Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]#[CH:11])=[C:6]([CH3:12])[C:3]=1[C:4]#[N:5].[F:13][C:14]([F:23])([F:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.C(N(CC)CC)C>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:18]2[CH:19]=[CH:20][C:15]([C:14]([F:23])([F:22])[F:13])=[CH:16][CH:17]=2)=[C:6]([CH3:12])[C:3]=1[C:4]#[N:5]
Reactant: FC(F)(F)c1ccc(I)cc1
Reactant: C#Cc1ccc(N)c(C#N)c1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(C#Cc2ccc(C(F)(F)F)cc2)ccc(N)c1C#N
Yield: 72.7 %

Procedure:
A solution of 3.5 grams (0.022 mole) of 2-amino-5-ethynyl-6-methylbenzonitrile, 8.4 grams (0.031 mole) of 4-trifluoromethylphenyl iodide, 10.7 grams (0.077 mole) of triethylamine, 0.5 gram (catalyst) of bis(triphenylphosphine)palladium(II) chloride, and 0.5 gram (catalyst) of copper(I)iodide in 100 mL of acetonitrile was stirred at ambient temperature for about 18 hours. After this time the reaction mixture was concentrated under reduced pressure to a residue. The residue was partitioned between ethyl acetate and aqueous 1N hydrochloric acid. The two-layered mixture was filtered to remove a solid. The aqueous layer and the organic layer were separated, and the aqueous layer was washed with ethyl acetate. The ethyl acetate wash was combined with the organic layer, and the combination was washed with an aqueous solution of 10% lithium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was triturated with methylene chloride and filtered. The filtrate was subjected to column chromatography on silica gel. Elution was accomplished using methylene chloride. The product-containing fractions were combined and concentrated under reduced pressure, yielding 4.8 grams of 2-amino-6-methyl-5-[(4-trifluoromethylphenyl)ethynyl]benzonitrile, mp 136°-138° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4](OS(C)(=O)=O)[CH2:3]1.[N-:13]=[N+:14]=[N-:15].[Na+].O>CN(C=O)C>[N:13]([CH:4]1[CH2:5][CH2:6][CH2:7][N:2]([CH3:1])[CH2:3]1)=[N+:14]=[N-:15]
Reactant: CN1CCCC(OS(C)(=O)=O)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCCC(N=[N+]=[N-])C1
Temperature: 80 °C

Procedure:
To a stirred solution of methanesulfonic acid 1-methyl-piperidin-3-yl ester (A) (3 g, 0.17 mmol) in DMF (35 cm3) was added sodium azide (11 g, 0.17 mol). The reaction was then heated to 80° C. for 16 h, and allowed to cool before water (80 cm3) was added and the organic material was extracted into ethyl acetate (80 cm3). The aqueous layer was then extracted with a further portion ethyl acetate (60 cm3) and the combined organic collections and washed with saturated aqueous sodium chloride solution (100 cm3). The organic mixture was and dried over sodium sulfate and then evaporated under reduced pressure to afford the title compound as a crude oil, which was used as crude in next reaction.
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1Cl.[C:10]1([CH3:17])[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=1.[Al+3].[Cl-].[Cl-].[Cl-].C1(C=CC=C(O)C=1)O.[Cl:30][C:31]1[N:36]=[C:35]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][C:38]=2[CH3:44])[N:34]=[C:33]([C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][C:46]=2[CH3:52])[N:32]=1>ClC1C=CC=CC=1>[Cl:30][C:31]1[N:32]=[C:33]([C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][C:46]=2[CH3:52])[N:34]=[C:35]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][C:38]=2[CH3:44])[N:36]=1.[CH3:17][C:10]1[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][C:15]=1[C:31]1[N:36]=[C:35]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][C:38]=2[CH3:44])[N:34]=[C:33]([C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][C:46]=2[CH3:52])[N:32]=1
Reactant: Cc1cccc(C)c1
Agent: Cc1ccc(-c2nc(Cl)nc(-c3ccc(C)cc3C)n2)c(C)c1
Agent: Clc1nc(Cl)nc(Cl)n1
Agent: Oc1cccc(O)c1
Solvent: Clc1ccccc1
Product: Cc1ccc(-c2nc(-c3ccc(C)cc3C)nc(-c3ccc(C)cc3C)n2)c(C)c1
Reaction time: 3 h

