Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:18]=[CH:17][O:16][CH:15]=1.[NH:19]1[C:27](=[O:28])[C:25](=O)[C:23](=[O:24])[NH:22][C:20]1=[O:21]>O1CCCC1>[Cl:13][C:14]1[CH:18]=[CH:17][O:16][C:15]=1[CH:25]1[C:23](=[O:24])[NH:22][C:20](=[O:21])[NH:19][C:27]1=[O:28]
Reactant: Clc1ccoc1
Reactant: O=C1NC(=O)C(=O)C(=O)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C1NC(=O)C(c2occc2Cl)C(=O)N1
Temperature: 25 °C

Procedure:
n-Butyl lithium and an equivalent of diisopropylamine are reacted with an equivalent of 3-chlorofuran for 1.5 hours in tetrahydrofuran at -80° C. according to the procedure of Ly and Schlosser [Helv. Chim. Acta 60 (6), p. 2087 (1977)]. At the same temperature, an equivalent of alloxan in tetrahydrofuran is added dropwise and the mixture allowed to warm to room temperature for 2 hours. 5-(3-Chloro-2-furyl)-2,4,6-(1H,3H,5H)pyrimidinetrione is isolated by the procedure of Example 5.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].COC.[CH3:10][CH:11]1[O:16][CH:15]([CH3:17])[CH2:14][N:13]([CH2:18][C:19](OCC)=[O:20])[CH2:12]1>>[OH:20][CH2:19][CH2:18][N:13]1[CH2:14][CH:15]([CH3:17])[O:16][CH:11]([CH3:10])[CH2:12]1
Reactant: CCOC(=O)CN1CC(C)OC(C)C1
Agent: COC
Agent: [Al+3]
Agent: [H-]
Product: CC1CN(CCO)CC(C)O1
Temperature: 0 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
To a flask was added 22.8 g. (0.6 mole) of lithium aluminum hydride in 300 ml. of dimethyl ether. The stirred slurry was cooled to 0° C. and then 26.5 g. (0.15 mole) of ethyl 2,6-dimethyl-4-morpholinylacetate was slowly added. The reaction was allowed to warm to room temperature and stirred for 18 hours. It was then quenched with aqueous ammonium chloride, filtered, and extracted with diethyl ether. The solvent was concentrated to give 15.5 g. (67% yield) of the desired intermediate.
Reaction SMILES: IC1C=CN(C)C(=O)C=1.OC(C)(C)C[C@@:13]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:18][C:17](=[O:19])[N:16]([C@H](C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)C)[CH2:15][CH2:14]1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:37]1([CH:13]2[O:18][C:17](=[O:19])[NH:16][CH2:15][CH2:14]2)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cn1ccc(I)cc1=O
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=C1NCCC(c2ccccc2)O1
Yield: 71.9 %

Procedure:
A mixture of 4-iodo-1-methylpyridin-2(1H)-one (0.909 g, 3.76 mmol), (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan -2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (1.5 g, 3.13 mmol), 2 M aq Cs2CO3 (3 mL, 6 mmol), and PdCl2(PPh3)2 (0.201 g, 0.282 mmol) in 1,4-dioxane (15 mL) was refluxed under N2 for 2 hours. The reaction mixture was filtered, and the filtrate was extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated to obtain the crude compound, which was purified by preparative HPLC and chiral HPLC to obtain (S)-6-(2-hydroxy-2-methylpropyl)-3-(S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (399 mg, 28%). LC-MS and 1H NMR (CD3OD) were the same as those of product made by Method 1. The compound was recrystallized using below methods.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.[F:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][CH2:27]Br)=[CH:24][CH:23]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:27][CH2:26][C:25]4[CH:29]=[CH:30][C:22]([F:21])=[CH:23][CH:24]=4)[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: Fc1ccc(CCBr)cc1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(CCc3ccc(F)cc3)C2=O)cn1
Yield: 34 %

