Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([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.CON(C)[C:39]([C:41]1[S:42][CH:43]=[CH:44][N:45]=1)=[O:40].C1COCC1>CC(OC)(C)C>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([C:39]([C:41]2[S:42][CH:43]=[CH:44][N:45]=2)=[O:40])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CON(C)C(=O)c1nccs1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@@H](C)O1
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)c3nccs3)c(F)c2F)C[C@@H](C)O1

Procedure:
Starting materials (2R,6R)-4-(6-((tert-butyldiphenylsilyloxy)methyl)-2,3-difluorophenyl)-2,6-dimethylmorpholine (Intermediate 43) and N-methoxy-N-methylthiazole-2-carboxamide (MTBE was used as solvent instead of THF).
Reaction SMILES: [C:1](Cl)(=[O:10])[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.[CH2:13]([NH2:17])/[CH:14]=[CH:15]/[CH3:16].CCN(C(C)C)C(C)C>C(#N)C.[Cl-].[Na+].O>[CH2:13]([NH:17][C:1](=[O:10])[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)/[CH:14]=[CH:15]/[CH3:16]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C/C=C/CN
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C/C=C/CNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Benzyl carbonochloridate (22.8 mL, 167 mmol) was added to a solution of (2E)-but-2-en-1-amine hydrochloride (12.0 g, 112 mmol) and Hunig's base (43.2 g, 330 mmol) in acetonitrile (120 mL) under a nitrogen atmosphere at 0° C. The reaction mixture was stirred under nitrogen at 0° C. for 1 hour and then allowed to warm to ambient temperature. After 3 hours, the reaction mixture was diluted with brine (50 mL) and was extracted with ethyl acetate (3×50 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product residue. The crude product residue was purified by silica gel chromatography (ethyl acetate/petroleum ether) to give benzyl (2E)-but-2-en-1-ylcarbamate. MS ESI calc'd. for C12H16NO2 [M+H]+ 206. found 206.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14]=1[CH2:15][NH:16][CH3:17])=[CH:12][C:11]([F:18])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH:30](OC1C=CC([N+]([O-])=O)=CC=1)=[O:31]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14]=1[CH2:15][N:16]([CH:30]=[O:31])[CH3:17])=[CH:12][C:11]([F:18])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(CNC)c2cc(F)ccc2n1Cc1cccc2ccccc12
Reactant: O=COc1ccc([N+](=O)[O-])cc1
Product: CCOC(=O)c1c(CN(C)C=O)c2cc(F)ccc2n1Cc1cccc2ccccc12

Procedure:
5-Fluoro-3-methylaminomethyl-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester (from Example 86.1.) was reacted with 4-nitrophenyl formate as described in Example 77.1. to give 5-fluoro-3-[(formyl-methyl-amino)-methyl]-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give the title compound as a colorless solid. MS: 389.5 ([M−H]−).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[S:14]([Cl:17])(=[O:16])=[O:15].[Cl:18][C:19]1[CH:20]=[C:21]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:22]=[CH:23][CH:24]=1.C(N(CC)CC)C>C(Cl)Cl>[ClH:17].[Cl:18][C:19]1[CH:20]=[C:21]([N:25]2[CH2:30][CH2:29][N:28]([S:14]([C:2]3[CH:3]=[CH:4][C:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[CH2:12][C:13]=4[CH:1]=3)(=[O:16])=[O:15])[CH2:27][CH2:26]2)[CH:22]=[CH:23][CH:24]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)Cc1ccccc1-2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cl
Product: O=S(=O)(c1ccc2c(c1)Cc1ccccc1-2)N1CCN(c2cccc(Cl)c2)CC1
Reaction time: 8 h
Yield: 35 %