Procedure:
Cyanuric chloride was allowed to react with 2.05 eq of m-xylene, in the presence of 3 eq of AlCl3 and 0.2 of resorcinol, in chlorobenzene at 5° C. for 0.5 h and then at room temperature for 3 h. The first step (conversion to 2-chloro-4,6-bis(2,4-dimethylphenyl)-1,3,5-triazine) was completed in less than 16 h, with more than 98% cyanuric chloride conversion as determined by HPLC analysis. 2-chloro-4,6-bis(2,4-dimethylphenyl)-1,3,5-triazine and 2,4,6-tris(2,4-dimethylphenyl)-1,3,5-triazine were formed in an 86:14 ratio; no other products were detected. The reaction mixture was allowed to react with additional resorcinol at 110° C. for 1.5 h. HPLC analysis showed a product mixture of 82% 2-(2,4-dihydroxyphenyl)-4,6-bis(2,4-dimethylphenyl)-1,3,5-triazine, 14% 2,4,6-tris(2,4-dimethylphenyl)-1,3,5-triazine, and 2% 2,4,6-tris(2,4-dihydroxyphenyl)-1,3,5-triazine, with only 1.5% unreacted 2-chloro-4,6-bis(2,4-dimethylphenyl)-1,3,5-triazine.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].CN(C)[CH:8]=[CH:9][C:10]([C:12]1[C:21]([F:22])=[C:20]2[C:15]([C:16](=[O:30])[C:17]([C:25]([O:27]CC)=[O:26])=[CH:18][N:19]2[CH2:23][CH3:24])=[CH:14][C:13]=1[F:31])=O>>[NH2:4][C:3]1[N:5]=[C:10]([C:12]2[C:21]([F:22])=[C:20]3[C:15]([C:16](=[O:30])[C:17]([C:25]([OH:27])=[O:26])=[CH:18][N:19]3[CH2:23][CH3:24])=[CH:14][C:13]=2[F:31])[CH:9]=[CH:8][N:2]=1
Reactant: CCOC(=O)c1cn(CC)c2c(F)c(C(=O)C=CN(C)C)c(F)cc2c1=O
Reactant: N=C(N)N
Agent: Cl
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(-c3ccnc(N)n3)c(F)c21

Procedure:
In a similar fashion the 7-(2-amino-4-pyrimidinyl)-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, mp 285°-286° C. (42a) was prepared using guanidine hydrochloride and ethyl 7-(2'-dimethylaminoethenyl)carbonyl-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:22]([O:23]C)=[CH:21][C:20]4[C:19]5[C:14](=[CH:15][C:16]([C:25]6[O:26][C:27]7[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:28]=7[N:29]=6)=[CH:17][CH:18]=5)[C:13]([CH2:38][CH2:39][CH3:40])([CH2:35][CH2:36][CH3:37])[C:12]=4[CH:11]=3)=[N:7][C:6]=2[CH:41]=1.[I-].[Li+]>N1C(C)=CC(C)=CC=1C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:22]([OH:23])=[CH:21][C:20]4[C:19]5[C:14](=[CH:15][C:16]([C:25]6[O:26][C:27]7[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:28]=7[N:29]=6)=[CH:17][CH:18]=5)[C:13]([CH2:38][CH2:39][CH3:40])([CH2:35][CH2:36][CH3:37])[C:12]=4[CH:11]=3)=[N:7][C:6]=2[CH:41]=1
Reactant: CCCC1(CCC)c2cc(-c3nc4cc(C)ccc4o3)ccc2-c2cc(OC)c(-c3nc4cc(C)ccc4o3)cc21
Agent: [I-]
Agent: [Li+]
Solvent: Cc1cc(C)nc(C)c1
Product: CCCC1(CCC)c2cc(-c3nc4cc(C)ccc4o3)ccc2-c2cc(O)c(-c3nc4cc(C)ccc4o3)cc21
Temperature: 95 °C
Yield: 74 %

