Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:33][CH2:32][C:11]2([N:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][N:26]4[CH2:30][CH2:29][CH2:28][CH:27]4[CH3:31])=[CH:18][CH:17]=3)[O:13][CH2:12]2)[CH2:10][CH2:9]1)C1C=CC=CC=1>C(O)C.[OH-].[Pd+2].[OH-]>[CH3:31][CH:27]1[CH2:28][CH2:29][CH2:30][N:26]1[CH2:25][CH2:24][CH2:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([C:14]2[O:13][CH2:12][C:11]3([CH2:10][CH2:9][NH:8][CH2:33][CH2:32]3)[N:15]=2)=[CH:21][CH:20]=1
Reactant: CC1CCCN1CCCOc1ccc(C2=NC3(CCN(Cc4ccccc4)CC3)CO2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC1CCCN1CCCOc1ccc(C2=NC3(CCNCC3)CO2)cc1
Temperature: 50 °C
Reaction time: 48 h
Yield: 125.6 %

Procedure:
A suspension of 8-benzyl-2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-3-oxa-1,8-diazaspiro[4.5]dec-1-ene 30 (0.22 g, 0.49 mmol) and palladium hydroxide (0.02 g, 10% wt) in ethanol (10 ml) is placed in a Parr apparatus under a hydrogen atmosphere (40 psi) overnight. After this time, palladium hydroxide (0.02 g, 10% wt) is added again, and the mixture is stirred further under hydrogen at 50° C. for 2 days. The mixture is then filtered on celite and the filtrate is concentrated under reduced pressure to give 0.22 g of 2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-3-oxa-1,8-diazaspiro[4.5]dec-1-ene 36 as a paste.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=O)[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH:19]1[CH2:25][C:23](=[O:24])[NH:22][C:20]1=[O:21].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=[C:25]4[NH:19][C:20](=[O:21])[NH:22][C:23]4=[O:24])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CC=C(c2c[nH]c3ccc(C=O)cc23)CC1
Reactant: O=C1CNC(=O)N1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: CN1CC=C(c2c[nH]c3ccc(C=C4NC(=O)NC4=O)cc23)CC1
Yield: 76 %

Procedure:
A mixture of the product from step (b) (2.4 g), hydantoin (Aldrich, 0.98 g) and ammonium acetate (0.74 g) in glac. acetic acid (2.4 ml) was heated at 120° C. for 4 hours. The mixture was cooled and the resulting precipitate filtered off and dried to give the desired product as a yellow solid (2.4 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:11]=[C:10]3[NH:27][N:28]=[CH:29][C:9]=23)=[CH:4][CH:3]=1.[CH2:30]=[O:31]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:10](=[N:27][N:28]([CH2:30][OH:31])[CH:29]=3)[N:11]=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:13]=2[C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2nc3[nH]ncc3c(-c3ccc(F)cc3)c2-c2ccncc2)cc1
Reactant: C=O
Product: OCn1cc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1
Temperature: 130 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
A suspension of 4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (0.20 g, 0.5 mmol, obtained in example 1) in 30-40% aqueous formaldehyde (0.9 mL) was stirred at 130° C. under argon atmosphere for 4 h. The solvent was concentrated and the residue was dissolved in a mixture of CHCl3 and water and the phases were separated. The organic phase was dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified on chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 140 mg of the title compound in solid form (yield: 65%).
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([OH:12])[CH:5]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2([CH2:25]O)[CH2:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1.CCOC(/N=N/C(OCC)=O)=O>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2([CH2:25][O:12][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=3[O:10][CH3:11])[C:3]([OH:2])=[O:13])[CH2:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1
Reactant: OCC1(c2ccc(Cl)cc2)CCC1
Reactant: COC(=O)c1ccc(OC)c(O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Product: COc1ccc(C(=O)O)cc1OCC1(c2ccc(Cl)cc2)CCC1
Temperature: 25 °C

