Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27]CC)=[N:13][C:14]=1[CH2:15]C.Br[C:33]1N=C(C2CC2)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1C>>[CH:30]1([C:11]2[C:12]([NH:17][C@@H:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][C@@H:19]3[OH:27])=[N:13][C:14]([CH3:15])=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:10]=2)[CH2:31][CH2:33]1
Reactant: Cc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(C2CC2)nc1Br
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: Cc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(C2CC2)nc1-c1ccc(Cl)cc1Cl

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-[(5-bromo-3-cyclopropyl-6-methylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.96–0.99, 1.58, 1.81, 2.26, 2.85, 3.14, 3.26, 4.86, 5.44, 5.63, 7.26–7.50; MS (ESI+) for C23H21Cl2N3O m/z 426 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.CCN(C(C)C)C(C)C.[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24][C:23]=1[CH2:29][NH2:30]>CCCCO>[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24][C:23]=1[CH2:29][NH:30][C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2
Reactant: Fc1nc(Cl)c2[nH]cnc2n1
Reactant: Cc1cc(C)c(CN)cn1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)c(CNc2nc(F)nc3[nH]cnc23)cn1
Reaction time: 1 h

Procedure:
To a stirred solution of 6-chloro-2-fluoropurine (0.83 g, 4.9 mmol) in n-BuOH (50 ml) under an argon atmosphere at 0° C., was added DIEA (2.5 ml, 14.7 mmol) followed by (4,6-dimethylpyridine-3-yl)methanamine (1 g, 7.35 mmol). The reaction mixture was stirred at this temperature for 1 h and then allowed to return to room temperature and stirred for 4 h, it was still seen incomplete, hence heated the reaction to 100° C. and left at that temperature for 2 h. The solvent was evaporated in vacuo and the residue was purified by gradient flash column chromatography on silica gel, eluted with CHCl3:MeOH (100:0→90:10), to afford the product as a white solid; Yield: 0.86 g (65%); δH (250 MHz, CDCl3) 2.35 (3 H, s, CH3), 2.39 (3 H, s, CH3), 4.61 (2 H, s, br, NHCH2), 7.07 (1 H, s, ArH), 8.13 (1 H, s, ArH), 8.33 (1 H, s, ArH), 8.69 (1 H, s, br, NH); δC (250 MHz, CDCl3) 161.2 (C), 158.57 (C), 156.08 (C), 150 (C), 148.08 (CH), 148.14 (CH), 147.9 (CH), 145.93 (C), 129.92 (C), 129.76 (C), 124.37 (CH), 41.7 (CH2), 23.17 (CH3), 18.14 (CH3); m/z 273.2 (M+H)
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[Si:13]([O:20][CH2:21]/[CH:22]=[N:23]/[S@:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[Si:13]([O:20][CH2:21][C@@H:22]([NH:23][S@:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: Brc1ccccn1
Reactant: CC(C)(C)[S@](=O)/N=C/CO[Si](C)(C)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)[S@](=O)N[C@H](CO[Si](C)(C)C(C)(C)C)c1ccccn1
Yield: 46.4 %

