Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7](=O)[C:6]2=[C:9]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:15][CH:14]=3)[N:11]=[C:5]2[N:4]2[C@H:32]3[CH2:37][CH2:36][CH2:35][C@H:33]3[N:34]=[C:3]12.CC(C[AlH]CC(C)C)C>C1COCC1.C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH2:7][C:6]2=[C:9]([NH:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:10]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:17][CH:18]=3)[N:11]=[C:5]2[N:4]2[C@H:32]3[CH2:37][CH2:36][CH2:35][C@H:33]3[N:34]=[C:3]12
Reactant: CN1C(=O)c2c(nn(Cc3ccc(-c4ccccn4)cc3)c2Nc2ccccc2)N2C1=N[C@@H]1CCC[C@@H]12
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CN1Cc2c(nn(Cc3ccc(-c4ccccn4)cc3)c2Nc2ccccc2)N2C1=N[C@@H]1CCC[C@@H]12
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.5 %

Procedure:
(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-((4-Pyridin-2-yl)-benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one (26.9 mg, 0.055 mmol) is dissolved in 1 mL of anhydrous THF, and then 400 uL of 1.5 M DIBAL-H in toluene is added dropwise. After the reaction mixture is stirred at room temperature overnight, additional 800 uL of 1.5 M DIBAL-His added to the solution. The reaction mixture is stirred at room temperature for 24 hours, and then quenched with NH4Cl aqueous solution. After routine workup, the mixture is purified by a semi-preparative HPLC to give 3.0 mg of pure product as while solids. MS (ESI) m/z 476.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=3)[C:9]2=[O:12])=[CH:4][C:3]=1OS(C(F)(F)F)(=O)=O.[C:30](=[O:37])([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[NH2:31].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1COCC1>[C:33]([O:32][C:30](=[O:37])[NH:31][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[F:1])[C:9](=[O:12])[N:8]([C:13]1[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=1)[CH:7]=[CH:6]2)([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(N)=O
Reactant: O=c1c2cc(F)c(OS(=O)(=O)C(F)(F)F)cc2ccn1-c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc2ccn(-c3ccc([N+](=O)[O-])cc3)c(=O)c2cc1F
Temperature: 75 °C
Reaction time: 25 h
Yield: 80.1 %

Procedure:
In a dry flask was combined trifluoromethanesulfonic acid 7-fluoro-2-(4-nitro-phenyl)-1-oxo-1,2-dihydro-isoquinolin-6-yl ester (0.86 g, 2 mmol), t-butyl carbamate (0.33 g, 2.8 mmol), dry powdered cesium carbonate (1.1 g, 3.4 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (Xantphos, 0.14 g, 0.24 mmol), and tris(dibenzylideneacetone)dipalladium(0) (Pd2dba3, 38 mg, 0.08 mmol). Under Ar atmosphere, dry THF (17 mL) was added to the flask, and the mixture was stirred at 75° C. for 25 hr. The reaction was concentrated and purified on silica gel using EtOAc/hexane as eluent to give 0.64 g (80%) of pure [7-Fluoro-2-(4-nitro-phenyl)-1-oxo-1,2-dihydro-isoquinolin-6-yl]-carbamic acid tert-butyl ester as a white solid. RP-HPLC: 5.98 min; ES-MS (M+H)+=400.0; 1H-NMR (DMSO-d6) δ (ppm): 1.47 (s, 9), 6.77 (d, 1), 7.46 (d, 1), 7.78 (d, 2), 7.87 (d, 1), 8.17 (d, 1), 8.33 (d, 2), 9.54 (s, 1).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][Cl:17])=[C:11]([N+:18]([O-])=O)[CH:10]=1)C1C=CC=CC=1>[Pd].C1COCC1>[NH2:18][C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][C:12]=1[CH2:15][CH2:16][Cl:17]
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1CCCl
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cc(O)ccc1CCCl
Reaction time: 3 h
Yield: 78.1 %