Procedure:
A mixture of a solution of 2,7-bis(5-methylbenzoxazol-2-yl)-9,9-dipropyl-3-methoxyfluorene] (34.6 g, 0.0638 mol) and 2,4,6-collidine (250 mL) that was prepared under argon by stirring and heating to 95° C. To this solution, dry lithium iodide (14.9 grams, 0.111 mol) was added and the resulting mixture was heated to reflux for 30 minutes and then allowed to cool to room temperature. The reaction was quenched with a mixture of concentrated HCl (167 mL), water (300 mL) and ice (500 g). The product was collected and washed with a minimum of water and methanol to afford upon drying crude product (40 g). Purification by extraction from of acidic alumina (3 cm3) on Ace-Kauffman column with methylcyclohexane gave 2,7-bis(5-methylbenzoxazol-2-yl)-9,9-dipropyl-3-hydroxyfluorene (24.93 g, yield 74%).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11]([N:13]3[CH2:16][CH:15]([NH:17][C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)=[O:19])[CH2:14]3)=[O:12])[N:10]=2)[CH2:3]1.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C>C(Cl)Cl.N1C=CC=CC=1>[CH3:31][S:32]([O:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11]([N:13]3[CH2:14][CH:15]([NH:17][C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)=[O:19])[CH2:16]3)=[O:12])[N:10]=2)[CH2:3]1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NC1CN(C(=O)c2csc(N3CC(O)C3)n2)C1)OCc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CN(c2nc(C(=O)N3CC(NC(=O)OCc4ccc([N+](=O)[O-])cc4)C3)cs2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 103.3 %

Procedure:
To a solution of 3-hydroxy-1-{4-[3-(p-nitrobenzyloxycarbonylamino)-azetidine-1-carbonyl]-1,3-thiazol-2-yl}azetidine (630 mg, 1.45 mmol) (obtained as described in Reference Example 57(5)) in a mixture of methylene chloride (32 ml) and pyridine (12 ml) were added methanesulfonyl chloride (377 μl, 4.36 mmol) and triethylamine (611 μl, 4.36 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 4 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. To the residue were added ethyl acetate and diisopropyl ether, and the mixture was filtered off and washed with diisopropyl ether to afford 3-methanesulfonyloxy-1-{4-[3-(p-nitrobenzyloxycarbonylamino)-azetidine-1-carbonyl]-1,3-thiazol-2-yl}azetidine (766 mg, yield 100%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:23]([CH2:24][C:25]([O:27]C)=[O:26])[CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[C@H:23]([CH2:24][C:25]([OH:27])=[O:26])[CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C[C@@H]1Cc2c([nH]c3ccccc23)CN1C(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C[C@@H]1Cc2c([nH]c3ccccc23)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.2 %

Procedure:
0.87 g of methyl (3S)-2-benzyloxycarbonyl-1,2,3,4-tetrahydro-β-carboline-3-acetate is dissolved in 12 ml of tetrahydrofuran, and 5 ml of 1N NaOH are added thereto. The mixture is stirred at room temperature for 16 hours. The mixture is evaporated to remove the solvent. The residue is dissolved in water, and the aqueous solution is extracted with ethyl acetate. The aqueous layer is acidified with 10% HCl, and extracted with ethyl acetate. The extract is washed with a saturated aqueous sodium chloride solution, dried and then evaporated to remove the solvent. 630 mg of (3S)-2-benzyloxycarbonyl-1,2,3,4-tetrahydro-β-carboline-3-acetic acid are obtained as pale yellow powder. Yield: 75%
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([CH2:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:15](O)=[O:16])[CH:5]=[CH:6][C:7]=1[N:8]1[C:12]([CH3:13])=[N:11][N:10]=[N:9]1.C(Cl)(=O)C(Cl)=O.[CH3:30][NH:31][C:32]([NH2:34])=[O:33].N1C=CC=CC=1.Cl>FC1C=CC=CC=1.CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([CH2:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:15]([NH:34][C:32]([NH:31][CH3:30])=[O:33])=[O:16])[CH:5]=[CH:6][C:7]=1[N:8]1[C:12]([CH3:13])=[N:11][N:10]=[N:9]1
Reactant: CNC(N)=O
Reactant: Cc1nnnn1-c1ccc(C(CC2CCCC2)C(=O)O)cc1Cl
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: Fc1ccccc1
Solvent: CCOC(C)=O
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(-n2nnnc2C)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.3 %

