Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@:3]12[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH2:10][CH2:9][C@@H:8]1[CH2:7][C@:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)([OH:18])[C@:5]([CH3:26])([OH:25])[CH2:4]2)[CH3:2].[N+](C1C=CC(C(Cl)=O)=CC=1)([O-])=[O:28].[OH-].[Na+].C(=O)(O)[O-].[Na+].Cl>CC(C)=O.ClCCl>[CH2:1]([C@:3]12[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[C:10](=[O:28])[CH2:9][C@@H:8]1[CH2:7][C@@:6]([OH:18])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[C@@:5]([OH:25])([CH3:26])[CH2:4]2)[CH3:2]
Reactant: CC[C@@]12C[C@@](C)(O)[C@](O)(c3ccccn3)C[C@H]1CCc1cc(O)ccc12
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC[C@@]12C[C@@](C)(O)[C@](O)(c3ccccn3)C[C@H]1CC(=O)c1cc(O)ccc12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of the compound of Example 102 (80 mg, 0.23 mmol) in acetone (15 mL) was cooled to 0° C. p-Nitrobenzoyl chloride (46 mg, 0.25 mmol) and aqueous 1N sodium hydroxide solution were then added. After the mixture was stirred at 0° C. for 1.5 hours, aqueous saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried over magnesium sulfate and concentrated to afford the crude p-nitrobenzoyl ester derivative. This was dissolved in dichloromethane (15 mL) and treated with aqueous 6N hydrochloric acid solution (0.038 mL). After it was cooled to −30° C., ozone was bubbled through the solution until disappearance of starting material was evident by thin layer chromatography. Oxygen was bubbled for an additional 5 minutes and then dimethylsulfide (0.5 mL) was added. The mixture was allowed to warm to room temperature overnight and was then concentrated. The residue was taken up in tetrahydrofuran (10 mL), treated with aqueous 1N sodium hydroxide solution (5 mL) and stirred at room temperature for 2 hours. Excess aqueous IN hydrochloric acid solution was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium bicarbonate solution and brine. After drying over magnesium sulfate, evaporation provided a residue from which the title compound was isolated by chromatography on silica gel eluting with 40% ethyl acetate in hexane. Mass spectrum (m/e) 368 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([N:23]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.Br[CH2:37][CH2:38][OH:39]>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([N:23]5[CH2:24][CH2:25][N:26]([CH2:37][CH2:38][OH:39])[CH2:27][CH2:28]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1N1CCNCC1
Reactant: OCCBr
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1N1CCN(CCO)CC1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[4-(2-hydroxyethyl)piperazin-1-yl]-1,3-thiazolidine-2,4-dione was prepared from ((5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-piperazin-1-yl-1,3-thiazolidine-2,4-dione (Example 351) and 2-bromoethanol following General Procedure S.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][C:15]=3[CH3:24])=[CH:7][C:6]=2[C:5]2[CH:25]=[CH:26][C:27]([CH3:29])=[CH:28][C:4]=2[N:3]=1.[OH-].[Na+]>CO.C(OCC)(=O)C.O>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=3[CH3:24])=[CH:7][C:6]=2[C:5]2[CH:25]=[CH:26][C:27]([CH3:29])=[CH:28][C:4]=2[N:3]=1
Reactant: COC(=O)c1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(=O)O)cc3C)cc12
Temperature: 25 °C

Procedure:
A solution of methyl 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylbenzoate (from Example 115) (1.0 eq.), and 1N sodium hydroxide (1.5 eq.) in methanol (0.04 M) was stirred at 60° C. for 4 hours. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate and water. The two phases were separated. The organic layer was washed twice with water, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-50% ethyl acetate in hexane to give 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylbenzoic acid as a white solid.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][C:5]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH:22]1[CH2:24][CH2:23]1>O1CCCC1>[CH:22]1([CH2:21][O:12][C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][C:4]=2[O:3][CH:2]([F:13])[F:1])[CH:8]=[O:9])[CH2:24][CH2:23]1
Reactant: O=Cc1ccc(OC(F)F)c(O)c1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=Cc1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 0 °C
Reaction time: 7 h
Yield: 94.7 %

