Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[CH:10][C:3]=12.[CH:11](OCC)([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]>>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCOC(OCC)OCC
Reactant: Clc1nc[nH]c2nccc1-2
Product: CCOC(OCC)n1ccc2c(Cl)ncnc21
Reaction time: 63 h
Yield: 94 %

Procedure:
To a 1 liter round bottom flask equipped with a stir bar, condenser and nitrogen inlet was charged 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 31.0 g, 0.202 mol) and triethyl orthoformate (330 ml, 2.00 mol, 10.0 equiv). The reaction mixture was warmed to reflux to generate a clear solution. The reaction was checked after 63 hours by HPLC. When the reaction was deemed complete, the reaction mixture was concentrated under reduced pressure. The residue was purified by a silica gel flash column chromatography eluted with a 20% to 25% ethyl acetate/hexane (v/v) gradient (TLC conditions: 30% ethyl acetate/hexane) to afford 4-chloro-7-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (3b, 48.56 g, 51.65 g theoretical, 94% yield) as a light yellow oil. For 3b: 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.68 (s, 1H), 7.79 (d, 1H, J=3.8 Hz), 6.75 (s, 1H), 6.72 (d, 1H, J=3.8 Hz), 3.68 (dd, 2H, J=9.4, 7.2 Hz), 3.54 (dd, 2H, J=9.4, 7.2 Hz), 1.11 (t, 6H, J=7.2 Hz); C1H14ClN3O2 (MW, 255.70), LCMS (EI) m/e 182/184 (M++H for corresponding 7-formylation product of 1) and 154/156 (M++H for 1).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16](=[O:32])[N:17]([CH2:19][C@H:20]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=1)[CH2:21][CH2:22][OH:23])[CH3:18])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[C:11]([O:15][C:16](=[O:32])[N:17]([CH2:19][C@H:20]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=1)[CH2:21][CH:22]=[O:23])[CH3:18])([CH3:14])([CH3:12])[CH3:13]
Reactant: CN(C[C@@H](CCO)c1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C[C@@H](CC=O)c1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of oxalyl chloride (2.84 mL) in dichloromethane (70 mL) at −78° C. was added dimethylsulfoxide (4.6 mL) in dichloromethane (35 mL). This mixture was stirred for about 7 minutes at −78° C. before (S)-[2-(3,4-dichloro-phenyl)-4-hydroxy-butyl]-methyl-carbamic acid tert-butyl ester (9.1 g) was added as a solution in dichloromethane (25 mL). This mixture was stirred at −78° C. for 30 minutes before triethylamine (18.1 mL) was added neat. The mixture was then stirred for 30 minutes at −78° C., 45 minutes at 0° C., then warmed to ambient temperature. The solution was diluted with dichloromethane, washed with dilute hydrochloric acid, aqueous sodium bicarbonate, dried and evaporated. MS: m/z=346(M+1). The product was used with no further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[CH3:27][C:28]([CH3:33])([CH3:32])[C:29](Cl)=[O:30]>>[CH3:27][C:28]([CH3:33])([CH3:32])[C:29]([NH:23][C:22]1[CH:24]=[CH:25][CH:26]=[C:20]([CH2:19][CH2:18][N:15]2[CH2:14][CH2:13][N:12]([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]4[C:9]=3[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]4)[CH2:17][CH2:16]2)[CH:21]=1)=[O:30]
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Reactant: CC(C)(C)C(=O)Cl
Product: Cc1ccc2c(N3CCN(CCc4cccc(NC(=O)C(C)(C)C)c4)CC3)cccc2n1
Yield: 66 %