Procedure:
Prepared as in example 10-52 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 4-fluorophenethyl bromide. Yield: 34%. MS M+H calculated 398.16. Found 398.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.01 μM.
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1.Cl[C:15]1[N:23]2[CH:24]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[CH2:25][O:26][C:21]3=[C:22]2[C:17](=[C:18]([F:40])[CH:19]=[C:20]3[C:33]2[C:34]([CH3:39])=[N:35][O:36][C:37]=2[CH3:38])[N:16]=1>CN1CCCC1=O.CO>[CH3:39][C:34]1[C:33]([C:20]2[C:21]3[O:26][CH2:25][CH:24]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[N:23]4[C:15]([N:8]5[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]5)=[N:16][C:17]([C:22]=34)=[C:18]([F:40])[CH:19]=2)=[C:37]([CH3:38])[O:36][N:35]=1
Reactant: OC1CCNC1
Reactant: Cc1noc(C)c1-c1cc(F)c2nc(Cl)n3c2c1OCC3c1cccnc1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Solvent: CO
Product: Cc1noc(C)c1-c1cc(F)c2nc(N3CCC(O)C3)n3c2c1OCC3c1cccnc1
Temperature: 150 °C
Yield: 13.8 %

Procedure:
Triethylamine (16 μL, 0.12 mmol) and 3-pyrrolidinol (0.2 mL, 3 mmol) were added to 2-chloro-7-(3,5-dimethylisoxazol-4-yl)-9-fluoro-4-pyridin-3-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine (15 mg, 0.040 mmol) in N-methylpyrrolidinone (0.41 mL) and the mixture was heated in a microwave at 150° C. for 20 min. The mixture was diluted with methanol and purified by preparative LCMS using pH 10 buffer to afford the title compound (2.4 mg, 14%). LCMS calc. for C23H23FN5O3 (M+H)+: m/z=436.2. found: 436.1.
Reaction SMILES: [F:1][C:2]1([F:11])[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:35]([C:39]1[O:43][N:42]=[C:41]([NH:44][C:45]([C@@H:47]2[CH2:50][CH2:49][NH:48]2)=[O:46])[CH:40]=1)([CH3:38])([CH3:37])[CH3:36].Cl.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[C:35]([C:39]1[O:43][N:42]=[C:41]([NH:44][C:45]([C@@H:47]2[CH2:50][CH2:49][N:48]2[C:8]([CH:5]2[CH2:4][CH2:3][C:2]([F:1])([F:11])[CH2:7][CH2:6]2)=[O:10])=[O:46])[CH:40]=1)([CH3:38])([CH3:36])[CH3:37]
Reactant: O=C(O)C1CCC(F)(F)CC1
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2CCN2)no1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCN2C(=O)C2CCC(F)(F)CC2)no1
Reaction time: 0.33 h

Procedure:
To a solution of 4,4-difluorocyclohexanecarboxylic acid (74.5 mg; 0.454 mmol) and 1-hydroxybenzotriazole hydrate (102 mg; 0.756 mmol) in DMF (1.5 mL) is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (145 mg; 0.756 mmol). After 20 minutes of stirring, (S)-Azetidine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide; hydrochloride (150 mg; 0.378 mmol) is added, followed by diisopropylethylamine (0.066 mL; 0.378 mmol) and 4-diemthylaminopyridine (3 mg; 0.025 mmol). The reaction mixture is stirred at room temperature for 1 hour. After this time, the reaction mixture is diluted with ethyl acetate and washed with water, saturated sodium bicarbonate aqueous solution and saturated ammonium chloride aqueous solution then brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography on silica gel using methanol/methylene chloride provides the title compound, m/z 370 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].O=[C:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CC(O)=O.CCOC(C)=O>[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:2]([NH:1][CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[C:3]([C:4]([O:6][CH3:7])=[O:5])[CH:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COC(=O)c1cc(OCc2ccccc2)ccc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(OCc2ccccc2)ccc1NC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 297.9 %