Procedure:
To a solution of 300 mg 3-Hydroxy-4-methoxy-benzoic acid methyl ester, 388 mg [1-(4-Chloro-phenyl)-cyclobutyl]-methanol 1645 mg polymerbound triphenyl phosphine (Fluka, 3 mmol triphenyl phosphine/g resin) and 762 μl DEAD were introduced and the mixture was shaken over night at RT. After filtration, evaporation of the solvent the residue was taken up in 5 ml MeOH/H2O 3:1 and 20 mg LiOH monohydrate was added. After heating the mixture at 60° C. for 2 h the mixture was acidified with half concentrated HCl and filtered through a chem elut® cartridge by elution with ethyl acetate. After concentration under reduced pressure the crude product was subjected to the following amide coupling without further purification.
Reaction SMILES: [CH:1]([C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH:5]=1)([CH3:3])[CH3:2].[Li]CCCC.CN([CH:21]=[O:22])C>C1COCC1>[CH:1]([C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[CH:21]=[O:22])([CH3:3])[CH3:2]
Reactant: CC(C)c1coc2ccccc12
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)c1c(C=O)oc2ccccc12
Reaction time: 0.5 h

Procedure:
To a cooled (0° C.) solution of 3-isopropylbenzofuran (250 mg, 1.56 mmol) in THF (1 mL) is added nBuLi (2 mL, 2 mmol) drop wise and the reaction is stirred for 30 minutes. DMF (1 mL) was added to the reaction and stirred at room temperature overnight. The solution is placed in an ice bath and carefully quenched with 5% aqueous 110 solution (2 mL), and extracted with ethyl acetate (3×5 mL), dried over sodium sulfate and concentrated. The product was purified on silica with 100% hexanes to yield title compound in as a colorless oil (250 mg, 85%): 1H NMR (400 MHz, CDCl3) δ 10.10 (s, 1H), 7.78 (d, 1H, J=9.0 Hz), 7.55 (d, 1H, J=9.0 Hz), 7.32-7.24 (m, 2H), 3.11-3.07 (m, 1H), 1.33-1.31 (2s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:13][C:12]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:11][C:10]=2[CH2:20][OH:21])=[CH:4][CH:3]=1.[NH:22]1[C:30]2[C:25](=[CH:26][C:27](O)=[CH:28][CH:29]=2)[CH:24]=[N:23]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:13][C:12]([CH:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[N:11][C:10]=2[CH2:20][O:21][C:27]2[CH:26]=[C:25]3[C:30](=[CH:29][CH:28]=2)[NH:22][N:23]=[CH:24]3)=[CH:4][CH:3]=1
Reactant: Oc1ccc2[nH]ncc2c1
Reactant: OCc1nc(C2CCOCC2)oc1Sc1ccc(Cl)cc1
Product: Clc1ccc(Sc2oc(C3CCOCC3)nc2COc2ccc3[nH]ncc3c2)cc1

Procedure:
Prepared from {5-[(4-chlorophenyl)sulfanyl]-2-(tetrahydro-2H-pyran-4-yl)-1,3-oxazol-4-yl}methanol (INTERMEDIATE C6.1) and 1H-indazol-5-ol using a similar procedure as described in the preparation of example B2.1. MS: M+H=442.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:16]=[N:17][C:18]([CH2:40][CH2:41][CH2:42][CH3:43])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:23]([C:34]4[CH:35]=[N:36][N:37]([CH3:39])[CH:38]=4)[CH:22]=3)[CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:44]>CO.O1CCOCC1>[ClH:44].[ClH:44].[CH2:40]([C:18]1[N:17]=[N:16][C:15]([O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:20][C:19]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)=[C:23]([C:34]2[CH:35]=[N:36][N:37]([CH3:39])[CH:38]=2)[CH:22]=1)[CH2:41][CH2:42][CH3:43]
Reactant: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)c(-c2cnn(C)c2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCCCc1nnc(OC2CCNCC2)cc1-c1ccc(OC2CCCCC2)c(-c2cnn(C)c2)c1
Reaction time: 3 h

