ({5-(2-cyanopyridin-3-yl)-1-[(2,4-difluorophenyl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (208 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a white solid (yield 134 mg, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH:11]1[C:16](=[O:17])[CH2:15][C:14]([CH3:19])([CH3:18])[CH2:13][C:12]1=[O:20].S>[OH-].[NH4+].C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH:11]1[C:16](=[O:17])[CH2:15][C:14]([CH3:18])([CH3:19])[CH2:13][C:12]1=[O:20]
Reactant: CC1(C)CC(=O)C(c2ccc([N+](=O)[O-])cc2Cl)C(=O)C1
Agent: S
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CC(=O)C(c2ccc(N)cc2Cl)C(=O)C1
Reaction time: 24 h
Yield: 74.7 %

Procedure:
A solution of 20.0 g (0.067 mol) of 2-(2'-chloro-4'-nitrophenyl)-5,5-dimethyl-1,3-cyclohexanedione in 150 ml of concentrated ammonium hydroxide and 150 ml of ethanol was stirred at room temperature while passing hydrogen sulfide gas through the solution at such a rate that all of the H2S was absorbed. When the solution was saturated with H2S, the temperature was raised to the reflux point and H2S continuously passed slowly through the refluxing solution for 24 hours. The reaction mixture was filtered to remove sulfur, then the filtrate evaporated under reduced pressure. To the residue was added 300 ml of 0.25N NaOH, and the solution filtered once more. The filtrate was collect and carefully acidified to pH=4 with 6N HCl. A white solid formed which was collected by suction filtration to give 13.3 g (74%) of 2-(2'-Chloro-4'-aminophenyl)-5,5-dimethyl-1,3-cyclohexanedione, m.p. 218°-19° C.
Reaction SMILES: [C:1]([Si:5]([CH3:18])([CH3:17])[O:6][SiH:7]([CH3:16])[O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].[CH3:19][N:20]([CH2:22][CH:23]=[CH2:24])[CH3:21]>>[C:1]([Si:5]([CH3:17])([CH3:18])[O:6][Si:7]([CH2:24][CH2:23][CH2:22][N:20]([CH3:21])[CH3:19])([CH3:16])[O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[SiH](O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reactant: C=CCN(C)C
Product: CN(C)CCC[Si](C)(O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Temperature: 90 °C

Procedure:
1,5-Di(tert-butyl)-1,1,3,5,5-Pentamethyltrisiloxane and Karstedt's catalyst (30 ppm) were charged to a 100 mL Schlenk flask. The mixture was heated to 90° C. and N,N-dimethyl allyl amine (4.48 g) was added dropwise via syringe over 5 minutes. After complete addition, the reaction temperature was maintained at 90° C. for 3 hrs and the reaction was monitored by 1HNMR spectroscopy. Upon reaction completion, the volatiles were removed at 100° C./0.1 mmHg, and 15.2 g light yellow oil product was obtained.