Procedure:
A mixture of 2 g of methyl 2-amino-5-(benzyloxy)benzoate, 3.1 g of 1,1-dimethylethyl 4-oxopiperidine-1-carboxylate and 3.29 g of NaBH(OAc)3 in 10 ml of AcOH is irradiated under a microwave field (Biotage Initiator Sixty) at 110° C. for 20 min. The same reaction is repeated with two other lots of 2 g of methyl 2-amino-5-(benzyloxy)benzoate. The three reaction media are combined. The combined product is taken up in AcOEt. The organic phase is washed with water, with a saturated NH4Cl solution and with a saturated NaHCO3 solution, dried over Na2SO4 and filtered, and the solvent is evaporated under reduced pressure. The residue is chromatographed on silica gel, elution being carried out with an AcOEt/heptane mixture, (5/95, v/v) as far as (30/70, v/v), to give 10.2 g of the expected product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](/[CH:8]=[CH:9]/[N:10](C)[CH3:11])[C:5]2[C:13]([I:35])=[N:14][N:15]([C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:4]=2[CH:3]=1.Cl.[CH2:37](N)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CCO.CC(O)=O.ClCCCl>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][NH:10][CH2:11][CH3:37])[C:5]2[C:13]([I:35])=[N:14][N:15]([C:16]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:4]=2[CH:3]=1
Reactant: CN(C)/C=C/c1nc(Cl)cc2c1c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCO
Solvent: CC(=O)O
Product: CCNCCc1nc(Cl)cc2c1c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
(E)-2-(6-chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)-N,N-dimethylethenamine (1.0 g, 1.692 mmol) and ethanamine HCl (0.552 g, 6.77 mmol) were stirred in a 3:1:1 solution of DCE:AcOH:EtOH (5 ml) at 100° C. for 2 hrs. Solvent was removed by vacuum and the residue was taken in DCE (15 ml) and treated with sodium triacetoxyborohydride (0.9 g, 4.23 mmol), acetic acid (0.4 g, 6.7 mmol) and stirred at room temperature for 6 hours. The eaction mixture was partitioned between DCM and aqueous sodium bicarbonate and the organics was separated, washed with brine, dried with sodium sulfate and concentrated. Purification of the residue by flash column (0-15% MeOH-DCM) gave 2-(6-chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)-N-ethylethanamine. MS ESI calc'd. for C29H26ClIN4 [M+H]+ 593. found 593.
Reaction SMILES: [S:1]([C:5]1[S:13][C:8]2[CH2:9][NH:10][CH2:11][CH2:12][C:7]=2[CH:6]=1)(=[O:4])(=[O:3])[NH2:2].[CH2:14]1[O:16][CH2:15]1>CO.C(#N)C>[S:1]([C:5]1[S:13][C:8]2[CH2:9][N:10]([CH2:14][CH2:15][OH:16])[CH2:11][CH2:12][C:7]=2[CH:6]=1)(=[O:3])(=[O:4])[NH2:2]
Reactant: NS(=O)(=O)c1cc2c(s1)CNCC2
Reactant: C1CO1
Solvent: CC#N
Solvent: CO
Product: NS(=O)(=O)c1cc2c(s1)CN(CCO)CC2
Reaction time: 18 h
Yield: 80 %