Procedure:
4-Difluoromethoxy-3-hydroxybenzaldehyde (10 g, 52.8 mmol) was dissolved in tetrahydrofuran (100 ml) added with potassium carbonate (44 g, 105 mmol), cooled to 0° C. and added with a solution of bromomethylcyclopropane (11 ml, 116.6 mmol) in tetrahydrofuran (50 ml). The reaction mixture was heated to reflux under stirring for 7 hrs, then fresh bromomethylcyclopropane (5.5 ml, 58.3 mmol) was added and the heating continued for further 7 hrs. The solvent was removed by vacuum distillation, then the mixture was added with 2 N sodium hydroxide (100 ml) and extracted with dichloromethane (2×100 ml). The combined organic layers were dried over sodium sulphate (5 g) and the solvent removed under reduced pressure to afford 3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde (12 g, 50 mmol, 97% yield), that was used without further purification.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[C:9]([O:11]COC)[CH:8]=[CH:7][C:6]=1[C:15]1[CH2:24][CH2:23][C:18]2(OCC[O:19]2)[CH2:17][CH:16]=1.Cl.C(=O)(O)[O-].[Na+]>CO>[OH:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:6]=1[C:15]1[CH2:24][CH2:23][C:18](=[O:19])[CH2:17][CH:16]=1
Reactant: COCOc1ccc(C2=CCC3(CC2)OCCO3)c(OCOC)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: O=C1CC=C(c2ccc(O)cc2O)CC1
Temperature: 25 °C
Yield: 37.3 %

Procedure:
A round bottomed flask equipped with magnetic stirrer was charged with 8-[2,4-bis(methoxymethoxy)phenyl]-1,4-dioxaspiro[4.5]dec-7-ene (1.50 g, 4.24 mmol) and methanol (30 ml). To the stirred solution was added aqueous hydrochloric acid (30 ml, 1.0M) and the solution was heated to reflux temperature for 1.5 hr. After cooling to room temperature, saturated aqueous sodium bicarbonate (20 ml) was added and the layers separated. The aqueous layer was extracted with ethyl acetate (4×20 ml) and the combined organic layers washed with brine (20 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting oil was purified via flash column chromatography (SiO2, ethyl acetate/petroleum ether, 1:3, v/v) to afford the title compound as a yellow solid (323 mg, 37%). m/z (ES−) 203 (M−H+); δH(CD3OD) 2.62 (2H, t), 2.86 (2H, t), 3.04 (2H, m), 5.78 (1H, m), 6.28 (1H, m), 6.32 (1H, m), 6.96 (1H, d).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([N:8]2[C:16](=[O:17])[C:15]3[CH:14]4[C:18]([CH3:20])([CH3:19])[C:11]([CH3:21])([CH2:12][CH2:13]4)[C:10]=3[N:9]2[CH3:22])[CH:5]=[CH:6][CH:7]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.ClCCl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[C:16](=[O:17])[C:15]3[C@@H:14]4[C:18]([CH3:19])([CH3:20])[C@@:11]([CH3:21])([CH2:12][CH2:13]4)[C:10]=3[N:9]2[CH3:22])[CH:3]=1
Reactant: Cn1c2c(c(=O)n1-c1cccc(I)c1)C1CCC2(C)C1(C)C
Reactant: COc1ccccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: COc1ccccc1-c1cccc(-n2c(=O)c3c(n2C)[C@]2(C)CC[C@H]3C2(C)C)c1
Yield: 10.3 %