Procedure:
The title compound was prepared in 66% yield according to the general procedure for the preparation of the amides (Method B) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and 2,2-dimethylpropanoyl chloride.
Reaction SMILES: Br[C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[CH2:8][O:7][C:6]=2[N:13]=1.CC1(C)C(C)(C)OB([C:28]2[CH:42]=[CH:41][C:31]([CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:30][CH:29]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.[Cl-].[Na+].O>[CH3:11][N:10]1[C:9](=[O:12])[CH2:8][O:7][C:6]2[N:13]=[C:2]([C:28]3[CH:42]=[CH:41][C:31]([CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[CH:30][CH:29]=3)[C:3]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:4][C:5]1=2
Reactant: CC(C)(C)OC(=O)NCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CN1C(=O)COc2nc(Br)c(-c3ccccc3)cc21
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CN1C(=O)COc2nc(-c3ccc(CNC(=O)OC(C)(C)C)cc3)c(-c3ccccc3)cc21
Temperature: 80 °C
Yield: 71.8 %

Procedure:
In a 15 mL reaction tube was added 6-bromo-1-methyl-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (40 mg, 0.125 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (50 mg, 0.150 mmol) in 1,4-dioxane (2 ml), followed by a solution of sodium carbonate (40 mg, 0.3 mmol) in water (0.5 ml) to give a white suspension. This was degassed by bubbling nitrogen for 10 minutes, followed by the addition of [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (9 mg, 0.013 mmol). The reaction mixture was heated to 80° C. overnight. The reaction mixture was allowed to cool to room temperature, diluted with brine (4 ml) and extracted into ethyl acetate (3×4 ml). The combined organic phases were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The residue was purified by Biotage chromatography (cyclohexane:ethyl acetate, gradient elution from 90:10 to 20:80) to give the desired product as a white solid (40 mg, 72% yield). 1H-NMR (500 MHz, CDCl3) δ 7.27-7.32 (5H, m), 7.25 (1H, s), 7.16-7.20 (2H, m), 7.10 (2H, d), 4.89 (2H, s), 4.81 (1H, br s), 4.26 (2H, br s), 3.39 (3H, s), 1.23 (9H, br s). LCMS (Method D): RT=1.40 min, M+H+=446.20.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([N:44]3[C:48]([CH3:49])=[N:47][N:46]=[N:45]3)=[C:40]([F:50])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:51][C:52]1[S:53][CH:54]=[CH:55][N:56]=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([N:44]3[C:48]([CH3:49])=[N:47][N:46]=[N:45]3)=[C:40]([F:50])[CH:39]=2)[C:35]([NH:51][C:52]2[S:53][CH:54]=[CH:55][N:56]=2)=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Cc1nnnn1-c1ccc(C(CC2CCCC2)C(=O)O)cc1F
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nnnn1-c1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.3 %

Procedure:
A solution of triphenylphosphine (288 mg, 1.1 mmol) in methylene chloride (6 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (196 mg, 1.1 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with 3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-propionic acid (175 mg, 0.55 mmol). The clear solution was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-aminothiazole (275 mg, 2.75 mmol), and the resulting suspension was stirred for 2 d at 25° C. The reaction mixture was then concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (50 mL) and a 1N aqueous hydrochloric acid solution (25 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×25 mL). The combined organic extracts were successively washed with a 1N aqueous hydrochloric acid solution (1×50 mL), a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 2/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-N-thiazol-2-yl-propionamide (80 mg, 36%) as an amorphous white solid: EI-HRMS m/e calcd for C19H21FN6OS (M+) 400.1482, found 400.1476.
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:16])([F:15])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][NH2:14])[CH:8]=1.[C:17]([NH:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][N:29]=1)[C:24](O)=[O:25])(=[O:19])[CH3:18].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O>[C:17]([NH:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][N:29]=1)[C:24]([NH:14][CH2:13][C:9]1[CH:8]=[C:7]([O:6][CH2:5][C:4]([F:3])([F:15])[F:16])[CH:12]=[CH:11][N:10]=1)=[O:25])(=[O:19])[CH3:18]
Reactant: CC(=O)Nc1cc(C(=O)O)ccn1
Reactant: NCc1cc(OCC(F)(F)F)ccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(C(=O)NCc2cc(OCC(F)(F)F)ccn2)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
To a mixture of (4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanamine dihydrochloride (20 mg, 0.070 mmol, Amine-2), 2-acetamidoisonicotinic acid (15 mg, 0.084 mmol) and N,N-diisopropylethylamine (0.049 mL, 0.28 mmol) in N,N-dimethylformamide (0.5 mL) is added a solution of HBTU (40 mg, 0.11 mmol) in N,N-dimethylformamide (0.5 mL) at room temperature. After stirring at room temperature for 2 hours, the mixture is poured into water (2 mL) and extracted with ethyl acetate (3 mL). The organic layer is dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography on NH-silica gel eluting with ethyl acetate and then by preparative LC-MS to give 9.8 mg (38% yield) of the title compound.
Reaction SMILES: C([N:3]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]2[N:16]=[C:17]([NH:20][C:21](=[O:23])[CH3:22])[S:18][CH:19]=2)=[CH:9][CH:8]=1)C=O)=O.Cl>CO.C(OCC)(=O)C>[NH2:3][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]2[N:16]=[C:17]([NH:20][C:21](=[O:23])[CH3:22])[S:18][CH:19]=2)=[CH:9][CH:8]=1
Reactant: CC(=O)Nc1nc(CCc2ccc(CN(C=O)C=O)cc2)cs1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc(CCc2ccc(CN)cc2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.4 %

