Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.Br[C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[CH2:13][NH:14][C:15](=[O:17])[OH:16]>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[CH2:13][NH:14][C:15](=[O:16])[OH:17]
Reactant: OB(O)c1ccco1
Reactant: O=C(O)NCc1cccc(Br)c1
Product: O=C(O)NCc1cccc(-c2ccco2)c1

Procedure:
Using the same method as in Example 19-(ii), 2-furanboronic acid was reacted with the (3-bromobenzyl)carbamic acid.tert-butyl to give [3-(furan-2-yl)benzyl]carbamic acid.tert-butyl (yield: 84%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7](Cl)=[O:8].C(N(CC)CC)C.[NH2:17][CH:18]1[C:25](=[O:26])[N:24]2[CH:19]1[S:20][CH2:21][C:22]([C:43]1[S:47][C:46]([NH:48][C:49]3[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=3)=[N:45][CH:44]=1)=[C:23]2[C:27]([O:29][CH:30]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>O1CCCC1>[CH:30]([O:29][C:27]([C:23]1[N:24]2[CH:19]([S:20][CH2:21][C:22]=1[C:43]1[S:47][C:46]([NH:48][C:49]3[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=3)=[N:45][CH:44]=1)[CH:18]([NH:17][C:7](=[O:8])[CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[C:25]2=[O:26])=[O:28])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(Nc4cccnc4)s3)CSC12
Reactant: O=C(Cl)Cc1cccs1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(Nc4cccnc4)s3)CSC12
Reaction time: 0.58 h

Procedure:
Thien-2-yl-acetyl chloride (0.88 cc) and triethylamine (0.95 cc) are added successively to a solution, cooled to 5° C., of 7-amino-2-benzhydryloxycarbonyl-8-oxo-3-[2-(pyrid-3-yl-amino)-thiazol-5-yl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene (3.85 g) in dry tetrahydrofuran (100 cc), and the mixture is then stirred for 35 minutes at the same temperature. The cooling bath is removed and the mixture is stirred for 1 hour 30 minutes at 23° C. The reaction mixture is poured onto a mixture (50:50 by volume) (400 cc) of ethyl acetate and saturated sodium bicarbonate solution. The phases are allowed to separate and the organic phase is washed successively with distilled water (200 cc) and a saturated sodium chloride solution (200 cc). It is dried over anhydrous magnesium sulphate and filtered, and the filtrate is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C. The residue is chromatographed on a column (height: 30 cm, diameter: 3 cm) of silica gel (0.6-0.04 mm), elution being carried out with ethyl acetate (2 liters) and 100 cc fractions being collected. Fractions 5 to 8, containing the pure product, are combined and concentrated under reduced pressure (30 mm Hg; 4 kPa) at 30° C. to give 2-benzhydryloxycarbonyl-8-oxo-3-[2-(pyrid-3-yl-amino)-thiazol-5-yl]-7-(thien-2-yl-acetamido)-5-thia-1-azabicyclo[4.2.0]oct-2-ene (1.3 g) in the form of a yellow froth.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[OH:18][C:19]1[CH:20]=[CH:21][C:22]([N+:26]([O-:28])=[O:27])=[C:23]([CH:25]=1)[NH2:24].[OH-].[Na+]>>[OH:18][C:19]1[CH:20]=[CH:21][C:22]([N+:26]([O-:28])=[O:27])=[C:23]([CH:25]=1)[NH:24][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: Nc1cc(O)ccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1ccc(O)cc1Nc1cc(C(F)(F)F)nc(-c2cccnc2)n1
Yield: 63.4 %

Procedure:
The title compound was prepared from 4-chloro-2-(3-pyridinyl)-6-trifluoromethylpyrimidine (60 mg, 0.23 mmol) and 5-hydroxy-2-nitroaniline (52 mg, 0.34 mmol) similar to Example 180. The reaction mixture was neutralized with 2N NaOH to pH 7.0 and the solvent was removed under vacuo. The product was purified by column chromatography (20% ethyl acetate in hexane) to give 55 mg (63%) of the title compound as a light yellow solid. 1H NMR (CDCl3): 9.40 (d, J=1.2 Hz, 1H), 8.71 (dd, J=1.2, 4.8 Hz, 1H), 8.57 (ddd, J=2.1, 3.9, 7.8 Hz, 1H), 8.04 (d, J=2.7 Hz, 1H), 7.42 (dd, J=3.9, 8.7 Hz, 1H), 7.32 (dd, J=6.0, 9.0 Hz, 1H), 7.23 (s, 1H), 6.92 (d, J=9.0 Hz, 1H), 6.19 (s, 2H).
Reaction SMILES: C[N:2]1[C:10]2[C:5](=[C:6]([CH2:11][O:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:19]([O:21]CC)=O.Cl.[NH2:25][C:26]([NH2:28])=[NH:27].[CH3:29][O-].[Na+]>CO>[CH3:29][NH:27][C:26]([NH2:28])=[N:25][C:19]([C:3]1[NH:2][C:10]2[C:5]([CH:4]=1)=[C:6]([CH2:11][O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[CH:7]=[CH:8][CH:9]=2)=[O:21]
Reactant: CCOC(=O)c1cc2c(COC3CCCCO3)cccc2n1C
Reactant: N=C(N)N
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CNC(N)=NC(=O)c1cc2c(COC3CCCCO3)cccc2[nH]1