Procedure:
To a solution of toluene (40 mL) cooled to −78° C. was added butyl lithium (1.6 M in hexanes, 5.57 mL, 13.9 mmol) at a rate such that the internal temperature did not exceed −50° C., and the reaction stirred until the internal temperature returned to −78° C. 2-Bromopyridine (1.20 mL, 12.7 mmol) in toluene (4 mL) was added to the reaction mixture at a rate such that the temperature did not exceed −65° C. The reaction was stirred at −78° C. for 1 hour. To the reaction was added (S,E)-N-(2-(tert-butyldimethylsilyloxy)ethylidene)-2-methylpropane-2-sulfinamide (3.58 g, 13.9 mmol) in toluene (20 mL) at a rate such that the internal temperature did not exceed −60° C. The reaction was stirred at −78° C. for 2 hours. To the −78° C. solution was added brine (50 mL) and the mixture was partitioned between EtOAc/water (300 mL total). The organic layer was washed with brine (50 mL), dried over MgSO4 and concentrated in vacuo. The crude material was chromatographed using 40% EtOAc/DCM as eluent to yield (S)—N—((S)-2-(tert-butyldimethylsilyloxy)-1-(pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (2.1 g, 46.7%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[NH:7][CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:40])[C:17]2[CH:22]=[C:21]([OH:23])[CH:20]=[C:19]([O:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:27][CH:26]=3)[CH:18]=2)[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].F[C:43]1[CH:50]=[CH:49][C:46]([C:47]#[N:48])=[CH:45][CH:44]=1>>[C:1]([O:5][C:6](=[O:41])[NH:7][CH2:8][CH2:9][CH:10]1[CH2:11][CH2:12][N:13]([C:16](=[O:40])[C:17]2[CH:22]=[C:21]([O:23][C:43]3[CH:50]=[CH:49][C:46]([C:47]#[N:48])=[CH:45][CH:44]=3)[CH:20]=[C:19]([O:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:27][CH:26]=3)[CH:18]=2)[CH2:14][CH2:15]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCC1CCN(C(=O)c2cc(O)cc(Oc3ccc(CNC(=O)OC(C)(C)C)cc3)c2)CC1
Reactant: N#Cc1ccc(F)cc1
Product: CC(C)(C)OC(=O)NCCC1CCN(C(=O)c2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(CNC(=O)OC(C)(C)C)cc3)c2)CC1
Yield: 43.3 %

Procedure:
Using 1.2 g (2.1 mmol) of [2-(1-{3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-hydroxy-benzoyl}-piperidin-4-yl)-ethyl]carbamic acid tert-butyl ester and 4-fluorobenzonitrile (0.5 g, 4.2 mmol) and following the procedure of Example 42(b) afforded 0.610 g of the required product. Percentage purity (LCMS): 89.1%, (M+1)=670.3+1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[CH2:25]Br)[CH:7]=1)[CH3:2].[CH3:28][C@H:29]1[C@@H:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:32][C:31](=[O:40])[NH:30]1>>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[CH2:25][N:30]2[C@@H:29]([CH3:28])[C@@H:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:32][C:31]2=[O:40])[CH:7]=1)[CH3:2]
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1ccccc1
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(C(F)(F)F)cc2CBr)c1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 10, Step 7, using the following starting materials: [3-(2-bromomethyl-4-trifluoromethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and (4S,5R)-(−)-4-methyl-5-phenyl-2-oxazolidinone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[O:21]1[CH2:25][CH2:24][CH:23]([C:26](O)=[O:27])[CH2:22]1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:26]([CH:23]3[CH2:24][CH2:25][O:21][CH2:22]3)=[O:27])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: O=C(O)C1CCOC1
Solvent: CO
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1)C1CCOC1

Procedure:
The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example E) and tetrahydro-3-furancarboxylic acid, (CAN 89364-31-8) as starting materials; enantiomers were separated by chiral HPLC (ChiralPak AD, 30% ethanol/n-heptane (+) enantiomer isolated; LC-MS (UV peak area/ESI) 98.1%, 401.0869 (M+H)+; αD20 (MeOH)=+10.1°
Reaction SMILES: [SH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].N(C([O:25][CH2:26][CH3:27])=O)=NC(OCC)=O>C(OCC)C.C1C=CC=CC=1>[C:4]([C:3]1[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=1[S:1][S:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:26]([C:27]1[CH:10]=[CH:11][CH:6]=[CH:7][CH:8]=1)=[O:25])(=[O:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(c1ccccc1)c1ccccc1S
Reactant: CCOC(=O)N=NC(=O)OCC
Solvent: c1ccccc1
Solvent: CCOCC
Product: O=C(c1ccccc1)c1ccccc1SSc1ccccc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 50.7 %