Procedure:
To a solution of N-[4-(2-{4-[(diformylamino)methyl]-phenyl}ethyl)-1,3-thiazol-2-yl]acetamide (56 mg) in methanol (0.5 ml) was added 4N hydrogen chloride in ethyl acetate (0.5 ml), and the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated in vacuo. The residue was separated between chloroform (5 ml) and saturated aqueous sodium hydrogen bicarbonate (5 ml), and the aqueous layer was extracted with chloroform (5 ml). The organic layer was dried over sodium sulfate and concentrated in vacuo to give N-(4-{2-[4-(aminomethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (50 mg).
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[NH:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1.[CH3:19]I>>[CH3:19][N:6]1[S:2](=[O:1])(=[O:18])[N:3]([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:4][CH2:5]1
Reactant: CI
Reactant: CCOC(=O)c1ccc(N2CCNS2(=O)=O)cc1
Product: CCOC(=O)c1ccc(N2CCN(C)S2(=O)=O)cc1

Procedure:
Using ethyl 4-(1,1-dioxo-1λ6-[1,2,5]thiadiazolidin-2-yl)benzoate (195 mg) described in Preparation Example 46 and methyl iodide (99 μL) and by the reaction and treatment in the same manner as in Example 36, crude ethyl 4-(5-methyl-1,1-dioxo-1λ6-[1,2,5]thiadiazolidin-2-yl)benzoate (107 mg) was obtained. Using the obtained crude ethyl 4-(5-methyl-1,1-dioxo-1λ6-[1,2,5]thiadiazolidin-2-yl)benzoate (107 mg) and 1-(3,5-dimethylpyridin-2-yl)piperazine (75.7 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 109, the title compound (120 mg) was obtained.
Reaction SMILES: [I:1][C:2]1[CH:27]=[CH:26][C:5]([NH:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[C:10]([O:24][CH3:25])[CH:9]=2)=[C:4]([N+:28]([O-])=O)[CH:3]=1.O.[Cl-].[NH4+]>O1CCCC1.C(O)C.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2].[Zn]>[I:1][C:2]1[CH:3]=[C:4]([NH2:28])[C:5]([NH:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[C:10]([O:24][CH3:25])[CH:9]=2)=[CH:26][CH:27]=1
Reactant: COc1ccc(COc2ccc(CNc3ccc(I)cc3[N+](=O)[O-])cc2OC)cc1
Agent: [Fe+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(COc2ccc(CNc3ccc(I)cc3N)cc2OC)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 97 %