Procedure:
A mixture of 2-(3-iodo-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Example 23; 80 mg, 0.2 mmol), 2-methoxy-phenyl-boronic acid (46 mg, 0.29 mmol), potassium carbonate (66 mg, 0.47 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10 mg, 0.014 mmol) in dimethoxyethane (4 mL) was sealed under argon and heated at 80 degrees overnight and then at 90 degrees over the weekend. The reaction mixture was diluted with dichloromethane, filtered through a cotton plug and frit, evaporated, and purified using an Analogix Intelliflash 280 system (Analogix, Inc., Burlington, Wis.) with an RS-12 column, eluting with 0-80% ethyl acetate/hexanes to give (4S,7R)-2-(2′-methoxy-biphenyl-3-yl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (8 mg, 10%) as a white solid and unreacted starting material (54 mg, 67%). ES(+)-MS (M+H) 389.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:19]([OH:21])=O)[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl.C(N(CC)CC)C>[CH2:22]([NH:29][C:19](=[O:21])[C@@H:9]([CH2:10][O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N[C@H](COCc1ccccc1)C(=O)O
Reactant: NCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](COCc1ccccc1)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 41 %

Procedure:
To a cooled (−20° C.) solution of N-Boc-O-benzyl-D-serine (1 g) in dichloro methane (12 mL), triethylamine (0.44 mL) was added and stirred for 5 minutes and subsequently isobutylchloformate (0.51 mL) was added to the reaction mixture in 5 minutes at −20° C. The solution was stirred for 5 minutes at −20° C. and benzyl amine (0.44 mL) was added to in it in 5 minutes at −20° C. The solution was stirred for 1 hr at −20° C. The solution was allowed to warm to room temperature and stirred for 1 hour. The hydrochloride salt of N-methylmorpholine was filtered. Organic layer was concentrated under vacuum to obtain solid, 0.53 g N-benzyl-O-benzyl-N2-Boc-D-serinamide after crystallization by diisopropylether.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH:15]2[CH2:17][CH2:16]2)[C:6]=1[C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br:18][CH2:19][C:20](Br)=[O:21]>>[C:7]([C:6]1[C:5]([CH:15]2[CH2:16][CH2:17]2)=[CH:4][S:3][C:2]=1[NH:1][C:20](=[O:21])[CH2:19][Br:18])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Nc1scc(C2CC2)c1C(=O)c1ccccc1
Reactant: O=C(Br)CBr
Product: O=C(CBr)Nc1scc(C2CC2)c1C(=O)c1ccccc1

Procedure:
reacting the 2-amino-3-benzoyl-4-cyclopropylthiophene with bromoacetyl bromide to form 3-benzoyl-2-(α-bromoacetamido)-4-cyclopropylthiophene (IV),
Reaction SMILES: [F:1][C:2]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:3]=1[O:4][C:5]1[C:13]2[N:12]=[CH:11][N:10]([CH3:14])[C:9]=2[CH:8]=[CH:7][C:6]=1[C:15]1[C:16]2[CH:24]=[CH:23][N:22]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:17]=2[C:18](=[O:21])[NH:19][CH:20]=1.[CH3:40][C:41](C)([O-])C.[K+].ICC>O1CCCC1>[F:1][C:2]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:3]=1[O:4][C:5]1[C:13]2[N:12]=[CH:11][N:10]([CH3:14])[C:9]=2[CH:8]=[CH:7][C:6]=1[C:15]1[C:16]2[CH:24]=[CH:23][N:22]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:17]=2[C:18](=[O:21])[N:19]([CH2:40][CH3:41])[CH:20]=1
Reactant: CC(C)(C)[O-]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4ccc5c(ncn5C)c4Oc4ccc(F)cc4F)c[nH]c(=O)c32)cc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCn1cc(-c2ccc3c(ncn3C)c2Oc2ccc(F)cc2F)c2ccn(S(=O)(=O)c3ccc(C)cc3)c2c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
A suspension of 4-[4-(2,4-difluorophenoxy)-1-methyl-1H-benzimidazol-5-yl]-1-[(4-methylphenyl)sulfonyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (33.2 mg, 0.0607 mmol) in tetrahydrofuran (1.0 mL) at 0° C. was treated with 1.0 M solution of potassium tert-butoxide in THF (0.0850 mL, 0.0850 mmol) and the resultant reaction mixture was stirred at 0° C. for 30 min, after which time the reaction mixture was treated with iodoethane (0.00680 mL, 0.0850 mmol), warmed to RT and stirred at RT for 19 h. The reaction mixture was quenched with saturated ammonium chloride solution, diluted with water, and extracted with ethyl acetate. Layers were separated and the organic layer was washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo to give a crude residue. Purification via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water 0.1% ammonium hydroxide, at flow rate of 60 mL/min) gave the desired product (15.4 mg, 44%). LCMS calculated for C30H25F2N4O4S (M+H)+: m/z=575.2. found: 575.1.
Reaction SMILES: [CH2:1]=[CH2:2].[CH:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>>[CH:1]([C:3]1[CH:8]=[C:7]([C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH2:2])[CH:6]=[CH:5][CH:4]=1)=[CH2:2]
Reactant: c1ccccc1
Reactant: C=C
Product: C=Cc1cccc(C(=C)c2ccccc2)c1