Procedure:
A solution of 2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-propionic acid (303 mg, 0.9 mmol) in fluorobenzene (1 mL) and N,N-dimethylformamide (3 μL) at 25° C. was treated dropwise with oxalyl chloride (97 μL, 1.09 mmol) over 2-3 min. The clear solution was stirred at 25° C. for 1 h and then treated with methyl urea (201 mg, 2.72 mmol). The resulting suspension was heated at 70° C. (bath temperature) for 10 min and then treated with pyridine (146.6 μL, 1.81 mmol). The reaction mixture was then stirred at 70° C. for 20 h. The reaction mixture was then cooled to 25° C. and diluted with ethyl acetate (30 mL) and a 3N aqueous hydrochloric acid solution (30 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×20 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, I/1 hexanes/ethyl acetate) afforded 1-{2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-propionyl}-3-methyl-urea (110 mg, 31%) as a white solid: mp 185-186° C. EI-HRMS m/e calcd for C18H23ClN6O2 (M+H)+ 391.1649, found 391.1659.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([OH:14])=O)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[CH3:15][O:16][C:17]1[S:18][CH:19]=[C:20]([C:22]2[S:23][CH:24]=[CH:25][C:26]=2[NH2:27])[N:21]=1>>[CH:1]1[C:10]2[C:5](=[C:6]([CH2:11][C:12]([NH:27][C:26]3[CH:25]=[CH:24][S:23][C:22]=3[C:20]3[N:21]=[C:17]([O:16][CH3:15])[S:18][CH:19]=3)=[O:14])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: O=C(O)Cc1cccc2cnccc12
Reactant: COc1nc(-c2sccc2N)cs1
Product: COc1nc(-c2sccc2NC(=O)Cc2cccc3cnccc23)cs1

Procedure:
The title compound was prepared from 2-(isoquinolin-5-yl)acetic acid (72 mg, 0.36 mmol) and 2-(2-methoxythiazol-4-yl)thiophen-3-amine (78 mg, 0.36 mmol) according to protocol A. Retention time (min)=3.237, method [7], MS(ESI) 382.0 (M+H); 1H NMR (300 MHz, CDCl3) δ 10.99 (s, 1H), 9.69 (s, 1H), 8.60 (d, J=6.5 Hz, 1H), 8.39 (d, J=6.5 Hz, 1H), 8.23 (d, J=8.4 Hz, 1H), 8.06 (d, J=7.3 Hz, 1H), 7.96 (d, J=5.5 Hz, 1H), 7.89 (dd, J=8.4, 7.3, 1H), 7.15 (d, J=5.5, 1H), 6.70 (s, 1H), 4.26 (s, 2H), 4.17 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].[CH3:36][CH:37]([NH:39][CH2:40][CH2:41][CH2:42][NH2:43])[CH3:38]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:43][CH2:42][CH2:41][CH2:40][NH:39][CH:37]([CH3:38])[CH3:36])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35]
Reactant: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Reactant: CC(C)NCCCN
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(NCCCNC(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 68 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide (20 mg, 0.04 mmol) in THF (3 mL) was added N-(1-methylethyl)-1,3-propanediamine (0.025 mL, 0.179 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (15 mg, 68%). LC-MS m/z 554 (M+H)+; 1H-NMR (MeOD) δ 1.00 (d, 6H), 1.27 (d, 6H), 1.60 (m, 2H), 2.31 (s, 3H), 2.50 (m, 2H), 2.75 (m, 1H), 3.15 (m, 2H), 4.11 (s, 2H), 4.23 (m, 1H), 7.15 (t, 2H), 7.46 (d, 1H), 7.52 (m, 1H), 7.69 (s, 1H), 7.85 (d, 1H).
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]1[C@@H:24]([F:25])[CH2:23][C@H:22]([OH:26])[C@@H:21]1[CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:43][CH2:44][CH3:45].OS([O-])(=O)=O.[K+]>CN(C=O)C>[Si:1]([O:18][CH2:19][C@H:20]1[C@@H:24]([F:25])[CH2:23][C@H:22]([OH:26])[C@@H:21]1[CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][C:33]([O:35][CH:44]([CH3:45])[CH3:43])=[O:34])([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCI
Reactant: CC(C)(C)[Si](OC[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@@H]1F)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)OC(=O)CCC/C=C\C[C@@H]1[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](F)C[C@@H]1O
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 85.9 %