Procedure:
Into a solution of 2-sulfamoyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (1.74 g, 8.0 mmol) in methanol (25 ml) and acetonitrile (50 ml) was bubbled ethylene oxide gas for 10 minutes. The reaction vessel was stoppered and the mixture was stirred for 18 hours. The precipitated product was collected by filtration. The filtrates were concentrated to provide additional product (total weight, 2.02 g). This material was crystallized from acetonitrile to give 1.67 g (80% yield) of pure product; m.p. 184°-186° C.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:16]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:17][CH2:18][C:19]([CH3:21])=O.C(=O)(O)[O-].[Na+]>O.C1(C)C=CC=CC=1>[CH2:1]1[O:4][C:19]([CH3:21])([CH2:18][CH2:17][C:16]([O:23][CH2:24][CH3:25])=[O:22])[O:3][CH2:2]1
Reactant: CCOC(=O)CCC(C)=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)CCC1(C)OCCO1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of about 110.86 g of ethylene glycol, about 2 g of p-toluenesulfonic acid and about 800 ml of toluene was refluxed using a Dean-Stark trap until no more water came off. An about 250 g portion of ethyl levulinate was added and refluxing was continued until no more water came off. The mixture was then cooled to room temperature, poured into saturated sodium bicarbonate, the organic layer dried and the solvent removed. The residue was distilled (about 67°-70° C., 0.35 mm) and the distillate stirred for about 20 minutes with about 6 g of sodium borohydride in ethanol. The solvent was removed, the residue dissolved in ether, washed with saturated sodium bicarbonate, dried and then distilled (about 41°-45° C., 0.3 mm), giving about 83 g of the desired title compound.
Reaction SMILES: [CH2:1]([O:8][N:9]1[CH2:15][CH:14]=[CH:13][CH2:12][C@@H:11]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:10]1=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl.Cl[CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1.C(OCC)(=O)C>CS(C)=O>[CH2:1]([O:8][N:9]1[CH2:15][CH:14]=[CH:13][CH2:12][C@@H:11]([N:16]([CH2:43][CH2:44][N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)[S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=3)=[CH:22][CH:21]=2)(=[O:18])=[O:19])[C:10]1=[O:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCN1CCOCC1
Reactant: O=C1[C@H](NS(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CC=CCN1OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C1[C@H](N(CCN2CCOCC2)S(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CC=CCN1OCc1ccccc1
Temperature: 50 °C
Yield: 79.9 %

Procedure:
To a solution of 1.51 g of N-(1-benzyloxy-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-(R)-yl)-4-(4-chloro-phenoxy)-benzenesulfonamide from Example 1 Step E in 20 mL of methylsulfoxide (DMSO) was added 2.9 g of Cs2CO3(s) and 1.2 g of 4-(2-chloroethyl)-morpholine hydrochloride. The mixture was heated to 50° C. for 1 hour. The reaction was cooled, and then dissolved with ethyl acetate. The organic layer was washed with NH4Cl(aq) and NaCl(aq) solutions. The aqueous layers were re-extracted with ethyl acetate, and the organic layers were combined and dried over Na2SO4(s). Filtration and solvent removal was followed by column chromatography on silica gel using a hexanes-ethyl acetate gradient. Obtained 1.48 g of a pale brown oil (80% yield). MS: 612 (M+H).
Reaction SMILES: O.O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-].[C:12]([O:15][CH2:16][C@@H:17]1[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:21]([O:27][C:28](=[O:30])[CH3:29])[C@@H:20]([O:31][C:32](=[O:34])[CH3:33])[C@H:19]([N:35]2[C:43]3[C:38](=[C:39]([CH3:44])[CH:40]=[CH:41][CH:42]=3)[C:37]([C:45](=[O:60])[C:46]3[CH:51]=[CH:50][C:49]([O:52][CH2:53][C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)=[CH:48][CH:47]=3)=[CH:36]2)[O:18]1)(=[O:14])[CH3:13].[BH4-].[Na+].Cl>C(O)C.O.CC(OC)(C)C.O1CCCC1>[C:12]([O:15][CH2:16][C@@H:17]1[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:21]([O:27][C:28](=[O:30])[CH3:29])[C@@H:20]([O:31][C:32](=[O:34])[CH3:33])[C@H:19]([N:35]2[C:43]3[C:38](=[C:39]([CH3:44])[CH:40]=[CH:41][CH:42]=3)[C:37]([CH:45]([C:46]3[CH:47]=[CH:48][C:49]([O:52][CH2:53][C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)=[CH:50][CH:51]=3)[OH:60])=[CH:36]2)[O:18]1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C(=O)c3ccc(OCc4ccccc4)cc3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Agent: [BH4-]
Agent: [Ce+3]
Solvent: CCO
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C(O)c3ccc(OCc4ccccc4)cc3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 100 %