Procedure:
When benzene is alkylated with ethylene in the presence of an alkylation catalyst, a reaction product containing unreacted benzene, alkylbenzenes, polyalkylbenzenes and heavier products is obtained. The above 1-(3-ethylphenyl)-1-phenylethane of the formula (IV) is recovered as a fraction mainly containing components having boiling points of 285° to 290° C. (as atmospheric pressure) by distillation such as reduced-pressure distillation. The fraction is then dehydrogenated in the presence of a dehydrogenation catalyst, and if necessary, it is followed by distillation, to obtain 1-(3-vinylphenyl)-1-phenylethylene.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[N+:7]([C:10]1[CH:21]=[CH:20][C:13]([CH2:14]C2NC=CN=2)=[CH:12][CH:11]=1)([O-:9])=[O:8]>>[CH3:1][C:2]1[N:3]([CH2:14][C:13]2[CH:20]=[CH:21][C:10]([N+:7]([O-:9])=[O:8])=[CH:11][CH:12]=2)[CH:4]=[CH:5][N:6]=1
Reactant: O=[N+]([O-])c1ccc(Cc2ncc[nH]2)cc1
Reactant: Cc1ncc[nH]1
Product: Cc1nccn1Cc1ccc([N+](=O)[O-])cc1
Yield: 61.7 %

Procedure:
15.2 g of 2-methylimidazole and 40.7 g of 4-nitrobenzylimidazole were subjected to an alkylation reaction to obtain 24.8 g of 2-methyl-1-(4-nitrobenzyl)imidazole.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([CH3:26])[CH:21]=3)[C:16]3[C:11](=[C:12]([F:18])[CH:13]=[C:14]([Cl:17])[CH:15]=3)[C:10]([NH2:19])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[N:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[N:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:17][C:14]1[CH:15]=[C:16]2[C:11]([C:10]([NH2:19])=[N:9][C:8]2([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([CH3:26])[CH:21]=2)[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:31]3[CH:32]=[N:27][CH:28]=[N:29][CH:30]=3)[CH:3]=2)=[C:12]([F:18])[CH:13]=1
Reactant: Cc1cc(C2(c3cccc(Br)c3)N=C(N)c3c(F)cc(Cl)cc32)ccn1
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C2(c3cccc(-c4cncnc4)c3)N=C(N)c3c(F)cc(Cl)cc32)ccn1
Temperature: 90 °C
Reaction time: 2 h
Yield: 31.1 %