Procedure:
Pd/C 10% (45 mg) was added to 2-(4-benzyloxy-2-nitrophenyl)ethyl chloride (132 mg, 0.453 mmol). The mixture was then suspended in freezer chilled THF (30 mL). The suspension was degassed and purged 3 times with hydrogen and reduced under atmospheric pressure at room temperature. After 3 h the solution was checked by TLC (10% MeOH/CHCl3) and the solution was filtered by suction over Celite. The filter residue was washed with more CH2Cl2, and the filtrate was concentrated under reduced pressure to give 2-(2-amino-4-hydroxyphenyl)ethyl chloride as a white solid (60.7 mg, 0.354 mmol, 78%). Mp 96-100° C.; TLC (10% MeOH/CHCl3) Rf=0.34; 1H-NMR (CDCl3 in 1 drop DMSO-d6, 500 MHz) 8.20 (br s, 1H), 6.85 (d, 8.0, 1H), 6.27 (dd, 2.5, 8.0, 1H), 6.26 (d, 2.5, 1H), 4.00 (br s, 2H), 3.66 (t, 8.5, 2H), 2.90 (t, 8.5, 2H); IR (neat) 3139, 3020, 2954, 1622, 1594, 1513, 1464, 1560, 1306, 1265, 1246, 1197, 1175, 1079, 1049, 973, 848, 793, 722, 596, 646; EI-MS m/z (relative intensity) 171 (M+, 28); isotope pattern of M+ and M++2 agrees with the presence of one chlorine atom. Accurate mass (EI-MS) for C8H10ClNO: calcd. 171.0451, obsd. 171.0444.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[H-].[Na+].[CH3:22]I>CN(C)C=O>[CH3:22][O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(CO)cc(-c2ccc(C)cn2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1cc(C(=O)OC)cc(-c2ccc(C)cn2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of methyl 3-(hydroxymethyl)-5-(5-methylpyridin-2-yl)benzoate (110 mg, 0.41 mmol) in N,N-dimethylformamide (2 mL) at 0° C. was added sodium hydride (60% in mineral oil, 21 mg, 0.52 mmol). After 30 minutes, methyl iodide (73 mg, 0.51 mmol) was added at 0° C. The mixture was warmed to room temperature and stirred for 30 minutes. The mixture was quenched with water (2 mL) and extracted with EtOAc. The combined organic layers were dried over anhydrous MgSO4 and concentrated to get the tittle compound.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH2:24][CH2:25][CH3:26])[N:11]=[C:12]3[C:17]=2[CH:16]=[CH:15][CH:14]=[C:13]3[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[C:18]1([C:13]2[C:12]3[C:17](=[C:9]([C:6]4[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=4)[N:10]([CH2:24][CH2:25][CH3:26])[N:11]=3)[CH:16]=[CH:15][CH:14]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCCn1nc2c(-c3ccccc3)cccc2c1-c1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCn1nc2c(-c3ccccc3)cccc2c1-c1ccc(O)cc1
Reaction time: 0.25 h
Yield: 34.9 %

Procedure:
To a solution of 3-(4-methoxyphenyl)-7-phenyl-2-propyl-2H-indazole (0.140 g, 0.43 mmol) in CH2Cl2 (5 mL) was added BBr3 (0.081 mL, 0.865 mmol) at −78° C. The solution was stirred for 15 minutes and allowed to stand overnight in the refrigerator. The reaction was quenched with NH4OH (10 mL) and extracted with CH2Cl2. The organic layer was washed with water and dried (MgSO4). The reaction was purified by flash chromatography (5/1 hexane/ethyl Acetate) to give the title compound as a white solid (0.066 g, 0.15 mmol, 34%).
Reaction SMILES: [CH2:1]([C:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[S:13][C:14]([C:18]([OH:20])=O)=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:22][C@@H:23]([CH2:26][CH3:27])[CH2:24][OH:25]>>[OH:25][CH2:24][C@@H:23]([NH:22][C:18]([C:14]1[S:13][C:12](/[CH:11]=[CH:10]/[C:9]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=2[CH3:21])=[N:16][C:15]=1[CH3:17])=[O:20])[CH2:26][CH3:27]
Reactant: CC[C@H](N)CO
Reactant: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)O)s1
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)N[C@@H](CC)CO)s1
Yield: 79 %