Procedure:
To a temperature controlled stirred reactor charge cerium (III) chloride heptahydrate (4.55 moles; 1.12 kg) in ethanol (4.96 L) and stir to give a solution. Add [(2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-[3-(4-benzyloxybenzoyl)-4-methyl-indol-1-yl]tetrahydropyran-2-yl]methyl acetate (1.52 moles; 1.38 kg) and tetrahydrofuran (7.57 L). Cool the mixture to +2° C. and add sodium tetrahydroborate (4.55 moles; 172.18 g) in portions over 3 hours maintaining the internal temperature between 0 and +5° C. during addition. When the addition is complete, stir the mixture at 5° C. for 1 hour. Add further sodium tetrahydroborate (687.24 mmoles; 26.00 g) and stir the mixture for 30 minutes. Add additional sodium tetrahydroborate (0.45 equiv; 687.24 mmoles; 26.00 g) and stir the mixture overnight. Pour the mixture into MTBE (5 L) and water (10 L). Slowly add hydrochloric acid (2 N) with stirring until mixture is slightly acidic to pH paper. Separate the organic layer, wash with brine, dry over MgSO4, filter, and concentrate under reduced pressure to afford the title compound in acceptable purity for use in the next step (1547 g; assumed 66% purity and 100% yield for the purposes of calculation in the next reaction) mass spectrum (m/z): 656.4 (M+1-18).
Reaction SMILES: [C:1]1(=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl.[CH2:16]([N:18]([CH2:21][CH2:22][CH2:23][O:24][NH2:25])[CH2:19][CH3:20])[CH3:17].C(O)(=O)/C=C/C([O-])=O>>[CH2:16]([N:18]([CH2:21][CH2:22][CH2:23][O:24][N:25]=[C:1]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:19][CH3:20])[CH3:17]
Reactant: O=C1CCCCCCCCCCC1
Reactant: CCN(CC)CCCON
Agent: Cl
Agent: O=C([O-])/C=C/C(=O)O
Product: CCN(CC)CCCON=C1CCCCCCCCCCC1

Procedure:
Starting from 18.23 g. (0.1 moles) of cyclododecanone and 24.1 g. (0.1 moles) of diethylaminopropoxyamine dihydrochloride, the title compound is prepared as in Example 13. Yield: 25.7 g. (82.77%). Hydrogen fumarate, m.p.: 97°-98° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([CH:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[O:22][CH:23]([CH3:25])[CH3:24])=[N:6][CH:7]=1.Br[CH2:40][CH2:41][OH:42]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([CH:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])=[N:4][C:5]([NH:8][C:9]2[C:10]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:11][C:12]([CH:16]3[CH2:21][CH2:20][N:19]([CH2:40][CH2:41][OH:42])[CH2:18][CH2:17]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n2)c(OC(C)C)cc1C1CCNCC1
Reactant: OCCBr
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(Nc2ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n2)c(OC(C)C)cc1C1CCN(CCO)CC1
Temperature: 70 °C

Procedure:
5-Chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine (Example 7, 0.087 mmol) is dissolved in anhydrous DMF (1 mL). TEA (0.04 mL, 0.262 mmol, 3 equiv.) is added followed by 2-bromo-ethanol (0.019 mL, 0.262 mmol, 3 equiv.) dissolved in anhydrous DMF (0.7 mL). The reaction vessel is sealed and heated at 70° C. for 12 h. After cooling to room temperature, the reaction is diluted with ethyl acetate and washed with 1 N aqueous NaOH (5×), the organic layer is then dried over Na2SO4 and filtered. After concentration, the crude product is purified using preparative RP LC-MS to give 2-[4-(4-{5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-5-isopropoxy-2-methyl-phenyl)-piperidin-1-yl]ethanol (72) as a yellow powder:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]Cl)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:13]([S:15]([CH:18]=[CH2:19])(=[O:17])=[O:16])=[CH2:14].C(N(CC)CC)C>C1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH:14]=[CH:13][S:15]([CH:18]=[CH2:19])(=[O:17])=[O:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(SCl)cc1
Reactant: C=CS(=O)(=O)C=C
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)C=CSc1ccc(C(C)(C)C)cc1