Procedure:
1-(3-Bromophenyl)-6-chloro-4-fluoro-1-(2-methylpyridin-4-yl)-1H-isoindol-3-amine (1 g, 2.32 mmol), pyrimidine-5-boronic acid (0.316 g, 2.55 mmol) and [1,1′-bis (diphenylphosphino)ferrocene]palladium(II) chloride (0.096 g, 0.12 mmol) were dissolved in DMF (10 mL) and heated to 90° C. Then aqueous potassium carbonate (3.48 mL, 6.97 mmol) was added and the resulting mixture was stirred at 120° C. for 2 h. When cooled to rt the mixture was diluted with water (50 mL) and extracted with DCM (3×50 mL). The combined organics were washed with water (75 mL), passed through a phase separator, concentrated and purified on a silica gel column eluted with 0-10% 0.1M NH3 in MeOH in DCM to afford 310 mg (31% yield) of the title compound.
Reaction SMILES: [N:1]1([CH2:7][C@@H:8]2[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.CO>[NH:27]([C:28]([N:4]1[CH2:5][CH2:6][N:1]([CH2:7][C@@H:8]2[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)[CH2:2][CH2:3]1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CN2CCNCC2)C1
Reactant: O=C=Nc1ccccc1
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H](CN2CCN(C(=O)Nc3ccccc3)CC2)C1
Yield: 80.5 %

Procedure:
tert-Butyl (3S)-3-(piperazin-1-ylmethyl)piperidine-1-carboxylate (3.5 g) and phenyl isocyanate (1.62 g) were stirred in toluene (50 ml) at room temperature for 20 h. The solvent was then concentrated in-vacuo to afford a white solid. The solid was dissolved in methanol and passed through an SCX2 column. The SCX2 column was then flushed with 5% ammonia in methanol solution. The solution was collected and the solvent removed under reduced pressure. The resultant solid was re-crystallised from EtOAc and isoHexane, to afford the desired product as a white solid (4 g).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[CH3:13][CH:14]1[CH2:16][O:15]1.O>O1CCCC1.CCOCC>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH:14]([OH:15])[CH3:16])[CH:8]=[CH:7]2
Reactant: CC1CO1
Reactant: Clc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)Cn1ccc2cc(Cl)ccc21
Reaction time: 1 h
Yield: 87 %

Procedure:
A suspension of 0.4 g of sodium hydride dispersion in 60 ml of tetrahydrofuran was treated with 1.74 g of 5-chloroindole at 0° and stirred at this temperature for 1 hour. After the addition of 1.6 ml of (RS)-methyloxirane the reaction mixture was stirred at room temperature for 48 hours and subsequently treated with 11 ml of water. The mixture was diluted with 300 ml of ether, washed with 140 ml of water and with 70 ml of saturated sodium chloride solution and the organic phase was dried over sodium sulfate. After removal of the solvent the residue was chromatographed over 60 g of silica gel with toluene-ethyl acetate (19:1). There were obtained 2.1 g (87%) of (RS)-1-(5-chloro-indol-1-yl)-propan-2-ol as a yellow oil.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([P:18]([NH:23][CH2:24][CH3:25])([NH:20][CH2:21][CH3:22])=[O:19])[C:13]1=[O:26])=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([P:18]([NH:23][CH2:24][CH3:25])([NH:20][CH2:21][CH3:22])=[O:19])[C:13]1=[O:26]
Reactant: CCNP(=O)(NCC)N1CCC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CO
Product: CCNP(=O)(NCC)N1CCC[C@H](N)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Palladium black (60 mg) was added to a solution of (3S)-3-benzyloxycarbonylamino-1-bis(ethylamino)phosphinyl-2-piperidone (600.3 mg, 1.5698 mmol) in methanol (6 mL), and the resulting mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C@H:11]1[CH2:15][CH2:14][C@@H:13]([CH3:16])[O:12]1)[CH2:9][CH3:10])(C)(C)C.C(O)(C(F)(F)F)=O.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31]([OH:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1>C(Cl)Cl.CCOC(C)=O>[C:25]1([CH3:35])[CH:26]=[CH:27][C:28]([S:31]([OH:34])(=[O:32])=[O:33])=[CH:29][CH:30]=1.[CH3:16][C@H:13]1[O:12][C@@H:11]([C@H:8]([NH2:7])[CH2:9][CH3:10])[CH2:15][CH2:14]1
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)[C@H]1CC[C@@H](C)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC[C@@H](N)[C@H]1CC[C@@H](C)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To an ice-cooled solution of [(R)-1-(2R,5R)-(5-methyl-tetrahydro-furan-2-yl)-propyl]-carbamic acid tert-butyl ester (416 mg, 1.71 mmol) in dry DCM (4 ml) was added TFA (200 μl, 1.41 mmol) under an inert atmosphere of nitrogen. After stirring at room temperature for 3 h, the mixture was diluted with EtOAc (15 ml) and washed with saturated aqueous Na2CO3. The organic portion was dried (Na2SO4) and then para-toluenesulfonic acid (147 mg, 0.77 mmol) was added. After stirring, the solvent was removed in vacuo and recrystallisation from MeCN affords the title compound as a white solid. 1H NMR (DMSO) 0.90 (3H, t, CH3), 1.20 (3H, d, CH3), 1.45 (2H, m, 2×CH), 1.59 (1H, m, CH), 1.65 (1H, m, CH), 1.95 (2H, m, CH2), 2.30 (3H, s, CH3), 2.93 (1H, m, CH), 3.75 (1H, dd, CH), 3.95 (1H, m, CH), 7.10 (2H, d, 2×CH), 7.48 (2H, d, 2×CH), 7.75 (3H, s, NH3+).
Reaction SMILES: C([Li])CCC.[CH3:6][Si:7]([CH3:14])([CH3:13])[C:8]1[S:12][CH:11]=[N:10][CH:9]=1.[CH:15](N1CCOCC1)=[O:16].Cl>C1COCC1>[CH3:6][Si:7]([CH3:14])([CH3:13])[C:8]1[S:12][C:11]([CH:15]=[O:16])=[N:10][CH:9]=1
Reactant: O=CN1CCOCC1
Reactant: C[Si](C)(C)c1cncs1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cnc(C=O)s1
Temperature: 25 °C