Procedure:
The title compound is prepared by adding to a stirred solution of 2-fluorenesulfonylchloride (4 g, 0.015 mol) in 50 mL of methylene chloride, 1-(3-chlorophenyl)piperazine (3 g, 0.013 mol) and triethylamine (6 mL). The solution is stirred overnight and the methylene chloride layer is washed with water and dried over anhydrous Na2SO4. Evaporation of the methylene chloride under reduced pressure affords crude product which is purified as in Example 2 and converted to the hydrochloride salt; m.p. 219°-221° C. (35% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:21]=[C:20]3[C:16]([C:17]([CH:22]=O)=[N:18][NH:19]3)=[CH:15][CH:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][O:11][CH3:12].C(O)(=O)C.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH2:35]>C(O)C.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[NH:28]1[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[N:35]=[C:22]1[C:17]1[C:16]2[C:20](=[CH:21][C:13]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH2:10][O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:14][CH:15]=2)[NH:19][N:18]=1
Reactant: Nc1ccccc1N
Reactant: COCOc1ccc(-c2ccc3c(C=O)n[nH]c3c2)cc1OC
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: COCOc1ccc(-c2ccc3c(-c4nc5ccccc5[nH]4)n[nH]c3c2)cc1OC
Reaction time: 0.5 h
Yield: 54.6 %

Procedure:
6-(3-Methoxy-4-methoxymethoxy-phenyl)1H-indazole-3-carbaldehyde (from Example 1(a), step (vi)) (20 mg, 0.064 mmol, 1 equiv) was dissolved in degassed 1:1 MeOH-water (0.7 mL) and was treated with acetic acid (19 μL 5 equiv), 1,2-diaminobenzene (8.3 mg, 1.2 equiv) and copper(II) acetate (18 mg, 1.4 equiv) at 23° C. The mixture stirred for 30 min, was diluted with ethanol (3 mL) and water (2 mL) and was treated with a bubbling stream of SH2 for 3 min, which gave a black precipitate. The mixture was allowed to stir for 12 h. The mixture was filtered and concentrated. Purification by silica gel chromatography (6:4 ethyl acetate-hexane) gave 3-(1H-benzoimidazol-2-yl)-6-(3-methoxy-4-methoxymethoxy-phenyl)-1H-indazole as a solid (14 mg, 54%); Rf sm 0.39, p 0.24 (ethyl acetate-hexane 6:4); 1H NMR (CDCl3) δ 8.69 d, 1H, J=8 Hz), 7.70 (bs, 2H), 7.58 (s, 1H), 7.53 (d, 1H, J=8 Hz), 7.30-7.15 (m, 7H), 5.30 (s, 2H), 3.97 (s, 3H), 3.58 (s, 3H); MS (ES) [m+H]/z Calc'd 401, found 401, [m−H]/z Calc'd 399, found 399.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]([C:21]1[CH:29]=[CH:28][C:24](C(Cl)=O)=[CH:23][CH:22]=1)#[N:20].[CH2:30]([N:32]([CH2:36][CH3:37])[CH2:33][CH2:34][NH2:35])[CH3:31]>>[C:19]([C:21]1[CH:22]=[CH:23][C:24]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:35][CH2:34][CH2:33][N:32]([CH2:36][CH3:37])[CH2:30][CH3:31])=[O:18])=[O:7])=[CH:28][CH:29]=1)#[N:20]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CCN(CC)CCN
Product: CCN(CC)CCNC(=O)[C@@H]1CC(=NOC)CN1C(=O)c1ccc(C#N)cc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 4-cyanobenzoyl chloride, and N1,N1-diethyl-1,2-ethanediamine the title compound was obtained in 58% purity by LC/MS. MS(ESI+): m/z=386.2.
Reaction SMILES: [OH:1][N:2]=[C:3]([CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:4]#[N:5].[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(N(CC)CC)C.O>O1CCCC1>[CH3:16][S:17]([O:1][N:2]=[C:3]([CH:6]=[CH:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)[C:4]#[N:5])(=[O:19])=[O:18]
Reactant: COc1ccc(C=CC(C#N)=NO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C=CC(C#N)=NOS(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 40.4 %