Procedure:
To a solution of 2-mercaptobenzophenone (2.3 g, 7.4 mmol) in diethyl ether (10 mL) was added dropwise diethyl azodicarboxylate (0.65 g, 3.7 mmol). The solution was stirred for 5 minutes at room temperature, then diluted with benzene (40 mL) and refluxed for 16 hours. The solution was cooled and concentrated in vacuo leaving a yellow liquid. The crude product was purified using silica gel chromatography (75% hexane/25% ethyl acetate) to give the title compound as a yellow foam (0.8 g, 50%);
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:15]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:13]=[CH:12][C:11]=2[O:20][CH:21]([CH3:23])[CH3:22])=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[CH:21]([O:20][C:11]1[CH:12]=[CH:13][C:14]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:15][C:10]=1[C:8]([N:5]1[CH2:4][CH2:3][CH:2]([O:1][S:32]([CH3:31])(=[O:34])=[O:33])[CH2:7][CH2:6]1)=[O:9])([CH3:23])[CH3:22]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(O)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(OS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 93 %

Procedure:
To a solution of 0.29 mmol (4-hydroxy-piperidin-1-yl)-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone in 6 ml dichloromethane at 0° C. were added successively 0.73 mmol triethylamine and 0.35 mmol methanesulfonyl chloride. The reaction mixture was stirred at 0° C. for 20 min and then at RT for 2 h. The reaction mixture was then diluted with dichloromethane, washed with water, and the organic phase dried over sodium sulfate and concentrated in vacuo to afford the title compound as a light brown solid (yield 93%). MS (m/e): 420.1 (M+H+, 100%).
Reaction SMILES: [N+](C1C=CC(O[C:11]([C:13]2[C:14]3[CH:23]=[C:22]([CH2:24][O:25][CH3:26])[O:21][C:15]=3[C:16]([O:19][CH3:20])=[N:17][CH:18]=2)=[O:12])=CC=1)([O-])=O.[NH2:27][C:28]1[C:33]([Cl:34])=[CH:32][N:31]=[CH:30][C:29]=1[Cl:35]>>[Cl:35][C:29]1[CH:30]=[N:31][CH:32]=[C:33]([Cl:34])[C:28]=1[NH:27][C:11]([C:13]1[C:14]2[CH:23]=[C:22]([CH2:24][O:25][CH3:26])[O:21][C:15]=2[C:16]([O:19][CH3:20])=[N:17][CH:18]=1)=[O:12]
Reactant: COCc1cc2c(C(=O)Oc3ccc([N+](=O)[O-])cc3)cnc(OC)c2o1
Reactant: Nc1c(Cl)cncc1Cl
Product: COCc1cc2c(C(=O)Nc3c(Cl)cncc3Cl)cnc(OC)c2o1
Yield: 90.8 %

Procedure:
Starting from 7-methoxy-2-methoxymethylfuro[2,3-c]pyridine-4-carboxylic acid 4-nitrophenyl ester (300 mg) and 4-amino-3,5-dichloropyridine (54 mg). Purification by column chromatography on silica eluting with 1% methanol in dichloromethane gave the title compound (115 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9](O)=[O:10])=[CH:5][CH:4]=1.O=S(Cl)[Cl:16]>>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([Cl:16])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=CC(=O)O)cc1
Reactant: O=S(Cl)Cl
Product: COc1ccc(C=CC(=O)Cl)cc1
Yield: 61.9 %