Procedure:
To a stirring solution consisting of (Z)-7-((1R,2S,3S,5S)-2-((tert-butyldiphenylsilyloxy)methyl)-3-fluoro-5-hydroxycyclopentyl)hept-5-enoic acid (prepared in Step C, 30.8 g, 61.6 mmol) in anhydrous DMF (1.2 L) was added cesium carbonate (30.0 g, 92.4 mmol) followed by iodopropane (22 g, 13 mL, 130 mmol). The reaction mixture was heated to 50° C. and stirred for 1.5 hours, monitoring by TLC. The reaction mixture was acidified with 5% KHSO4, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and evaporated. The crude product was purified on silica gel, eluted with hexanes-ethyl acetate (4:1) to afford the title intermediate (28.6 g, 86%).
Reaction SMILES: [CH2:1]([CH:3]1[O:20][C:7]2([CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[CH2:6][N:5]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:4]1)[CH3:2].Cl.O1CCOCC1>ClCCl.C(=O)(O)[O-].[Na+]>[CH2:1]([CH:3]1[O:20][C:7]2([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][N:5]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:4]1)[CH3:2]
Reactant: CCC1CN(c2ccccn2)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCC1CN(c2ccccn2)CC2(CCNCC2)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
Tert-butyl 10-ethyl-8-(2-pyridyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (480 mg, 1.33 mmol) was dissolved in dichloromethane (5 mL) at 0° C. and treated dropwise with HCl in dioxane (2.65 mL of 4 M, 10.6 mmol). The reaction was then allowed to warm to room temperature and stirred for 1 h. The reaction mixture was diluted with dichloromethane (50 mL) and saturated sodium bicarbonate solution. The organic layer was separated and the aqueous layer extracted with dichloromethane (3×20 mL). The aqueous layer was further diluted with 25 mL of 1 N NaOH and extracted with dichloromethane (3×20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to provide 10-ethyl-8-(2-pyridyl)-11-oxa-3,8-diazaspiro[5.5]undecane (345 mg, 1.32 mmol, 99%) an orange-colored oil. ESI-MS m/z calc. 261.2. Found 262.3 (M+1)+; Retention time: 0.3 minutes (3 min run). 1H NMR (400 MHz, DMSO-d6) δ 8.08 (dd, J=4.9, 1.4 Hz, 1H), 7.50 (ddd, J=8.8, 7.1, 2.0 Hz, 1H), 6.84 (d, J=8.6 Hz, 1H), 6.60 (dd, J=6.6, 5.0 Hz, 1H), 4.17 (t, J=11.3 Hz, 2H), 3.58-3.54 (m, 2H), 2.96-2.84 (m, 1H), 2.81-2.71 (m, 1H), 2.71-2.65 (m, 2H), 2.55 (d, J=12.9 Hz, 1H), 2.40 (dd, J=12.6, 11.0 Hz, 1H), 1.93 (d, J=13.9 Hz, 1H), 1.59-1.38 (m, 5H), 0.96 (t, J=7.5 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.[CH3:23][O:24][C:25]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:26]=1[CH2:27][N:28]([CH3:39])[C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[C:34](=O)[O:33][CH2:32]2.Cl.[OH-].[Na+]>C(COC)OC.C1C=CC=CC=1>[CH3:23][O:24][C:25]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:26]=1[CH2:27][N:28]([CH3:39])[C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[C:34](=[C:6]1[C:5]3[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[NH:8][C:7]1=[O:11])[O:33][CH2:32]2
Reactant: O=C1Cc2ccc(F)cc2N1
Reactant: COc1ccc(CN(C)c2ccc3c(c2)COC3=O)c(OC)c1
Agent: Cl
Agent: [Li]CCCC
Agent: [Na+]
Solvent: COCCOC
Solvent: c1ccccc1
Solvent: CCCCCC
Product: COc1ccc(CN(C)c2ccc3c(c2)COC3=C2C(=O)Nc3cc(F)ccc32)c(OC)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63.9 %