Procedure:
In a manner analogous to Example 1, 4-t-butylphenylsulfenyl chloride was added in 1:1 proportion to divinyl sulfone, subjected to treatment with triethylamine in benzene, and purified by column chromatography. The product, vinyl 2-(4-t-butylphenylthio)vinyl sulfone, was obtained as a brown oil which crystallized on standing, m.p. 62°-64° C; calculated for C14H18O2S2 :S, 22.7; found: S, 22.0; Cl, 0.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=2)[C:6]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[C:25][Si](C)(C)C)=[CH:20][CH:19]=2)=[CH:5]1)([CH3:3])[CH3:2].C(N1C2C(=CC=C(NS(C)(=O)=O)C=2)C(C2C=CC(C#C[Si](C)(C)C)=CN=2)=C1)(C)C.C(=O)([O-])[O-].[K+].[K+].Cl>[Cl-].[Na+].O.O.CO.ClCCl>[C:24]([C:21]1[CH:20]=[CH:19][C:18]([C:6]2[C:7]3[C:12](=[CH:11][C:10]([NH:13][S:14]([CH3:17])(=[O:15])=[O:16])=[CH:9][CH:8]=3)[N:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=2)=[CH:23][CH:22]=1)#[CH:25]
Reactant: CC(C)n1cc(-c2ccc(C#C[Si](C)(C)C)cc2)c2ccc(NS(C)(=O)=O)cc21
Agent: CC(C)n1cc(-c2ccc(C#C[Si](C)(C)C)cn2)c2ccc(NS(C)(=O)=O)cc21
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: C#Cc1ccc(-c2cn(C(C)C)c3cc(NS(C)(=O)=O)ccc23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Add N-[1-isopropyl-3-(4-trimethylsilanylethynyl-phenyl)-1H-indol-6-yl]-methanesulfonamide (0.223 mmoles; 95.0 mg, prepared similarly to N-[1-isopropyl-3-(5-trimethylsilanylethynyl-pyridin-2-yl)-1H-indol-6-yl]-methanesulfonamide), dichloromethane (4.0 mL), methanol (4.0 mL); followed by Potassium Carbonate (1.119 mmoles; 154.6 mg) to a round bottom flask equipped with a stir bar. Stir the resulting material for 2 hours at room temperature. Dilute the reaction with water and acidify to pH of 6-7 with 1N HCl. Dilute the resulting aqueous mixture with brine and extract with dichloromethane. Concentrated the resulting mixture in vacuo and then purify the resulting material on a chromatotron (2MM silica gel plate; load CH2Cl2; run 30%-50% ethyl acetate gradient in hexanes) to obtain the desired product as a light-yellow crystalline solid, 50 mg (63%). MS (IS+) m/e 353.0 (M+1)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11](=[O:12])[C:10]2([CH2:17][CH2:16][N:15]([CH2:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)[N:9]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:8]1.C(N(C(C)C)CC)(C)C.[N+]([O-])(O)=O.CC1C=C(C)[N:51]([C:55](N)=[NH:56])N=1>CN(C)C=O.O>[C:19]1([CH2:18][N:15]2[CH2:14][CH2:13][C:10]3([N:9]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:8][N:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:55]([NH2:56])=[NH:51])[C:11]3=[O:12])[CH2:17][CH2:16]2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: Cc1cc(C)n(C(=N)N)n1
Reactant: NCCCCCN1CN(c2ccccc2)C2(CCN(Cc3cccc4ccccc34)CC2)C1=O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N=C(N)NCCCCCN1CN(c2ccccc2)C2(CCN(Cc3cccc4ccccc34)CC2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.2 %

Procedure:
3-(5-Aminopentyl)-8-naphthalen-1-ylmethyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one, di-trifluoroacetate (0.137 g, 0.2 mmol) prepared as described in Example 13, was dissolved in dimethylformamide (1 ml) and diisopropylethylamine (0.233 g, 1.8 mmol) and 3,5-dimethylpyrazol-1-carboxamidine nitrate (0.060 g, 0.3 mmol) was added. The mixture was stirred at room temperature for 1 h and the addition of an equal amount 3,5-dimethylpyrazol-1 carboxamidine nitrate was repeated. After stirring for 16 h the mixture was diluted with water (10 ml) and extracted with ether (5×10 ml). The aqueous phase and undissolved syrup were extracted with dichloromethane (10 ml), the dichloromethane solution was washed with water (5×10 ml), dried over MgSO4 and concentrated in vacuo, affording the title compound (0.047 g, 5.2%) as an amorphous powder.