Procedure:
As described for example 105, 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid (153 mg, 0.5 mmol) was converted, using (S)-2-amino-1-butanol instead of (R)-2-amino-1-butanol, to the title compound (150 mg, 79%) which was obtained as a light yellow solid after purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) and recrystallization from ethyl acetate/heptane. MS: m/e=378.4 [M+H]+.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:74][CH:75]([CH3:77])[CH3:76])[C:10]([NH:12][CH2:13][CH2:14][C:15]([O:17][C@@H:18]([CH2:41][O:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[C:54]([C:55]#[N:56])=[C:53]([S:57][CH2:58][C:59]3[N:60]=[C:61]([C:64]4[CH:69]=[CH:68][C:67]([Cl:70])=[CH:66][CH:65]=4)[O:62][CH:63]=3)[N:52]=[C:51]([NH2:71])[C:50]=2[C:72]#[N:73])=[CH:45][CH:44]=1)[CH2:19][O:20][C:21](=[O:40])[CH2:22][CH2:23][NH:24][C:25](=[O:39])[C@H:26]([CH2:35][CH:36]([CH3:38])[CH3:37])[NH:27]C(=O)OC(C)(C)C)=[O:16])=[O:11])=O)(C)(C)C.[F:78][C:79]([F:84])([F:83])[C:80]([OH:82])=[O:81]>ClCCl>[F:78][C:79]([F:84])([F:83])[C:80]([OH:82])=[O:81].[F:78][C:79]([F:84])([F:83])[C:80]([OH:82])=[O:81].[NH2:27][C@@H:26]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:25]([NH:24][CH2:23][CH2:22][C:21]([O:20][CH2:19][C@@H:18]([O:17][C:15](=[O:16])[CH2:14][CH2:13][NH:12][C:10](=[O:11])[C@@H:9]([NH2:8])[CH2:74][CH:75]([CH3:77])[CH3:76])[CH2:41][O:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[C:54]([C:55]#[N:56])=[C:53]([S:57][CH2:58][C:59]3[N:60]=[C:61]([C:64]4[CH:65]=[CH:66][C:67]([Cl:70])=[CH:68][CH:69]=4)[O:62][CH:63]=3)[N:52]=[C:51]([NH2:71])[C:50]=2[C:72]#[N:73])=[CH:45][CH:44]=1)=[O:40])=[O:39]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NCCC(=O)OC[C@H](COc1ccc(-c2c(C#N)c(N)nc(SCc3coc(-c4ccc(Cl)cc4)n3)c2C#N)cc1)OC(=O)CCNC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](N)C(=O)NCCC(=O)OC[C@H](COc1ccc(-c2c(C#N)c(N)nc(SCc3coc(-c4ccc(Cl)cc4)n3)c2C#N)cc1)OC(=O)CCNC(=O)[C@@H](N)CC(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An amount of 85 mg (0.077 mmol) of the compound from example 33A was introduced in 0.5 ml of dichloromethane, admixed with 0.059 ml (0.771 mmol) of trifluoroacetic acid and stirred at RT overnight. The reaction mixture was then concentrated and the residue was purified by means of preparative HPLC (eluent gradient: acetonitrile/water 10:90→95:5 with addition of 0.1% TFA). This gave 47 mg (51% of theory) of the target compound.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([N:8]([CH2:18][C:19]2[CH:24]=[C:23](OCC)[CH:22]=[C:21](OC(C)C)[C:20]=2[F:32])[C:9]2[CH:17]=[CH:16][C:12]([C:13](N)=[NH:14])=[CH:11][CH:10]=2)[N:5]([CH3:7])[CH:6]=1.[CH2:33](C1C=CC(F)=C(C=1)C=CC1C=CC(C#N)=CC=1)[CH3:34].BrC1N=CN(C)C=1>>[Br:1][C:2]1[N:3]=[C:4]([N:8]([CH2:18][C:19]2[CH:24]=[C:23]([CH2:33][CH3:34])[CH:22]=[CH:21][C:20]=2[F:32])[C:9]2[CH:17]=[CH:16][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[N:5]([CH3:7])[CH:6]=1
Reactant: CCc1ccc(F)c(C=Cc2ccc(C#N)cc2)c1
Reactant: CCOc1cc(CN(c2ccc(C(=N)N)cc2)c2nc(Br)cn2C)c(F)c(OC(C)C)c1
Agent: Cn1cnc(Br)c1
Product: CCc1ccc(F)c(CN(c2ccc(C#N)cc2)c2nc(Br)cn2C)c1