Procedure:
To a stirred solution of 4-iodo-N-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-2-nitroaniline (9.10 g, 17.49 mmol) in tetrahydrofuran (50 mL), ethanol (50 mL), and water (10 mL) was added ammonium chloride (7.48 g, 139.9 mmol) and iron (II) sulfate heptahydrate (14.59 g, 52.47 mmol). The bright orange suspension was treated with zinc (3.43 g, 52.47 mmol). The mixture was gradually warmed to reflux. After 3.5 h, the color of the reaction mixture had turned from orange to olive-green. At this point the recation mixture was allowed to cool to room temperature. The mixture was filtered through Celite, and the filtercake was washed with methanol. The filtrate concentrated, the residue was suspended in water. The aqueous mixture was extracted with chloroform (×3). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to afford 8.32 g (97%) of 4-iodo-N1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)benzene-1,2-diamine as a tan solid.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([C:14]3[N:18]4[CH:19]=[C:20]([C@@H:23]([N:28]5[CH2:32][CH2:31][C@H:30]([NH:33]C(=O)OC(C)(C)C)[CH2:29]5)[C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:22][C:17]4=[N:16][N:15]=3)=[N:11]2)=[CH:6][CH:5]=1)[CH3:2]>C(O)(C(F)(F)F)=O>[CH2:1]([S:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([C:14]3[N:18]4[CH:19]=[C:20]([C@@H:23]([N:28]5[CH2:32][CH2:31][C@H:30]([NH2:33])[CH2:29]5)[C:24]([F:26])([F:25])[F:27])[CH:21]=[CH:22][C:17]4=[N:16][N:15]=3)=[N:11]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCSc1ccc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc2c1
Solvent: O=C(O)C(F)(F)F
Product: CCSc1ccc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](N)C5)C(F)(F)F)cn34)nc2c1
Yield: 69.7 %

Procedure:
tert-Butyl (S)-1-((R)-1-(3-(7-(ethylthio)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate (95 mg, 0.17 mmol) was stirred in TFA for 30 minutes. The reaction was concentrated to dryness, then diluted in 1 mL of methanol and added dropwise into 4N HCl in ether. The resulting precipitate was filtered and dried under vacuum to yield (S)-1-((R)-1-(3-(7-(ethylthio)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-amine (56 mg, 71% yield) hydrochloride as a solid. LCMS APCI (+) m/z 473 (M).
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][C@H:11]2[N:21]3[C:22]4[N:13]([C:14](=[O:24])[CH:15]=[N:16][C:17]=4[CH:18]=[CH:19][C:20]3=[O:23])[CH2:12]2)[CH2:6][CH2:5]1.C(N(CC)CC)C.[S:32]1[C:41]2[CH:40]=[C:39]([CH:42]=O)[N:38]=[CH:37][C:36]=2[O:35][CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO.ClCCl.CO>[ClH:1].[S:32]1[C:41]2[CH:40]=[C:39]([CH2:42][NH:3][CH:4]3[CH2:9][CH2:8][N:7]([CH2:10][C@H:11]4[N:21]5[C:22]6[N:13]([C:14](=[O:24])[CH:15]=[N:16][C:17]=6[CH:18]=[CH:19][C:20]5=[O:23])[CH2:12]4)[CH2:6][CH2:5]3)[N:38]=[CH:37][C:36]=2[O:35][CH2:34][CH2:33]1
Reactant: NC1CCN(C[C@@H]2Cn3c(=O)cnc4ccc(=O)n2c43)CC1
Reactant: O=Cc1cc2c(cn1)OCCS2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=c1cnc2ccc(=O)n3c2n1C[C@H]3CN1CCC(NCc2cc3c(cn2)OCCS3)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
A suspension of (1R)-1-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione dihydrochloride (160 mg, 0.428 mmol) (for a preparation see Example 13(k) or 15(d)) in chloroform (10 ml) and methanol (0.400 ml) under argon at room temperature was treated with triethylamine (0.179 ml, 1.283 mmol) and stirred for 0.25 h at room temperature (everything went into solution). 2,3-Dihydro[1,4]oxathiino[2,3-c]pyridine-7-carbaldehyde (for a synthesis see WO2004058144, Example 60) (77 mg, 0.428 mmol) was then added and the reaction was stirred at room temperature for 0.5 h. Sodium triacetoxyborohydride (272 mg, 1.283 mmol) was then added and the reaction was stirred at room temperature. After 1.5 h there was still some imine present by LCMS so 1 equivalent of sodium triacetoxyborohydride was added. After 1 h sat NaHCO3 (50 ml) was added followed by 20% methanol/dichloromethane (80 ml) and the aqueous was extracted and then separated from the organic layer. The aqueous layer was extracted again twice with 20% methanol/dichloromethane (2×80 ml). The combined organic extracts were dried on MgSO4, filtered and evaporated to afford 215 mg of crude product which was purified by silica chromatography using a 0-20% methanol/dichloromethane gradient to afford the free base of the title compound as yellow foam (179 mg, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH3:19])=[C:9]2[CH2:20][CH2:21][C:22](O)=[O:23])=[O:7])=[CH:4][CH:3]=1.[CH3:27][S:28]([NH2:31])(=[O:30])=[O:29].[N+](=C1CCCCC2C1CCCC=2)=[N-].CC(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH3:19])=[C:9]2[CH2:20][CH2:21][C:22]([NH:31][S:28]([CH3:27])(=[O:30])=[O:29])=[O:23])=[O:7])=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)c(C)c(CCC(=O)O)n2C(=O)c1ccc(Cl)cc1
Reactant: CS(N)(=O)=O
Agent: [N-]=[N+]=C1CCCCC2=CCCCC21
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc2c(c1)c(C)c(CCC(=O)NS(C)(=O)=O)n2C(=O)c1ccc(Cl)cc1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 64.8 %