Procedure:
n-Butyllithium (1.50M in hexane, 39 mmol, 22 ml) was added dropwise at -78° C. to a solution of 5-(trimethylsilyl)thiazole (A. Dondoni et al, J. Org. Chem, 1988, 53, 1748) (5.2 g, 33 mmol) in THF (40 ml). After 30 min. a solution of N-formylmorpholine (4.57 g) in THF (40 ml) was added dropwise over 15 min. The resulting red solution was stirred a further 30 mi. and then allowed to warm to room temperature , dilute d with 4N hydrochloric acid and extracted three times with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride, dried over sodium sulphate and evaporated to leave a brown oil (5.5 g). M+ 185; 360 MHz 1H n.m.r (CDCl3) 9.89 (1H, s), 7.95 (1H, s), 0.24 (9H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2([CH3:16])[NH:14][C:13](=S)[CH2:12][O:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH3:17].C(OO)(C)(C)C>CO.O>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2([CH3:16])[CH2:10][O:11][CH2:12][C:13]([NH2:17])=[N:14]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC1(c2ccc(F)c(Br)c2)COCC(=S)N1
Reactant: N
Agent: CC(C)(C)OO
Solvent: O
Solvent: CO
Product: CC1(c2ccc(F)c(Br)c2)COCC(N)=N1
Reaction time: 8 h

Procedure:
A solution of (RS)-5-(3-bromo-4-fluoro-phenyl)-5-methyl-morpholin-3-thione (intermediate XVIII-1) (202 mg, 0.7 mmol) in methanol (15 ml) was treated with a solution of ammonia in methanol (7M, 5.7 ml, 39.8 mmol) and an aqueous solution of tert-butyl hydroperoxide (70% in water, 0.91 ml, 6.6 mmol). After stiffing at room temperature overnight, the reaction mixture was diluted with water and extracted three times with dichloromethane. The combined organic layers were washed with water, then dried over sodium sulphate and evaporated. The crude product was purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100/0 to 0/100 as the eluent. The (RS)-5-(3-bromo-4-fluoro-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine was obtained as a colorless gum (109 mg, 57% of theory). MS (ISP): m/z=287.2 [M+H]+, 289.1 [M+2+H]+.