Procedure:
According to procedure for the preparation of Intermediate 259.1, Intermediate 262.1 and 4-bromo-1-methyl-1H-imidazole afforded Intermediate 262.2.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][CH:6]=[CH:5][C:4]=2[C:3]=1[C:11]#[N:12]>N.CO.[Ni]>[CH3:1][C:2]1[C:3]([CH2:11][NH2:12])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: Cc1ccc2[nH]ccc2c1C#N
Agent: [Ni]
Agent: N
Solvent: CO
Product: Cc1ccc2[nH]ccc2c1CN
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
A mixture of 302 (54 mg, 0.346 mmol) and Raney Ni (100 mg) in 7M ammonia in MeOH (20 mL) was stirred under hydrogen at RT for 3 h. It was filtered through Celite®, and the filtrate was concentrated under reduced pressure to afford 53 mg (95.7%) of (5-methyl-1H-indol-4-yl)methanamine (304) as yellow solid: MS (ESI) m/z=144.3 (M−16).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9]Br)=[CH:4][N:3]=1.[CH:12]1([CH2:15][NH:16][C:17]([NH2:19])=[S:18])[CH2:14][CH2:13]1.C(=O)(O)[O-].[Na+]>C(O)C>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[N:19]=[C:17]([NH:16][CH2:15][CH:12]3[CH2:14][CH2:13]3)[S:18][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(Br)nc1
Reactant: NC(=S)NCC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Brc1ccc(-c2csc(NCC3CC3)n2)cn1
Yield: 61 %

Procedure:
Slurry crude 2-bromo-5-(2-bromo-acetyl)-pyridine (11.5 g, ca. 48%), cyclopropylmethyl-thiourea (2.2 g, 16.9 mmol) and sodium bicarbonate (1.7 g, 20 mmol) in ethanol (100 mL) at room temperature. Stir the mixture at reflux for 1 h under a nitrogen atmosphere. Turn off heat and stir the mixture for 16 h at room temperature. Filter the slurry, then wash the solids with ethanol (50 mL), water (2×50 mL) and hexane (excess). Dry the solid in a vacuum oven for 20 h at 50° C. to obtain the desired intermediate as a tan solid (3.2 g, 61% over 2 steps). MS (ES+) m/z: 312 (M+2)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:30]=[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:28]([C:39]([CH3:41])=[CH2:40])=[CH:27][C:10]=1[C:11](NC1C=CC(CN2CCOCC2)=CC=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:42]([C:45]1[CH:46]=[C:47]2[C:51](=[CH:52][CH:53]=1)[CH2:50][NH:49][CH2:48]2)([O-:44])=[O:43].C(O)(C(F)(F)F)=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:30]=[C:29]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:28]([CH:39]([CH3:41])[CH3:40])=[CH:27][C:10]=1[C:11]([N:49]1[CH2:48][C:47]2[C:51](=[CH:52][CH:53]=[C:45]([N+:42]([O-:44])=[O:43])[CH:46]=2)[CH2:50]1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)c1cc(C(=O)Nc2ccc(CN3CCOCC3)cc2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc2c(c1)CNC2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1cc(C(=O)N2Cc3ccc([N+](=O)[O-])cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1

Procedure:
A solution of 2,4-bis-benzyloxy-5-isopropenyl-benzoic acid (505 mg; 1.3 mmol) (Preparation B5), 5-nitroisoindoline, TFA (360 mg; 1 equiv.), EDAC (300 mg; 1.2 equiv.), HOBt (210 mg; 1.2 equiv.) and NEt3 (270 μl; 1.5 equiv.) in DMF (10 ml) was stirred at room temperature overnight then evaporated in vacuo The residue was partitioned between EtOAc and 2M HCl, the EtOAc layer was separated, washed with saturated NaHCO3, dried (MgSO4) and evaporated. Purification by flash column chromatography (1:4 then 1:2 then 1:1 EtOAc/P.E. as eluant) gave 460 mg of (2,4-bis-benzyloxy-5-isopropyl-phenyl)-(5-nitro-1,3-dihydro-isoindol-2-yl) methanone. MS: [M+H]+ 328.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH:10]=[C:9]([C:20]([O:22][CH3:23])=[O:21])[C:8]=2[C:24]([O:26][CH3:27])=[O:25])=[CH:3][CH:2]=1.[CH:28](I)([CH3:30])[CH3:29]>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH:28]([CH3:30])[CH3:29])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH:10]=[C:9]([C:20]([O:22][CH3:23])=[O:21])[C:8]=2[C:24]([O:26][CH3:27])=[O:25])=[CH:3][CH:2]=1
Reactant: CC(C)I
Reactant: COC(=O)c1cc2cc(O)c(OC)cc2c(-c2ccncc2)c1C(=O)OC
Product: COC(=O)c1cc2cc(OC(C)C)c(OC)cc2c(-c2ccncc2)c1C(=O)OC