Procedure:
2-hydroxyimino-4-(4-methoxy-phenyl)-but-3-enenitrile (1.8 g; 9 mmol) is dissolved in 15 ml of anhydrous tetrahydrofuran, and cooled to 0° C. Methanesulfonyl chloride (0.93 ml, 0.012 mol) is added at once, followed by triethylamine (2 ml, 0.015 mol) dropwise over 20 min, keeping the temperature of the mixture below 5° C. The mixture is then stirred at 2° C. for 1 h 15 min, and poured into 200 ml of iced water. The suspension is extracted with ethyl acetate, the organic extract is washed neutral with water, then with brine, and dried over magnesium sulfate. Rotary evaporation of the solvent and recrystallization from 80 ml of ethanol yields 2-methylsulfonyloxyimino-4-(4-methoxy-phenyl)-but-3-enenitrile (1.02 g; 41%) as light yellow hair-like crystals, mp 147-152° C. (dec). 1H-NMR reveals the presence of only one isomer.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][CH:11]=2)[CH:3]=1.[Li]CCCC.C[Si](C)(C)[O:33][C@@H:34]1[C@@H:39]([O:40][Si](C)(C)C)[C@H:38]([O:45][Si](C)(C)C)[C@@H:37]([CH2:50][O:51][Si](C)(C)C)[O:36][C:35]1=O.[SiH](CC)(CC)CC.B(F)(F)F.CCOCC>C1(C)C=CC=CC=1.C1COCC1.C1(C)C=CC=CC=1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C@H:35]2[C@H:34]([OH:33])[C@@H:39]([OH:40])[C@H:38]([OH:45])[C@@H:37]([CH2:50][OH:51])[O:36]2)=[CH:3][C:4]=1[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:12][CH:11]=1
Reactant: C[Si](C)(C)OC[C@H]1OC(=O)[C@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C
Reactant: Clc1ccc(Br)cc1Cc1ccc(OCCOC2CCCCC2)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCCOC4CCCCC4)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-1-chloro-2-(4-(2-(cyclohexyloxy)ethoxy)benzyl)benzene (intermediate AE) (0.3 g, 0.64 mmol) in anhydrous toluene/THF (v/v=2:1, 6 mL), n-BuLi (2.5 N, 0.39 mL, 0.96 mmol) was added dropwise at −78° C. and stirred for 1 h. Then the mixture was transferred to a solution of 2,3,4,6-tetra-O-trimethylsilyl-β-D-glucolactone (also called (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one) (0.447 g, 0.96 mmol) in anhydrous toluene (5 mL) at −78° C. The mixture was stirred at −78° C. for 2 h until starting material was consumed. The reaction was quenched with methanesulfonic acid (0.3 g in 10 mL MeOH), and the mixture was allowed to warm to room temperature and stirred overnight. Then 20 mL of water was added. The organic phase was separated, and the water phase was extracted with EtOAc. The organic phases were combined, washed with saturated NaHCO3, water and brine, and then dried with anhydrous Na2SO4, filtered and concentrated. The residue was dissolved in anhydrous CH3CN (4 mL), Et3SiH (0.2 mL, 1.25 mmol) was added and the mixture was cooled to −20° C. Then BF3.Et2O (0.12 mL, 0.94 mmol) was added dropwise, and the mixture was allowed to warm to 20° C. and stirred overnight. After the reaction reached completion, it was quenched with saturated aqueous NaHCO3. The solvent was removed under reduced pressure and the residue was extracted with EtOAc and washed with water and brine. The product was dried with anhydrous Na2SO4, filtered, concentrated to a solid, and purified by preparative HPLC to obtain compound AF as a white powder upon freeze-drying. 1H NMR (400 MHz, CD3OD): δ 7.37-7.30 (m, 3H), 7.12 (d, 2H, J=8.8 Hz), 6.85 (d, 2H, J=8.8 Hz), 4.11-4.03 (m, 5H), 3.87-3.79 (m, 4H), 3.47-3.33 (m, 4H); 3.32-3.30 (m, 1H), 2.00-1.90 (m, 2H), 1.76-1.75 (m, 2H), 1.60-1.50 (m, 1H), 1.33-1.28 (m, 5H); MS ESI (m/z): 508 (M+H)+, calc. 507.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([CH3:11])[S:7][C:6]1=[NH:12].CCN(CC)CC.[Cl:20][C:21]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>C1COCC1>[Cl:20][C:21]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](/[N:12]=[C:6]1\[S:7][C:8]([CH3:11])=[C:9]([CH3:10])[N:5]\1[CH2:4][CH2:3][O:2][CH3:1])=[O:24]
Reactant: COCCn1c(C)c(C)sc1=N
Reactant: O=C(Cl)c1cccc(Cl)c1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCn1c(C)c(C)s/c1=N\C(=O)c1cccc(Cl)c1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 26.4 %