Procedure:
To a cooled mixture (0-5° C.) of 3-(1-(4-chlorobenzoyl)-5-methoxy-3-methyl-1H-indol-2-yl)propanoic acid (40 mg, 0.11 mmol) in CH2Cl2 (1 mL), 1′1′-carbonyldiimidazole (CDI) (17.4 mg, 0.11 mmol) was added. After the mixture was stirred for 2 h at 0-5° C., methansulfonamide (10 mg, 0.11 mmol) and diazobicyclo-[5.4.0]undec-7-ene (DBU) (16.1 μL, 0.11 mmol) were added. The mixture was left stirring overnight. Glacial AcOH (13.2 μL) was added, the reaction mixture was diluted with CH2Cl2 (1 mL), and the organic layer was washed with 10% NaH2PO4 (pH 4) (1×1 mL) and water (3 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude residue that was purified by flash chromatography (SiO2, ethyl acetate/hexane, 0.5% AcOH gradient) to afford the title compound as a bright yellow solid (32 mg, 66%). C21H21ClN2O5S, Mr=448.92; 1H NMR (400 MHz, DMSO-d6) d: 2.21 (s, 3H), 2.55 (t, J=7.2 Hz, 2H), 3.11 (t, J=7.2 Hz, 2H), 3.16 (s, 3H), 3.75 (s, 3H), 6.43 (d, J=9.2 Hz, 1H), 6.64 (dd, J=9.0 Hz, 1H), 7.02 (d, J=2.4 Hz, 1H), 7.64-7.69 (m, 4H); LCMS (ESI) tR: 2.74 min (>95%, UV254, ELSD), m/z: 249.1 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:11]2[CH2:12][CH2:13][CH2:14][CH:7]1[CH2:8][C:9](=O)[CH2:10]2)=[O:5])[CH3:2].[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH:11]2[CH2:12][CH2:13][CH2:14][CH:7]1[CH:8]=[C:9]([N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[CH2:10]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1C2CCCC1CC(=O)C2
Reactant: C1CCNC1
Agent: Cl[Ti](Cl)(Cl)Cl
Product: CCOC(=O)N1C2C=C(N3CCCC3)CC1CCC2
Temperature: 25 °C