Procedure:
53.5 g of the 4-methoxy cinnamic acid (Aldrich 0.3 mol)) and 124.9 g of SOCl2 (Thionyl Chloride, 1.05 mol) were put into the two-neck flask having the volume of 250 ml, and then reacted with each other at normal temperature for 24 hours. After the reaction was finished, the distillation was performed to remove an excessive amount of SOCl2, and the reactant was diluted with 100 ml of toluene and neutralized by using the NaHCO3 solution. After the neutralization, the resulting substance was dried by using anhydrous MgSO4, and filtered, and the solvent was removed by using the rotary evaporator. Next, the substance was passed through the silica gel to remove the impurity, thus obtaining 36.5 g of the white solid (yield: 62%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[C:14]([OH:23])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:26]I>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[C:14]([O:23][CH3:26])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CI
Reactant: Cc1nc2c(cc1O)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2c(nc1C)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 90.0 mg (0.28 mmol) (4R,9aR)-7-hydroxy-4,6-dimethyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (example 7, intermediate) in 1.0 mL N,N-dimethylformamide was added 14.8 mg (0.34 mmol) sodium hydride (55–65% dispersion in oil) and the reaction was stirred for 30 min. Then, 35 μl (80.0 mg, 0.56 mmol) methyl iodide was added. After 2 h the reaction mixture was diluted with ethyl acetate, washed with 10% aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate and filtered. The solvent was removed at a rotary evaporator and the residue was purified by column chromatography on silica gel (0.032–0.063 mm) with ethyl acetate:n-hexane (1:1) as eluant.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[SH:7].C[O-].[Na+].Cl[C:12]([CH3:19])([C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[CH3:13].Cl>CO.O>[CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[S:7][C:12]([CH3:19])([CH3:13])[C:14]([CH:15]([CH3:17])[CH3:16])=[O:18]
Reactant: Cc1occc1S
Reactant: CC(C)C(=O)C(C)(C)Cl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1occc1SC(C)(C)C(=O)C(C)C
Temperature: 35 °C
Reaction time: 0.17 h

Procedure:
Into a 25 ml round bottom 3 neck flask equipped with magnetic stirrer, Y tube, nitrogen inlet, reflux condenser, thermometer and heating mantle, is added 0.57 g (0.005 moles) 2-methyl-3-furan thiol in 3 ml absolute methanol and a solution of 0.27 g (0.005 moles) sodium methoxide in 3 ml of absolute methanol. After 10 minutes stirring, 0.74 g (0.005 moles) 2-chloro-2,4-dimethyl-3-pentanone in 1 ml absolute methanol is added slowly. The reaction mass is then warmed to 35° C using a hot water bath and while maintaining the temperature of the reaction mass at 35° C it is placed under a nitrogen blanket. The reaction mass is then heated to reflux (65°-66° C) and refluxed for a period of 1 hour. At the end of the 1 hour reflux period, the reaction mass is allowed to cool and is worked up by adding thereto 10 ml of water. The reaction mass, being at a basic pH (9-10), is acidified with dilute HCl bringing the pH down to 6. N-Hexane is added to the reaction mass giving rise to two phases; an aqueous phase and an organic phase. The aqueous phase is extracted with 2 × 10 ml of hexane. The hexane extracts are separated, combined, washed with saturated sodium chloride solution and then dried over anhydrous sodium sulfate. The resulting solution is then concentrated to a weight of 1.02 g and the desired compound is isolated using GLC apparatus (conditions: SE-30 Column, 8 foot × 1/4 inch). NMR, IR and Mass Spectral analyses confirm that the structure of the resulting material is: ##SPC20##
Reaction SMILES: [OH:1][C@H:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][C:4](OC)=[O:5].O.[NH2:15][NH2:16]>CO>[OH:1][C@H:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][C:4]([NH:15][NH2:16])=[O:5]
Reactant: COC(=O)C[C@H](O)c1ccccc1
Reactant: NN
Solvent: CO
Solvent: O
Product: NNC(=O)C[C@H](O)c1ccccc1
Temperature: 70 °C
Yield: 74 %