Procedure:
The reaction was carried out in a manner similar to Example 1 except for using 1.50 g (4.73 mmol) of ethyl 1-methyl-4-(2-tetrahydropyranyl)oxymethyl-2-indolecarboxylate, 6.02 g (63.0 mmol) of guanidine hydrochloride and a solution of 3.40 g (63.0 mmol) of sodium methoxide in 60 ml of methanol. 1-Methyl-4-(2-tetrahydropyranyl)oxymethyl-2-indoloylguanidine was obtained. After the compound was dissolved in a mixture of 30 ml of 2N hydrochloric acid and 60 ml of tetrahydrofuran, the mixture was stirred at room temperature for an hour. The reaction mixture was poured onto ice water and the aqueous layer was rendered alkaline with 28% aqueous ammonia. The mixture was then extracted three times with ethyl acetate. The combined extracts were washed with saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 4-hydroxymethyl-1-methyl-2-indoloylguanidine. Next, the compound was treated with hydrogen chloride/methanol to convert into the hydrochloride. 4-Hydroxymethyl-1-methyl-2-indoloylguanidine hydrochloride was thus obtained in an amount of 0.58 g (44.2%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([NH:21][C:22](=[O:25])[CH2:23][OH:24])[C@@H:18]([OH:26])[C@H:17]3[OH:27])=[C:9]([NH:28][CH2:29][CH:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:8]=2)C=1.[N+:43](C1N=CNC=1)([O-])=O>>[NH2:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([NH:21][C:22](=[O:25])[CH2:23][OH:24])[C@@H:18]([OH:26])[C@H:17]3[OH:27])=[C:9]([NH:28][CH2:29][CH:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:8]=2)[N:43]=1
Reactant: O=[N+]([O-])c1c[nH]cn1
Reactant: Nc1cn(-c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)CO)[C@@H](O)[C@H]4O)c3n2)cn1
Product: Nc1ncn(-c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)CO)[C@@H](O)[C@H]4O)c3n2)n1

Procedure:
The title compound is prepared analogously to N-{(1S,2R,3S,4R)-4-[2-(4-amino-imidazol-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-hydroxy-acetamide (Intermediate ZU) from {(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentylcarbamoyl}-methyl ester (Intermediate Q1) by substituting 3-nitro-1H-[1,2,4]triazole for 4-nitro-1H-imidazole in step ZU1.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:22][C:23]1[CH:27]=[CH:26][O:25][CH:24]=1>C(OCC)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:22][C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ccccc23)CC1
Reactant: BrCc1ccoc1
Solvent: CCOCC
Product: CCOC(=O)N1CCC(c2cn(Cc3ccoc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
This compound was prepared following the procedure described in example 13 (part B) starting with 4 g (13.7 mmol) 4-(1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester and 16 mL (16 mmol) of a freshly prepared 1M solution in ethyl ether of 3-bromomethyl-furan. The reaction mixture was stirred at room temperature for 18 hours. After standard work-up, 5.3 g (99% of yield) of 4-(1-furan-3-ylmethyl-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester were obtained.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].CS([CH2:27][CH:28]1[O:33][C:32]2[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=2[O:30][CH2:29]1)(=O)=O>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:27][CH:28]4[O:33][C:32]5[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=5[O:30][CH2:29]4)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)CC1COc2ccccc2O1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc2c(C3CCN(CC4COc5ccccc5O4)CC3)noc2c1