Procedure:
At room temperature, under a nitrogen atmosphere and with stirring, a solution of 110 g of titanium tetrachloride in 450 ml of petroleum ether is added dropwise, within 2.5 hours, to a solution of 223 g of 9-azabicyclo-[3,3,1]nonan-3-one-9-carboxylic acid ethyl ester (e) and 300 g of pyrrolidine in 2.5 liters of absolute petroleum ether (b.p. 50° to 70° C.). The mixture is stirred for 24 hours. The light-yellow precipitate formed is filtered, suspended in benzene, suctionfiltered and washed with benzene. The united filtrates are concentrated in a vacuum; the orange-red oil which remains behind is purified through vacuum distillation to obtain 260 g (93.5 percent) of yellow, viscous oil (b.p. 140° C. at 6.7 Pa.)
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[C:10](Br)[CH3:11])=[CH:5][CH:4]=1.[Mg].II.Cl[P:27]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:28]([CH3:31])([CH3:30])[CH3:29]>[Cu](Cl)Cl.C(OCC)C.CCCCCCC.C1COCC1>[CH3:1][N:2]([CH3:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[C:10]([P:27]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH3:11])=[CH:5][CH:4]=1
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Reactant: CC(Br)=C(c1ccc(N(C)C)cc1)c1ccc(N(C)C)cc1
Agent: Cl[Cu]Cl
Agent: II
Agent: [Mg]
Solvent: CCCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=C(c1ccc(N(C)C)cc1)c1ccc(N(C)C)cc1)P(C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Yield: 20 %

Procedure:
Into a reactor were introduced 1.44 g (4.00 mmol) of the 1,1-bis(4-dimethylaminophenyl)-2-bromopropene obtained in Example 4 (2), 0.107 g (4.4 mmol) of magnesium, and 11.5 mL of THF under a nitrogen atmosphere. A slight amount of iodine was added to the mixture to ascertain initiation of a reaction. Thereafter, the reaction mixture was refluxed for 2 hours and then cooled. Thereto were added 0.416 g (4.2 mmol) of copper chloride and 0.91 mL (4.4 mmol) of chlorodi-tert-butylphosphine. The reaction mixture was refluxed for 18 hours and then cooled to room temperature. Thereto were added 22.5 mL of heptane and 7.5 mL of diethyl ether. The crystals yielded were taken out by filtration and dissolved in 30 mL of ethyl acetate. The resultant solution was washed with 28% ammonia water and an aqueous sodium chloride solution and then dried with anhydrous magnesium sulfate. Thereafter, the solvent was removed under reduced pressure. The concentrate was recrystallized from ethanol to obtain 0.34 g (20%) of the target compound as white crystals.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][OH:5].[H-].[Na+].[CH2:9]([CH:11]1[O:13][CH2:12]1)Br>O1CCCC1>[CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][O:5][CH2:9][CH:11]1[O:13][CH2:12]1
Reactant: CC(C)=CCO
Reactant: BrCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)=CCOCC1CO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3,3-dimethylallyl alcohol (17.3 g, 20.5 mL, 0.2 mol) in dry tetrahydrofuran (THF) (200 mL) was added sodium hydride (4.8 g, 0.2 mol) in portions and the mixture was stirred at room temperature for 1 hr. Epibromohydrin (27.4 g, 17.12 mL, 0.2 mol) was added dropwise and the reaction mixture was stirred at room temperature for 24 hrs. THF was removed on a rotary evaporator and the residue was taken up in ether and filtered. The ether solution was concentrated on a rotary evaporator and the brown oil obtained was distilled under vacuum. bp: 93°-94° C./10 mm. Yield: 17.2 g (60.5%). 1H NMR (CDCl3) ε 1.68 and 1.75 (s, 6H, CH3), 2.61 and 2.88 (dd, 2H, oxirane CH2), 3.17 (m, 1H, oxirane CH), 3.38 and 3.7 (m, 2H, CH2OCH2CH), 4.05 (m, 2H, CH2OCH2CH), 5.35 (m, 1H, >C=CH).