Procedure:
In a 1 liter four-necked flask were charged 200 g (1.11 mol) of methyl (S)-3-hydroxy-3-phenylpropionate (optical purity: 87%e.e.), 77.8 g (1.56 mol) of hydrazine monohydrate, and 400 ml of methanol, and the mixture was heated at 70° C. for 3 hours. The reaction mixture was cooled to 5° C. with ice-water, followed by filtration. The collected crystals were dissolved in 4.7 liter of methanol while hot and cooled to 5° C. The crystals thus precipitated were collected by filtration and dried to give 148 g (74%) of the title compound. Melting point: 179.5° C. Optical purity: >99.9%e.e.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][O:6][C:5](=[O:8])[NH:4]1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>ClCCl.CN(C)C1C=CN=CC=1>[CH3:19][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:1][CH2:2][C@H:3]2[CH2:7][O:6][C:5](=[O:8])[NH:4]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: O=C1N[C@@H](CO)CO1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2COC(=O)N2)cc1

Procedure:
To a stirred solution of Intermediate 98 (11.0 g, 94.0 mmol) in dichloromethane (250 mL), 4-dimethylamino pyridine (22.94 g, 188.0 mmol) and p-toluene sulfonylchloride (26.88 g, 141.0 mmol) were added at 0° C. and it was stirred for an hour before bringing to the room temperature, and the reaction was stirred for an hour. The reaction mixture was washed with 1.5N hydrochloric acid (50 mL), water (50 mL), saturated sodium bicarbonate (50 mL) and finally with brine. The organic layer was dried over sodium sulfate and the solvent was removed under vacuum. The crude product was then purified by flash column chromatography in silica gel using a gradient of ethyl acetate in pet. ether. 1H NMR (300 MHz, DMSO-d6) δ: 2.49 (s, 3H), 3.91-3.95 (m, 2H), 3.99-4.02 (m, 2H), 4.30 (t, 1H), 7.49 (d, 2H), 7.80 (d, 2H), 7.88 (s, 1H). Yield: 12.0 g (47%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[CH2:14]Br.CN(C)C=O.[N-:22]=[N+:23]=[N-:24].[Na+]>O>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[CH2:14][N:22]=[N+:23]=[N-:24]
Reactant: COC(=O)c1cc(F)cc([N+](=O)[O-])c1CBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(F)cc([N+](=O)[O-])c1CN=[N+]=[N-]
Reaction time: 8 h
Yield: 95.8 %

Procedure:
2.47 g (8.46 mmol) of 2-(bromomethyl)-5-fluoro-3-nitrobenzoic acid methyl ester is mixed with 8.3 ml of N,N-dimethylformamide and 5.5 ml of water. After 0.82 g (12.66 mmol) of sodium azide is added, the batch is stirred overnight. The reaction mixture is added to water and extracted three times with methyl tert-butyl ether. The combined organic extracts are washed with water and with brine. After drying on sodium sulfate, it is filtered, and the solvent is spun off. Chromatography on a Flashmaster yields 2.06 g (95.8%) of the desired azide.
Reaction SMILES: [O:1]([CH2:8][CH:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:25]([CH3:27])=[O:26]>CC(CC)=O>[O:1]([CH2:8][CH:9]([N:11]1[CH2:12][CH2:13][N:14]([CH:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:25]([CH3:27])=[O:26])[CH2:15][CH2:16]1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(COc1ccccc1)N1CCNCC1
Reactant: CC(=O)C(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(=O)C(c1ccccc1)N1CCN(C(C)COc2ccccc2)CC1