Procedure:
To a solution of 4-{6-butyl-5-[4-cyclohexyloxy-3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyridazin-3-yloxy}-piperidine-1-carboxylic acid tert-butyl ester (0.109 mmol, 64.1 mg) in MeOH (0.5 mL) was added 4 N HCl in dioxane (0.5 mL), and the reaction mixture was stirred for 3 h. The organic solvents were removed in vacuo and the residue was triturated with anhydrous diethyl ether and hexanes. The green-yellow solid was dried overnight under high vacuum to provide 3-butyl-4-[4-cyclohexyloxy-3-(1-methyl-1H-pyrazol-4-yl)-phenyl]-6-(piperidin-4-yloxy)-pyridazine dihydrochloride (61.3 mg).
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[O:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][NH:14][CH2:13][CH2:12]1>ClCCl>[CH:1]([N:14]1[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:11][CH2:12][CH2:13]1)=[O:2]
Reactant: c1ccc2c(c1)CNCCO2
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: O=CN1CCOc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To 15 ml of formic acid was added dropwise 5 ml of acetic anhydride, and the mixture was stirred for 20 minutes at room temperature. To the mixture was added dropwise a solution of 2.2 g of 2,3,4,5-tetrahydro-1,4-benzoxazepine in 10 ml of dichloromethane, and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was poured into ice-water, then the mixture was subjected to extraction with dichloromethane. The extract was washed successively with a saturated aqueous solution of sodium bicarbonate, and water. The mixture was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 2.6 g of 4-formyl-2,3,4,5-tetrahydro-1,4-benzoxazepine as an oily anhydrous substance.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][C@H:8]([CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1)/[CH:9]=[CH:10]/[CH:11]([CH2:19][O:20][Si](C(C)(C)C)(C)C)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2]>F.C(#N)C>[C:1]([O:5][C:6](=[O:39])[NH:7][C@H:8]([CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1)/[CH:9]=[CH:10]/[CH:11]([CH2:19][OH:20])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](/C=C/C(CO[Si](C)(C)C(C)(C)C)Cc1ccccc1)Cc1ccc2ccccc2c1
Agent: F
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](/C=C/C(CO)Cc1ccccc1)Cc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.8 %

Procedure:
((1R,2E)-4-(tert-Butyldimethylsilanyloxymethyl)-1-(2-naphthyl)methyl-5-phenylpent-2-enyl)carbamic acid tert-butyl ester (0.75 g, 1.38 mmol) was dissolved in 2% hydrogen fluoride in acetonitrile (50 ml) and stirred at room temperature for 3 h. The solvent was removed in vacuo and the residue was chromatographed on silica (80 g) using dichloromethane/heptane/methanol (4/10/1) as eluent. Three fractions were isolated containing compounds with Rf 0.1-0.2. The major fraction (eluting second) was concentrated in vacuo to give 0.35 g of ((1R,2E)-4-hydroxymethyl-1-(2-naphthyl)methyl-5-phenylpent-2-enyl)carbamic acid tert butyl ester as a mixture of diastereomers.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH:26]([CH3:28])[CH3:27])[C:21]([C:29](O)=[O:30])=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:33][C:34]1([F:40])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.Cl.C(N=C=NCCCN(C)C)C>C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH:26]([CH3:28])[CH3:27])[C:21]([C:29]([N:37]2[CH2:38][CH2:39][C:34]([F:40])([F:33])[CH2:35][CH2:36]2)=[O:30])=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: FC1(F)CCNCC1
Reactant: CC(C)n1c(C(=O)O)cc2cc(C(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(C)n1c(C(=O)N2CCC(F)(F)CC2)cc2cc(C(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)ccc21

Procedure:
The title compound was synthesized in analogy to Example 1, from 5-(4-tert-butoxycarbonyl-[1,4]diazepane-1-carbonyl)-1-isopropyl-1H-indole-2-carboxylic acid, 4,4-difluoropiperidine hydrochloride, triethylamine and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride, to afford the product as a yellow solid (70%).
Reaction SMILES: [CH2:1]([N:3]([CH2:10][CH3:11])[CH2:4][CH2:5][C:6]([CH3:9])([NH2:8])[CH3:7])[CH3:2].[C:12](ON1C(=O)CCC1=O)([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]>C1COCC1>[CH2:10]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][C:6]([NH:8][C:12](=[O:13])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:9])[CH3:7])[CH3:11]
Reactant: CCN(CC)CCC(C)(C)N
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: C1CCOC1
Product: CCN(CC)CCC(C)(C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 51.8 %