Procedure:
To the product of Example 126A (0.20 g, 1.1 mmol) in 35 mL THF was added Et3N (0.37 mL, 2.7 mmol). This mixture was cooled to 0° C. and 2,3-dichlorobenzoyl chloride (Lancaster, 0.27 g, 1.3 mmol) in 5 mL THF was added dropwise via syringe. This mixture stirred at ambient temperature for 1 hour then was warmed to reflux and was allowed to stir for 3 hours. The mixture was cooled to ambient temperature and was quenched with 5 mL saturated, aqueous NH4Cl and diluted with 10 mL EtOAc. The layers were separated and the aqueous layer was extracted 2×5 mL EtOAc and 2×5 mL CH2Cl2. The combined organics were washed 1×5 mL saturated, aqueous NaCl then were dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and purified via flash column chromatography (SiO2, 10% CH3OH:EtOAc). The material was still impure so it was purified again via flash column chromatography (SiO2, 1:1 hexanes:EtOAc) to provide the title compound (0.105 g, 0.29 mmol, 27% yield). 1H NMR (300 MHz, CDCl3) δ ppm 2.26 (s, 3H), 2.28 (s, 3H), 3.30 (s, 3H), 3.76 (t, J=4.6 Hz, 2H), 4.40 (t, J=4.2 Hz, 2H), 7.23 (t, J=7.7 Hz, 1H), 7.49 (dd, J=8.0, 1.5 Hz, 1H), 7.72 (dd, J=7.6, 1.5 Hz, 1H); MS (DCI/NH3) m/z 359 (M+H)+; Anal. calculated for C15H16Cl2N2O2S: C, 50.15; H, 4.49; N, 7.80. Found; C, 50.17; H, 4.26; N, 7.69
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[N:3]=[CH:2]1.[NH:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[N:13]1([C:10]([C:6]2[N:5]=[C:4]3[N:3]=[CH:2][NH:1][C:9]3=[CH:8][CH:7]=2)=[O:12])[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12
Reactant: O=C(O)c1ccc2[nH]cnc2n1
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc2[nH]cnc2n1)N1CCC[C@@H]2c3ccccc3C[C@@H]21
Yield: 74 %

Procedure:
The title compound is prepared from 1H-imidazo[4,5-b]pyridine-5-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 74% of theory; LC (method 3): tR=2.10 min; Mass spectrum (ESI+): m/z=319 [M+H]+.
Reaction SMILES: [O:1]1[CH2:15][CH:2]1[CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][C:8](=[O:14])[NH:9]2.[NH:16]1[C:20](C=O)=[CH:19][CH:18]=[N:17]1.[CH3:23]N(C)C>CS(C)=O>[O:1]1[CH2:15][CH:2]1[CH2:3][O:4][CH:5]1[C:13](=[CH2:23])[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:14])[CH:7]([C:18]3[NH:17][N:16]=[CH:20][CH:19]=3)[C:6]1=2
Reactant: CN(C)C
Reactant: O=C1Cc2c(cccc2OCC2CO2)N1
Reactant: O=Cc1ccn[nH]1
Solvent: CS(C)=O
Product: C=C1C=CC2=C(C1OCC1CO1)C(c1ccn[nH]1)C(=O)N2
Yield: 68 %

Procedure:
4.1 g. 4-(2,3-Epoxypropoxy)-indolin-2-one (Example 6) are dissolved in 40 ml. dimethyl sulphoxide, mixed with 2.0 g. pyrazole-5-aldehyde and 2.8 ml. trimethylamine and stirred for 2 days at ambient temperature. The reaction mixture is mixed with 150 ml. water and extracted with ethyl acetate. After drying with anhydrous sodium sulphate and evaporating, there crystallise out 3.9 g. 4-(2,3-epoxypropoxy)-3-(pyrazol-5-yl)-methyleneindolin-2-one; m.p. 229° C.; yield 68% of theory.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3]1.[C:14](OC(=O)C)(=[O:16])[CH3:15].[OH-].[Na+]>C(Cl)Cl>[C:14]([NH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3]1)(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: NC1CCN(Cc2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(=O)NC1CCN(Cc2ccccc2)C1
Temperature: 0 °C