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 13.6 mmol), K2CO3 (2.45 g, 17.7 mmol), 2-methanesulfonylmethyl-1,4-benzodioxan (3.35 g, 13.7 mmole) in acetonitrile (100 ml) was heated at reflux for 12 hours. At the end of the reaction, the insolubles were filtered and rinsed with dichloromethane. The organic solution was concentrated. The crude oil was purified by flash chromatography on a silica gel column. The fractions containing the pure product were pooled and concentrated to a light yellow oil (3.94 g, 74%). Crystallization from ethanol and petroleum ether gave 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]methyl-1,4-benzodioxan as off-white crystals, 2.22 g, m.p.=86°-87° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:13]1([S:19]([NH2:22])(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([NH:22][S:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:21])=[O:20])=[O:6]
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=C(O)c1cc(F)c(F)cc1F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(NS(=O)(=O)c1ccccc1)c1cc(F)c(F)cc1F
Reaction time: 18 h
Yield: 68 %

Procedure:
To a solution of 2,4,5-trifluorobenzoic acid (0.50 g, 2.8 mmol) in dichloromethane (5 mL) was added N-di-isopropylethylamine (1.8 mL, 1.3 g, 8.5 mmol), WSCDI (0.82 g, 4.2 mmol) and DMAP (0.52 g, 4.2 mmol). After 10 minutes phenylsulfonamide (0.45 g, 4.2 mmol) was added and the reaction left at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue purified by reverse phase chromatography using CH3CN/water as eluent (5:95-95/5 over 30 mins) to yield the title compound (0.60 g, 67%) as a white solid
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[CH:17]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:24]1([CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:30]2[CH2:31][CH2:32][N:33]([CH2:16][CH:2]([OH:1])[CH2:3][CH2:4][N:5]3[C:13](=[O:14])[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:6]3=[O:15])[CH2:34][CH2:35]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCC(O)CN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
5 g (˜25 mmol) 2-(3,4-epoxybutyl)-isoindolin-1,3-dione, 7.5 g (30 mmol) benzhydrylpiperazine and 3.5 g (25 mmol) potassium carbonate are stirred in DMF for 6 hours 80° C. After cooling, the reaction mixture is filtered and concentrated under vacuum. The residue is taken up in 300 ml acetic acid ethyl ester and washed three times each with 20 ml water. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The residue is chromatographically purified over silica gel with CHCl3/CH3OH.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Cl[C:25]1[N:30]2[N:31]=[C:32]([CH3:34])[N:33]=[C:29]2[N:28]=[C:27]([CH3:35])[CH:26]=1>>[CH3:34][C:32]1[N:33]=[C:29]2[N:28]=[C:27]([CH3:35])[CH:26]=[C:25]([NH:1][CH2:2][C@@H:3]3[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]3[C:10]([C:12]3[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=3[N:19]3[N:23]=[CH:22][CH:21]=[N:20]3)=[O:11])[N:30]2[N:31]=1
Reactant: Cc1cc(Cl)n2nc(C)nc2n1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2cc(C)nc3nc(C)nn23)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 7-chloro-2,5-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine. ESI-MS (m/z): 460 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][O:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[N:26]([C:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:25]=[CH:24]4)[N:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][O:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[N:26]([CH:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:25]=[CH:24]4)[N:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: CCOC(=O)C=C(c1ccccc1)n1ccc2cc(OCCc3ccc4c(n3)N(C(=O)OC(C)(C)C)CCC4)ccc21
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CC(c1ccccc1)n1ccc2cc(OCCc3ccc4c(n3)N(C(=O)OC(C)(C)C)CCC4)ccc21
Yield: 95.7 %

Procedure:
10% Palladium on activated carbon (0.06 g) was added to 7-{2-[1-(2-ethoxycarbonyl-1-phenyl-vinyl)-1H-indol-5-yloxy]-ethyl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (0.50 g, 0.88 mmol) in methanol (10 mL) under argon. The solution was exposed to a hydrogen atmosphere (50 psi) using a Parr shaker for 24 h. The reaction was filtered through celite and washed with methanol. The filtrate was concentrated in vacuo to yield the title compound (0.48 g, 98%). 1H NMR (CDCl3) δ 7.15–7.36 (m, 9H), 6.96 (d, 1H, J=7.6 Hz), 6.83 (dd, 1H, J=2.3, 6.6 Hz), 6.46 (d, 1H, J=3.0 Hz), 6.06 (d, 1H, J=7.6 Hz), 4.39 (m, 2H), 4.06 (q, 2H, J=7.1 Hz), 3.78 (m, 2H), 3.31–3.20 (m, 4H), 2.75 (m, 2H), 1.94 (m, 2H), 1.54 (s, 9H), 1.11 (t, 3H, J=7.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[C:10]#N)[CH:5]=[CH:6][C:7]=1[Cl:8].[Li+].C[CH:23]([N-:25]C(C)C)C.BrC[C:31]([O:33][CH2:34][CH3:35])=[O:32]>C1COCC1>[CH2:34]([O:33][C:31](=[O:32])[CH:10]([C:23]#[N:25])[CH:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:12][CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)[CH3:35]
Reactant: CC(C)[N-]C(C)C
Reactant: N#CC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)CBr
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)C(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Temperature: 20 °C
Reaction time: 1.25 h
Yield: 69.4 %