Procedure:
To a stirred solution of 6-fluorooxindole (0.60 g, 3.99 mmol) in anhydrous dimethoxyethane (20 ml) under nitrogen was added 2.5M n-BuLi solution in hexane (3.5 ml, 8.75 mmol). After the reaction was stirred at room temperature for 10 minutes, 5-[(2,4-dimethoxy-benzyl)-methyl-amino]-3H-isobenzofuran-1-one (1.0 g, 3.19 mmol) was added. After stirred at room temperature for 2.5 hours, the reaction mixture was poured into 1M HCl aqueous solution (70 ml), and then basified with NaOH aqueous solution. The solid was separated, washed with water, and dried under vacuum to give a crude product. Trituration of the crude product with benzene yielded 3-{5-[(2,4-dimethoxy-benzyl)-methyl-amino]-3H-isobenzofuran-1-ylidene}-6-fluoro-1,3-dihydro-indol-2-one as a yellow solid (0.91 g, 64%).
Reaction SMILES: [Br:1][C:2]1[C:3]([Br:15])=[C:4]([Br:14])[C:5]([Br:13])=[C:6]2[C:11](=[O:12])[NH:10][C:8](=[O:9])[C:7]=12.[CH2:16]=[O:17]>C(O)C>[CH2:16]([N:10]1[C:11](=[O:12])[C:6]2=[C:5]([Br:13])[C:4]([Br:14])=[C:3]([Br:15])[C:2]([Br:1])=[C:7]2[C:8]1=[O:9])[OH:17]
Reactant: C=O
Reactant: O=C1NC(=O)c2c(Br)c(Br)c(Br)c(Br)c21
Solvent: CCO
Product: O=C1c2c(Br)c(Br)c(Br)c(Br)c2C(=O)N1CO
Temperature: 85 °C
Yield: 87.6 %

Procedure:
Tetrabromophthalimide (30 gm) was suspended in 100 ml of ethanol and 50 gm of 38 percent formaldehyde was added. Then the solution was stirred and heated for three hours at 85° C. Upon cooling, the product was filtered yielding 28 gm of a white solid having a melting point greater than 350° C. The infrared spectrum of the product showed the disappearance of the imide NH and the appearance of an OH absorption at 3450 cm-1. Analysis: Calculated for C9H3Br4NO3 ; Br, 64.8; hydroxyl number: 89.0; Found: Br, 63.28; hydroxyl number: 90.45.
Reaction SMILES: C([O:5][C:6](=[O:23])[C:7]1[CH:12]=[CH:11][C:10](/[C:13](/[S:20][CH3:21])=[N:14]\[CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[CH:9][C:8]=1[CH3:22])(C)(C)C.FC(F)(F)C(O)=O.O>ClCCl>[CH3:22][C:8]1[CH:9]=[C:10](/[C:13](/[S:20][CH3:21])=[N:14]/[CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:11]=[CH:12][C:7]=1[C:6]([OH:23])=[O:5]
Reactant: CS/C(=N/C[Si](C)(C)C)c1ccc(C(=O)OC(C)(C)C)c(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CS/C(=N\C[Si](C)(C)C)c1ccc(C(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2-methyl-4-{methylsulfanyl-[(E)-trimethylsilanylmethylimino]-methyl}-benzoic acid tert-butyl ester (see Example I9) (118 mg) in dichloromethane (15 ml) was added trifluoroacetic acid (0.22 ml). The reaction mixture was stirred at ambient temperature for 20 hours. Further trifluoroacetic acid (0.11 ml) was added and the mixture was stirred for another 3 hours at ambient temperature. Water was added and the mixture was extracted twice with dichloromethane. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated to give 2-methyl-4-{methylsulfanyl-[(Z)-trimethylsilanyl methylimino]methyl}-benzoic acid which was used without further purification in the subsequent step.