Procedure:
3-Amino-1-benzylpyrrolidine [8.3 g, prepared by a method of G. C. Helsley et al., J. Med. Chem. 11, 1034 (1968)] was dissolved in methylene chloride (40 ml) and thereto acetic anhydride (5.3 g) was added dropwise with stirring under cooling with ice-water and the mixture was stirred for 1.5 hours. After addition of 2N sodium hydroxide (40 ml), the mixture was extracted with methylene chloride. The extract was washed with water and dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure to give 3-acetylamino-1-benzylpyrrolidine (9.0 g) as oil.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:26]=[CH:25][C:13]([O:14][CH:15]([CH3:24])[C:16](=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[BH4-].[Na+].O.C(Cl)Cl>C(O)C>[F:27][C:2]([F:1])([F:28])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:26]=[CH:25][C:13]([O:14][CH:15]([CH3:24])[CH:16]([OH:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][CH:11]=2)=[N:7][CH:8]=1
Reactant: CCOC(=O)CC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CC(O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reaction time: 0.25 h

Procedure:
To a solution of ethyl 4-[4-(5-trifluoromethyl-2-pyridyloxy)phenoxy]-3-oxopentanoate (175 mg, 0.44 mmol) in 5 ml of absolute ethanol at 0° is added sodium borohydride (32 mg, 0.84 mmol). The mixture is stirred for 15 minutes, after which it is poured into water and methylene chloride. The aqueous phase is separated and back-extracted with methylene chloride. The combined solvent extracts are washed with brine and dried. Solvent is removed by rotoevaporation, and the residue is purified by prep. thin layer chromatography (silica gel, 25% ethyl acetate/hexane) to yield ethyl 4-[4-(5-trifluoromethyl-2-pyridyloxy)phenoxy]-3-hydroxypentanoate.
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9](=[O:18])[O:10]CC2C=CC=CC=2)[CH2:3]1>C(O)=O.CO.[Pd]>[CH:9]([O-:18])=[O:10].[F:1][C:2]1([F:19])[CH2:7][CH2:6][CH2:5][CH:4]([NH3+:8])[CH2:3]1
Reactant: O=C(NC1CCCC(F)(F)C1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: O=C[O-]
Product: [NH3+]C1CCCC(F)(F)C1
Reaction time: 20 h
Yield: 103.5 %

Procedure:
To a suspension of benzyl (3,3-difluorocyclohexyl)carbamate (0.43 g, 1.6 mmol) in 4% formic acid in methanol (25 mL) was added 10% palladium on carbon (0.4 g, 50% wet). The resulting mixture stirred under an atmosphere of hydrogen for 20 hrs. The mixture was filtered through Celite, washing with methanol, and concentrated under vacuum to give an off-white solid (0.3 g). 1H NMR (d6-DMSO, 300 MHz) δ 8.36 (s, 1H), 3.03 (m, 1H), 2.97 (m, 1H), 1.97-1.63 (m, 5H), 1.39-1.22 (m, 2H). 19F NMR (d6-DMSO, 400 MHz) −60.33-−60.97 (d, 1F, J=252 Hz), −70.73-71.54 (dt, 1F, J=252, 36 Hz). ESI (m/z) 136.2 (M+H).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[S:16](=[O:18])(=[O:17])[N:15]([O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:14](=[O:26])[CH:13]2[CH3:27])=[C:8]([Br:28])[CH:7]=1)(=O)C.C(Cl)(=O)C>C(#N)C.CO>[Br:28][C:8]1[CH:7]=[C:6]([CH2:5][OH:4])[CH:11]=[CH:10][C:9]=1[CH:12]1[S:16](=[O:18])(=[O:17])[N:15]([O:19][CH2:20][CH2:21][Si:22]([CH3:24])([CH3:23])[CH3:25])[C:14](=[O:26])[CH:13]1[CH3:27]
Reactant: CC(=O)OCc1ccc(C2C(C)C(=O)N(OCC[Si](C)(C)C)S2(=O)=O)c(Br)c1
Solvent: CC(=O)Cl
Solvent: CO
Solvent: CC#N
Product: CC1C(=O)N(OCC[Si](C)(C)C)S(=O)(=O)C1c1ccc(CO)cc1Br
Reaction time: 24 h
Yield: 88.8 %