Procedure:
2-(3,4-dichloro-phenyl)-4-(tetrahydro-pyran-2yloxy)-butyronitrile (10.8669 g, 34.62 mmol) was dissolved in THF (20 mL) at -78° C. and treated dropwise with LDA (27.2 mL, 40.8 mmol, 1.18 eq.) over 30 minutes. The solution was allowed to stir for 1.25 hour. Ethyl bromoacetate (4.2 mL, 37.87 mmol, 1.09 eq.) was added dropwise at -78° C. and the solution was allowed to warm to 20° C. and stir for 4 hours. The solution was partitioned between ammonium chloride and diethyl ether. The organic solution was extracted with water and brine and the organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel (400 g) with a gradient from 20% ethyl acetate in hexane to 30% ethyl acetate in hexane to give 9.6243 g (69.5%) of the title compound.
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C@H:20]([NH2:24])[CH:21]([CH3:23])[CH3:22])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[C:25](OC(=O)C)(=[O:27])[CH3:26]>>[CH:1]([O:4][C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C@H:20]([NH:24][C:25](=[O:27])[CH3:26])[CH:21]([CH3:23])[CH3:22])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(Oc2ccc(CC[C@H](N)C(C)C)cc2)cn1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N[C@@H](CCc1ccc(Oc2ccc(OC(C)C)nc2)cc1)C(C)C

Procedure:
(S)-1-{2-[4-(6-Isopropoxypyridin-3-yloxy)phenyl]ethyl}-2-methylpropylamine (50 mg, 0.152 mmol) was reacted with acetic anhydride in analogy to example 2a. Yield: 49 mg (88%), M+H+: 371.3.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CN(C=O)C>O>[Cl:1][C:2]1[N:3]([CH2:10][C@:11]([OH:12])([CH3:14])[CH2:13][N:18]2[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C[C@](C)(O)Cn2cc([N+](=O)[O-])nc2Cl)CC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
A mixture of (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (7.00 g, 32.2 mmol) and tert-butyl piperazine-1-carboxylate (6.29 g, 33.8 mmol) and DMF (70 ml) was stirred at 70° C. for 8 hours. The reaction mixture was allowed to return to room temperature, then diluted with water, and then the solution was extracted with ethyl acetate twice. The organic phases were combined, washed with water three times, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. To the residue, diethyl ether was added. The precipitates were filtered off, and dried at room temperature under reduced pressure to afford tert-butyl (S)-4-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]piperazin-1-carboxylate (10.25 g, yield 79%) as a light yellow powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH3:18])[CH:13]=[CH:12][C:11]=2[F:19])[CH:3]=1.CN1C(=O)[CH2:24][CH2:23][CH2:22]1.C([Mg]Cl)(C)C>C1COCC1.CCOCC>[CH2:17]([O:16][C:14]1[CH:13]=[CH:12][C:11]([F:19])=[C:10]([C:4]2[CH:3]=[C:2]([CH:23]([CH3:24])[CH3:22])[N:7]=[C:6]([C:8]#[N:9])[CH:5]=2)[CH:15]=1)[CH3:18]
Reactant: CN1CCCC1=O
Reactant: CCOc1ccc(F)c(-c2cc(Cl)nc(C#N)c2)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOc1ccc(F)c(-c2cc(C#N)nc(C(C)C)c2)c1
Temperature: 0 °C