Procedure:
Crude N1,N1-diethyl-3-methylbutane-1,3-diamine (7.00 g, 44.2 mmol) was dissolved into THF (100 mL). To this solution was added CbzOSu (11.0 g, 1 equiv, 44.2 mmol) in one portion. The reaction was left to stir at room temperature for 2 d. The solvent was removed and the residue was taken up in a mixture of ethyl acetate (150 mL) and water (100 mL). The layers were separated and the organic layer washed with saturated sodium bicarbonate (2×100 mL), water (100 mL) and brine (100 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated to a pale yellow oil. The crude oil was purified on an ISCO purification system with gradient elution from 1-5% methanol in DCM. The desired fraction was collected and concentrated to give a colorless oil (6.7 g, yield: 37.8%). 1H NMR (CDCl3, 400 MHz): δ 1.00-1.04 (t, J=7.0, 6H),1.37 (s, 6H), 1.57-1.61 (t, J=6.2, 2H), 2.45-2.51 (q, J=7.0, 4H), 2.52-2.56 (t, J=6.0, 2 H), 5.04 (s, 2H), 7.27-7.36 (m, 5H), 7.57 (bs, 1H). LRMS (ESI+) for C17H28N2O2 (292.2); Found: 293 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:23])=[C:6]([CH:8]([O:21][CH3:22])[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[O:10])[CH:7]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][NH:11][C:9](=[O:10])[CH:8]([C:6]2[CH:7]=[C:2]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:3]=[CH:4][C:5]=2[F:23])[O:21][CH3:22])=[CH:14][CH:15]=1)#[N:20]
Reactant: OB(O)c1ccccc1
Reactant: COC(C(=O)NCc1ccc(C#N)cc1)c1cc(Br)ccc1F
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1cc(-c2ccccc2)ccc1F

Procedure:
In analogy to example 57.1, (RS)-2-(5-bromo-2-fluoro-phenyl)-N-(4-cyano-benzyl)-2-methoxy-acetamide (example 75.2) was reacted with phenylboronic acid to give (RS)-N-(4-cyano-benzyl)-2-(4-fluoro-biphenyl-3-yl)-2-methoxy-acetamide. Off-white solid. MS 374.1 (M).
Reaction SMILES: C1(O[C:8](=[O:27])[NH:9][C:10]2[S:11][C:12]3[C:18]([CH:19]4[CH2:24][O:23][CH2:22][CH2:21][O:20]4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)C=CC=CC=1.N1C=CC=CC=1.[CH3:34][NH:35][C@@H:36]1[CH2:41][CH2:40][C@H:39]([OH:42])[CH2:38][CH2:37]1>C(Cl)(Cl)Cl>[O:20]1[CH2:21][CH2:22][O:23][CH2:24][CH:19]1[C:18]1[C:12]2[S:11][C:10]([NH:9][C:8](=[O:27])[N:35]([C@H:36]3[CH2:41][CH2:40][C@@H:39]([OH:42])[CH2:38][CH2:37]3)[CH3:34])=[N:14][C:13]=2[C:15]([O:25][CH3:26])=[CH:16][CH:17]=1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)Oc3ccccc3)nc12
Reactant: CN[C@H]1CC[C@@H](O)CC1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)N(C)[C@H]3CC[C@@H](O)CC3)nc12
Reaction time: 16 h