Procedure:
To a solution of 3-bromo-4-(1,1-dioxido-3-oxo-2-[2-(trimethylsilyl)ethoxy]-methylisothiazolidin-5-yl)benzyl acetate (10 mg, 0.02 mmol) in acetonitrile (0.5 mL) and methanol (0.5 mL) was added acetyl chloride (2.9 μL, 0.041 mmol) at room temperature. The resulting solution was stirred for 24 h and then the reaction was concentrated. The residue was purified by silica gel chromatography (5%–40% ethyl acetate/hexanes) to afford product as oil (8.0 mg, 87%). 1H NMR (400 MHz, CDCl3): δ 7.74 (m, 1H), 7.36 (m, 2H), 5.54 (dd, J=8.0, 6.3 Hz, 1H), 5.07 (dd, J=16.4, 11.3 Hz, 2H), 4.73 (d, J=5.6 Hz, 2H), 3.66 (dd, J=9.4, 7.4 Hz, 2H), 3.50 (dd, J=17.6, 8.0 Hz, 1H), 3.24 (dd, J=17.6, 6.3 Hz, 1H), 1.82 (t, J=5.6 Hz, 1H), 0.96 (dd, J=9.4, 7.4 Hz, 2H), 0.01 (s, 9H). LCMS found for C16H24BrNO5SSiNa (M+Na)+: m/z=472, 474.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][Br:5].[C:6]1([P:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[Br-:5].[F:1][CH2:2][CH2:3][CH2:4][PH:12]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: FCCCBr
Solvent: Cc1ccccc1
Product: FCCC[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Yield: 85.2 %

Procedure:
To 3 l of toluene was dissolved 200.0 g (1.42 mol) of 3-fluorobromopropane, 372 g (1.42 mol) of triphenylphosphine was added thereto, and refluxed for 15 hours. Deposited crystals were filtered off and subjected to suction drying to obtain 486 g (1.21 mol) of 3-fluoropropyltriphenylphosphine bromide. Yield of this compound from 3-fluorobromopropane was 85.2%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]23[CH2:14][C@@H:13]2[CH2:12][C:11](=O)[CH2:10]3)[CH:5]=[CH:6][C:7]=1[Cl:8].C([O-])(=O)C.[NH4+].C([BH3-])#[N:22].[Na+].C(OCC)(=O)C.CO.C(N(CC)CC)C>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]23[CH2:14][C@@H:13]2[CH2:12][CH:11]([NH2:22])[CH2:10]3)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: [BH3-]C#N
Reactant: O=C1C[C@H]2C[C@@]2(c2ccc(Cl)c(Cl)c2)C1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: NC1C[C@H]2C[C@@]2(c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
To a solution of (1R,5R)-1-(3,4-dichlorophenyl)bicyclo[3.1.0]hexan-3-one (0.9 g, 3.73 mmol) in methanol (112 mL) was added ammonium acetate (28.3 g, 373 mmol), stirred for 15 minutes at room temperature and sodiumcyano borohydride (1.87 g, 30.8 mmol) was added and the mixture was heated to 60° C. for 2 hours. The reaction was monitored by TLC (ethyl acetate/methanol/triethylamine (89:10:1)). The reaction mixture was concentrated under reduced pressure to remove methanol at 30° C., the residual mass was quenched with water (50 mL) and the aqueous layer was extracted again with ethyl acetate (3×100 mL). The aqueous layer was saturated with sodium chloride and re-extracted with ethyl acetate (3×100 mL). The organic layers were combined, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to yield 2.4 g of crude oil, which was purified by preparative HPLC to give 600 mg (66%) of 99% pure product. 1H NMR δ(300 MHz,CD3OD): 0.92-0.99 (2H,m), 1.27 (1H,m), 1.78-1.83 (3H,m), 2.04-2.15 (2H,m), 2.57-2.74 (3H,m), 3.98-4.01 (1H,m), 7.11-7.14 (1H,m), 7.36-7.41 (2H,m). 13CNMR(CD3OD) δ: 145.92, 133.22, 131.50, 130.76, 129.77, 129.30, 127.57, 127.06, 54.35, 40.52, 37.67, 35.74, 34.36, 33.53, 31.10, 28.25, 26.08, 25.87, 18.50. Purity: 99.15% (a/a) by HPLC. MS, M+(241).