Procedure:
1-(4-Pyridyl)-2,3-bis(methoxycarbonyl)-6-hydroxy-7-methoxynaphthalene and isopropyl iodide are treated in the same manner as in Reference Example 117-(2) to give 1-(4-pyridyl)-2,3-bis(methoxycarbonyl)-6-isopropyloxy-7-methoxynaphthalene.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[NH:6][N:5]=1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>C1COCC1>[Br:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[N:6]([S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:13])=[CH:15][CH:16]=2)(=[O:22])=[O:21])[N:5]=1
Reactant: Brc1n[nH]c2ncccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2nc(Br)c3cccnc32)cc1
Reaction time: 0.17 h
Yield: 69.8 %

Procedure:
NaH (1.8 g, 44.9 mmol, 60% suspension in mineral oil) was added portionwise to a cold (0° C.) solution of 3-bromo-1H-pyrazolo[3,4-b]pyridine (3.7 g, 18.7 mmol) in dry THF (50 mL). After 10 minutes, 4-methylbenzene-1-sulfonyl chloride (5.3 g, 28.0 mmol) was added. The cold bath was removed, and the reaction mixture was left at room temperature overnight. The reaction mixture was placed in an ice bath, diluted with ethyl acetate (200 mL) and carefully quenched with water (20 mL). The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried, filtered and concentrated. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (7:3) to give 3-bromo-1-tosyl-1H-pyrazolo[3,4-b]pyridine (4.6 g, 70%) as a solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH3:7])[CH2:3]1.Cl[C:9]1[C:14]([C:15]#[N:16])=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([C:23]#[N:24])=[C:11]([S:25][CH2:26][C:27]2[N:28]=[C:29]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)[S:30][CH:31]=2)[N:10]=1>C1COCC1>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([C:29]2[S:30][CH:31]=[C:27]([CH2:26][S:25][C:11]3[C:12]([C:23]#[N:24])=[C:13]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:14]([C:15]#[N:16])=[C:9]([O:1][CH:2]4[CH2:6][CH2:5][N:4]([CH3:7])[CH2:3]4)[N:10]=3)[N:28]=2)=[CH:33][CH:34]=1
Reactant: CN1CCC(O)C1
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccccc1
Solvent: C1CCOC1
Product: CN1CCC(Oc2nc(SCc3csc(-c4ccc(Cl)cc4)n3)c(C#N)c(-c3ccccc3)c2C#N)C1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
25 μl (0.229 mmol) of 3-hydroxy-N-methylpyrrolidine are initially charged in 0.5 ml of THF, the mixture is cooled to 0° C., 249 μl (0.249 mmol) of phosphazene base P(4)-t-Bu (1M in THF) are added and the mixture is stirred at this temperature for 10 minutes. 120 mg (0.208 mmol) of the compound from Example 3A are then added, and the mixture is stirred at RT overnight. The reaction mixture is then purified by preparative HPLC (addition of 0.15% hydrochloric acid). This gives 38 mg of the impure target compound. This is dissolved in dichloromethane and washed twice with 1N hydrochloric acid, once with water and once with saturated aqueous sodium chloride solution. After drying over sodium sulphate, the organic phase is concentrated on a rotary evaporator and the crude product is purified once more by preparative HPLC (addition of 0.15% hydrochloric acid).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:13]2[CH:8]([NH:9][CH2:10][CH2:11][N:12]=2)[C:7](=[O:14])[NH:6][C:5]1=[O:15].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]=[CH2:27].O>CS(C)=O>[CH2:27]([N:6]1[C:7](=[O:14])[CH:8]2[C:13](=[N:12][CH2:11][CH2:10][NH:9]2)[N:4]([CH3:3])[C:5]1=[O:15])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=[CH2:17]
Reactant: C=CCCCCCCCCCBr
Reactant: CN1C(=O)NC(=O)C2NCCN=C21
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCCCCCCCCCN1C(=O)C2NCCN=C2N(C)C1=O
Reaction time: 0.33 h
Yield: 74.7 %