Procedure:
To a stirred solution of 100 mg (0.26 mmol) (+)-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-carbamic acid phenyl ester and 0.06 ml (0.78 mmol) pyridine in 5 ml chloroform at room temperature was added 47 mg (0.36 mmol) cis-4-methylamino-cyclohexanol and stirring continued at 50° C. for 16 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (1/1 acetone/heptane then acetone) followed by trituration in ether and hexane afforded 75 mg (69%) (+)-cis-3-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-1-(4-hydroxy-cyclohexyl)-1-methyl-urea as a white solid. [α]D20=+18.8° (c=1.07, CHCl3), ES-MS m/e (%): 422 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([CH3:13])=[CH2:12].O.C1C=C(Cl)C=C(C(OO)=[O:23])C=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1([CH3:13])[CH2:12][O:23]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C)c1cc([N+](=O)[O-])ccc1F
Solvent: O
Solvent: ClCCl
Product: CC1(c2cc([N+](=O)[O-])ccc2F)CO1
Temperature: 10 °C
Reaction time: 48 h

Procedure:
1-fluoro-4-nitro-2-(prop-1-en-2-yl)benzene (1 eq) was dissolved in dichloromethane and cooled to 10° C. using and ice/salt/water bath under nitrogen. MCPBA (1.5 eq) in dichloromethane was then added dropwise and resulting solution allowed to warm to room temperature and allowed to stir 48 h. Solution was quenched with 10% sodium sulfite, neutralized with saturated solution of sodium bicarbonate, extracted with dichloromethane. Organics were washed with brine, dried with sodium sulfate and concentrated. Crude product was purified with flash chromatography (85% Hex:15% EtoAc) to afford 2-(2-fluoro-5-nitrophenyl)-2-methyloxirane.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:37])[CH:10]([N:19]1[C:23]2[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:22]=2[N:21]=[C:20]1[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[CH:11]1[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.C(OC(=O)C)(=O)C.[N:49]([O-])=[O:50].[Na+]>>[CH2:1]([N:8]([N:49]=[O:50])[C:9](=[O:37])[CH:10]([N:19]1[C:23]2[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:22]=2[N:21]=[C:20]1[C:30]1[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=1)[CH:11]1[CH2:16][CH2:15][C:14]([F:17])([F:18])[CH2:13][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCc1ccccc1)C(C1CCC(F)(F)CC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=NN(Cc1ccccc1)C(=O)C(C1CCC(F)(F)CC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a ice-cold solution of 3.10 g (5.85 mMol) N-benzyl-2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-(4,4-difluoro-cyclohexyl)-acetamide in 19.1 ml (333 mmol) acetic acid and 40.14 ml (708 mmol) acetic anhydride were added in portions over 20 min. 2.02 g (29.25 mmol) sodium nitrite. The reaction mixture was stirred overnight at room temperature and evaporated. The residue was taken up in saturated aqueous sodium bicarbonate solution and ethyl acetate and the pH was adjusted to 7 by adding solid sodium bicarbonate. The aqueous layer was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness. Yellow foam (85%). MS (Turbo Spray): m/z=559.2 [M+H].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:17](O)=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O[N:30]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.N>CN(C)C=O.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:20][C:21](=[O:22])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:17](=[O:18])[NH2:30])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 30.6 %