Procedure:
To N(1-phenoxy-2-propyl)piperazine (1 mole) dissolved in methylethylketone (1000 ml) are added dry potassium carbonate (2 moles) and 1-bromo-1-phenyl-acetone (1 mole). The mixture is refluxed during 5 hours, with stirring. The solvent is evaporated off in vacuo. The residue is taken up into water and is then extracted with methylene chloride. The organic phase is washed with water to neutral pH. The organic phase is extracted with a dilute aqueous hydrochloric acid solution and is then concentrated in vacuo, over a water-bath. The resulting oil is taken up into boiling 95% ethyl alcohol, to give, on cooling, white crystals, M.p. 177°-180° C. N.M.R.: consistent.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:8]=[C:7]([CH3:16])[N:6]=1)([CH3:4])[CH3:3].[H-].[Na+].[CH3:19][O:20][CH2:21][CH2:22][O:23][CH2:24]Cl>O1CCCC1>[CH3:4][C:2]([C:5]1[C:10]([O:11][CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:8]=[C:7]([CH3:16])[N:6]=1)([CH3:1])[CH3:3]
Reactant: COCCOCCl
Reactant: Cc1nc(C(C)(C)C)c(O)c(C(C)(C)C)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOCOc1c(C(C)(C)C)nc(C)nc1C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4,6-Bis(1,1-dimethylethyl)-5-hydroxy-2-methyl pyrimidine (9.8 g, 44.1 moles) is dissolved in 100 mL of tetrahydrofuran and added dropwise to a suspension of sodium hydride (1.2 g, 48.5 mmoles) in THF (50 mL) at 0° C. The reaction mixture is warmed to room temperature over 15 minutes. 2-Methoxyethoxymethyl chloride (7.1 g, 57.3 mmoles) is added to the reaction mixture at room temperature. After being stirred at room temperature for 4 hours, the reaction is quenched by the addition of saturated ammonium chloride and the tetrahydrofuran is evaporated. The organics are extracted into 300 mL of ether. The ether is washed with 100 mL of brine and dried over magnesium sulfate. Evaporation of the solvent gives the crude product which is purified by flash chromatography (silica, 10% ether/hexane). Yield of 4,6-bis(1,1-dimethylethyl)-5-[(2-methoxyethoxy)methoxy]-2-methylpyrimidine=11.3 g (82%) as a clear oil.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]([NH2:6])=[S:5].[C:7]1([N:13]=[C:14]=[S:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl>O.CC#N>[C:7]1([NH:13][C:14]([NH:3][C:4]([NH2:6])=[S:5])=[S:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NC(N)=S
Reactant: S=C=Nc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: NC(=S)NC(=S)Nc1ccccc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 28.2 %

Procedure:
To a stirring solution of NaOH (0.52 g, 13.1 mmol) in 60 mL of 10% H2O:CH3CN was added thiourea (1.0 g, 13.1 mmol). The resulting suspension was heated to 40° C. for 20 min. and then cooled to RT. To this mixture was added phenylisothiocyanate (1.5 ml, 13.1 mmol), and the clear yellow solution was stirred overnight. After stirring for 12 h, 1 N HCl was added until a white precipitate formed. The precipitate was filtered, washed with H2O, and dried under vacuum to produce the title compound as a light yellow powder (0.78 g, 30%). 1H-NMR (400 MHz, d6-DMSO) δ7.25 (t, 2H, J=7.3 Hz), 7.40 (t, 2H, J=7.9 Hz), 7.56 (d, 1H, J=7.9 Hz), 9.13-9.29 (broad singlet, 1H), and 10.26-10.79 (broad singlet, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:16]1[CH:21]=[CH:20][C:19]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:16]2[CH:17]=[CH:18][C:19]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])=[CH:20][CH:21]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(S(=O)(=O)c3ccc(F)cc3)cc2)CC1
Temperature: 120 °C
Yield: 77.3 %

Procedure:
A solution of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (427 mg; 2.13 mmol), bis(4-fluorophenyl) sulfone (493 mg; 1.94 mmol) and potassium carbonate (1.01 g; 7.76 mmol) in dimethylsulfoxide (5 mL) is heated over night at 100° C. The temperature is then increased to 120° C. and the mixture is reacted at this temperature for 24 hours. The reaction is then diluted with dichloromethane (100 mL), filtered and the filtrate is washed with aq. 1N hydrochloric acid (2×20 mL), and water (2×20 mL). The organic layer is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue obtained is finally purified by column chromatography on silica gel (dichloromethane:methanol 100:0 (200 mL) and then 98:2 (150 mL)) to afford the desired product (653 mg; 1.50 mmol).