Procedure:
A mixture of 6-chloro-4-(5-ethoxy-2-fluoro-phenyl)pyridine-2-carbonitrile (which may be prepared as described in Description 113) (1.5 g, 5.42 mmol) NMP (2.61 mL, 27.07 mmol) and Fe(acac)3 (95.73 mg, 0.2700 mmol) in THF (27.106 mL) was stirred at 0° C. and treated with 2M isopropyl magnesium chloride in THF (7.59 mmol) and the mixture was stirred at 0° C. for 30 mins. The mixture was diluted with ether (200 ml) and quenched with brine. The product was extracted into ether (3x) and the extracts were dried (Na2SO4) and evaporated. The product was purified by flash chromatography (0-100% DCM in isohexane) to give 4-(5-ethoxy-2-fluoro-phenyl)-6-isopropyl-pyridine-2-carbonitrile (D114) as a white solid;
Reaction SMILES: C([Li])CCC.CCCCCC.[O:12]([C:30]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[C:32]([O:38][CH3:39])[CH:31]=1)[Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CN(C)[CH:42]=[O:43].[Cl-].[NH4+]>C(OCC)C>[O:12]([C:30]1[CH:35]=[C:34]([O:36][CH3:37])[C:33]([CH:42]=[O:43])=[C:32]([O:38][CH3:39])[CH:31]=1)[Si:13]([C:26]([CH3:28])([CH3:29])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1cc(OC)cc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1cc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc(OC)c1C=O
Temperature: 0 °C
Yield: 41.3 %

Procedure:
Under nitrogen, a 1.60 M solution of n-butyl lithium in hexane (31 mL, 49 mmol) was added to a solution of 1-t-butyldiphenylsiloxy-3,5-dimethoxybenzene (14.68 g, 39.0 mmol) in anhydrous diethyl ether (200 mL) stirred in an ice bath. The reaction mixture was stirred at 35° C. for 3 hours and cooled in the ice bath, followed by the addition of dimethylformamide (9.21 mL, 119.4 mmol). After stirring at room temperature for 1 hour, saturated aqueous ammonium chloride was added, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to yield 4-t-butyldiphenylsiloxy-2,6-dimethoxybenzaldehyde as a colorless crystalline powder (melting point: 177.5-120.0° C.) (6.77 g, yield: 41%).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:26]=[C:25]([O:27][CH2:28][C@H:29]([OH:32])[CH2:30][OH:31])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[OH:32][C@H:29]([CH2:30][OH:31])[CH2:28][O:27][C:25]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[C:17]([N:14]2[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]2)[N:26]=1
Reactant: O=C(OCc1ccccc1)N1CCN(c2nc(OC[C@H](O)CO)c3ccccc3n2)CC1
Agent: [Pd]
Solvent: CO
Product: OC[C@@H](O)COc1nc(N2CCNCC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.8 %

Procedure:
2-[4-(Benzyloxycarbonyl)piperazin-1-yl]-4-[(2R)-(2,3-dihydroxypropan-1-yl)oxy]quinazoline (5.8 g) is dissolved in methanol (50 ml), and thereto is added 10% palladium/carbon (0.6 g), and the mixture is stirred under hydrogen atmosphere and under atmospheric pressure at room temperature overnight. The reaction mixture is filtered, and the filtrate is evaporated to dryness under reduced pressure, and the residue is recrystallized from methanol to give 4-[(2R)-(2,3-dihydroxypropan-1-yl)oxy]-2-(1-piperazinyl)quinazoline (1.4 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([NH:17][C:18]3[C:19]([O:24][CH3:25])=[N:20][CH:21]=[CH:22][CH:23]=3)[C:14]([N+:26]([O-])=O)=[CH:13][CH:12]=2)[CH3:9])=[N:6][CH:7]=1>[Pd].C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([NH:17][C:18]3[C:19]([O:24][CH3:25])=[N:20][CH:21]=[CH:22][CH:23]=3)[C:14]([NH2:26])=[CH:13][CH:12]=2)[CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncccc1Nc1nc(N[C@@H](C)c2ccc(F)cn2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1ncccc1Nc1nc(N[C@@H](C)c2ccc(F)cn2)ccc1N
Temperature: 25 °C
Reaction time: 7 h

Procedure:
N6-[(1S)-1-(5-Fluoropyridin-2-yl)ethyl]-N2-(2-methoxypyridin-3-yl)-3-nitropyridine-2,6-diamine (Preparation 22b, 131 mg, 0.34 mmol) was added to a suspension of palladium on carbon (10%, 18 mg) in ethanol (5 mL) and the reaction mixture was stirred at ambient temperature under a hydrogen atmosphere. After 7 hours, additional palladium on carbon was added (18 mg) and the reaction mixture was stirred at ambient temperature under a hydrogen atmosphere for further 15 hours. The mixture was then filtered through Celite® and the filter cake was washed with ethanol (5×10 mL). The combined filtrate and washings containing the title compound as a methanolic solution was used in the next synthetic step without further purification.