Procedure:
To a solution of (S)-3-(4-benzyloxyphenyl)-2-tert-butoxycarbonylaminopropionic acid (5.00 g, 13.5 mmol) and 1-hydroxybenzotriazole monohydrate (2.50 g, 16.1 mmol) in N,N-dimethylformamide (50 ml) were added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (3.10 g, 16.1 mmol) and 28% aqueous ammonia solution (5 ml) under ice-cooling, and the mixture was stirred at room temperature for 24 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:ethyl acetate=2:1-1:1) to give tert-butyl (S)-[2-(4-benzyloxyphenyl)-1-carbamoylethyl]carbamate (1.53 g, yield 31%).
Reaction SMILES: C1C=CN=CC=1.[FH:7].[Br:8][C:9]1[CH:29]=[CH:28][C:12]2[O:13][CH2:14][C:15]3([C:18]4[S:22][C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:20][C:19]=4[C:11]=2[CH:10]=1)[CH2:17][O:16]3>ClCCl>[Br:8][C:9]1[CH:29]=[CH:28][C:12]2[O:13][CH2:14][C:15]([F:7])([CH2:17][OH:16])[C:18]3[S:22][C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:20][C:19]=3[C:11]=2[CH:10]=1
Reactant: CCOC(=O)c1nc2c(s1)C1(COc3ccc(Br)cc3-2)CO1
Reactant: F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1nc2c(s1)C(F)(CO)COc1ccc(Br)cc1-2
Temperature: 0 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
HF-pyridine (70%) (2 mL) was added dropwise to a stirred solution of ethyl 9-bromo-5H-spiro[benzo[2,3]oxepino[4,5-d]thiazole-4,2′-oxirane]-2-carboxylate (600 mg, 1.57 mmol, 1.00 equiv) in dichloromethane (10 mL) at 0° C. After being stirred for 1 h at 0° C. the reaction was quenched with brine, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column with ethyl acetate/petroleum ether (1:10) to give 270 mg (43%) of the titled compound as a off-white solid; LC-MS (ES, m/z) 402, 404 [M+H]+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[SH:11].Br[CH2:13][CH2:14][CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1.O>C1COCC1>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[S:11][CH2:13][CH2:14][CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1
Reactant: Fc1ccc(S)c(F)c1
Reactant: BrCCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(SCCCOC2CCCCO2)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.2 %

Procedure:
Sodium hydride (60% dispersion in mineral oil) (120 mg, 3.01 mmol) was added to a solution of 2,4-difluorothiophenol (0.4 g, 2.74 mmol) in THF (10 mL) at 0° C., under argon. The reaction was allowed to warm to RT and 2-(3-bromopropoxy)tetrahydro-2H-pyran (672 mg, 3.01 mmol) added. The reaction was stirred at RT for 4 hours then poured into iced water (50 mL) and extracted into ethyl acetate (50 mL). The organics were washed with brine (50 mL), dried (MgSO4), filtered and the solvent removed in vacuo to give a yellow oil which was chromatographed on silica, eluting with 0-10% ethyl acetate in isohexane, to give the desired compound as a colourless oil (610 mg). 1H NMR δ (CDCl3): 1.49-1.61 (m, 4H), 1.65-1.73 (m, 1H), 1.75-1.90 (m, 3H), 2.96 (t, 2H), 3.46-3.52 (m, 2H), 3.79-3.87 (m, 2H), 4.55-4.56 (m, 1H), 6.80-6.86 (m, 2H), 7.38-7.44 (m, 1H)
Reaction SMILES: [H-].[Na+].[S:3]1(=[O:10])(=[O:9])[CH2:8][CH2:7][CH2:6][CH2:5][NH:4]1.Br[CH2:12][CH2:13][Cl:14]>CN(C)C=O>[Cl:14][CH2:13][CH2:12][N:4]1[CH2:5][CH2:6][CH2:7][CH2:8][S:3]1(=[O:10])=[O:9]
Reactant: O=S1(=O)CCCCN1
Reactant: ClCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S1(=O)CCCCN1CCCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cold (0° C.) suspension of sodium hydride (823 mg, 60% in oil, 0.0206 mol) in N,N-dimethylformamide (20 mL) was added a solution of tetrahydro-2H-1,2-thiazine 1,1-dioxide (2.53 g, 0.0187 mol) in N,N-dimethylformamide (30 mL). The resulting mixture was stirred at room temperature 1 hour. 1-Bromo-2-chloroethane was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, then chromatographed on silica gel (30 to 70%, ethyl acetate in hexanes). The resulting residue was triturated with ether and the solids were filtered off. The filtrate was concentrated to give 2-(2-chloroethyl)tetrahydro-2H-1,2-thiazine 1,1-dioxide, which was partially contaminated with starting material, and was taken on to the next step. 1H NMR (400 MHz, CDCl3) δ 3.60 (t, J=6.6 Hz, 2 H), 3.47-3.42 (m, 4 H), 3.01 (t, J=6.0 Hz, 2 H), 2.18 (m, 2 H), 1.66 (m, 2 H).