Procedure:
This example illustrates a synthesis of 7-(11,10-Oxidondecyl)-1-methyl-2,4-dioxotetrahydropteridine (inventive compound no. 1426). 1-Methyl-4,5-diaminouracil (13.6 g; 59.4 mole) was suspended in water (150 mL) and converted to its hydrochloride by drop-wise addition of concentrated hydrochloric acid unitl the solution is strongly acidic. Glyoxan sodiumbisulphite (20.4 g; 71.8 mmol) was then added and the reaction mixture refluxed for 30 minutes. The reaction mixture was cooled to room temperature and the precipitated 1-methyl-2,4-dioxotetrahydropteridine isolated by filteration, yielding 6.5 g (62%). Sodium hydride (95%,) (0.575 g, 24 mmol) was added to a solution of 1-methyl-2,4-dioxotetrahydropteridine (3.56 g, 20 mmol) in dimethylsulfoxide (100 mL). After 20 minutes of stirring, 1-bromoundec-10-ene (4.66 g, 20 mmol) was added and stirred for 12 hours at room temperature. The reaction mixture was then poured into a separatory funnel containing water (300 mL) and extracted with ethyl acetate (5×100 mL). The organic extracts were combined, washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product obtained was further purified by flash chromatography over silica gel using 50% hexane/ethyl acetate eluant to yield 5 g (94% yield) of 3-(10-undecenyl)-1-methyl-2,4-dioxotetrahydropteridine (inventive compound no. 1421). A solution of 3-(10-undecenyl)-1-methyl-2,4-dioxotetrahydropteridine (3.3 g, 10 mmol) and m-chloroperoxybenzoic acid (5.13 g; 15 mmol) (50% by wt) in dichloromethane (50 mL) was stirred for 5 hours. The reaction mixture was diluted with 40 mL of dichloromethane and washed successively with 20% aqueous sodium sulphite solution (20 mL), saturated sodium bicarbonate solution (20 mL), water (30 mL) and brine solutions (30 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product obtained was further purified by flash chromatography over silica gel using 40% petroleum ether/ethyl acetate eluant to yield 2.61 g (75% yield) of 7-(11,10-Oxidondecyl)-1-methyl-2,4-dioxotetrahydropteridine.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[C:4]([F:11])[CH:3]=1.[CH3:12][C:13]([CH3:18])([CH3:17])[CH2:14][CH:15]=O.[OH-].[Na+]>CC(O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5](/[C:6](=[CH:15]/[CH2:14][C:13]([CH3:18])([CH3:17])[CH3:12])/[C:7]#[N:8])=[C:4]([F:11])[CH:3]=1
Reactant: CC(C)(C)CC=O
Reactant: N#CCc1ccc(Cl)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CC(C)(C)C/C=C(\C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
To a solution of 4-chloro-2-fluoro-benzyl cyanide (Oakwood) (1.70 g, 10.0 mmol) and 3,3-dimethyl-butyraldehyde (Aldrich) (1.0 g, 10.0 mmol) in iPrOH (20 mL) was added 2 N NaOH (2.0 mL) dropwise at rt and the reaction mixture was stirred at rt overnight. The reaction mixture was diluted with EtOAc and the organic layer was separated, washed with water, brine, dried over Na2SO4 and concentrated. The residue was dried overnight in vacuum to give (Z)-2-(4-chloro-2-fluoro-phenyl)-5,5-dimethyl-hex-2-enenitrile (2.52 g, 100%) as a colorless oil which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1C(OC(C)(C)C)=O.C(N(CC)C(C)C)(C)C.[F:24][CH:25]([F:37])[O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([Cl:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1.Cl>C(Cl)Cl.O1CCOCC1>[ClH:36].[F:37][CH:25]([F:24])[O:26][C:27]1[CH:28]=[CH:29][C:30]([S:33]([N:6]2[CH2:5][CH2:4][NH:3][C@@H:2]([CH3:1])[CH2:7]2)(=[O:35])=[O:34])=[CH:31][CH:32]=1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)F)cc1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[C@H]1CN(S(=O)(=O)c2ccc(OC(F)F)cc2)CCN1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.3 %

Procedure:
To a solution of 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate (1.5 g, 7.49 mmol, supplier Aldrich) and N,N-diisopropylethylamine (1.962 mL, 11.23 mmol) in dry DCM (20 mL) was added 4-[(difluoromethyl)oxy]benzenesulfonyl chloride (1.253 mL, 7.86 mmol, supplier Aldrich) dropwise. The solution was stirred at room temperature for 4 h and then left to stand for 16 h. The solution was washed with aqueous sodium bicarbonate (20 mL), 0.5 M HCl (20 mL) and brine (20 mL) before the organic phase was isolated by phase separator. To the solution was added hydrochloric acid (1.872 mL, 7.49 mmol) 4M in dioxane and the reaction stirred at room temperature for 3 h. LCMS showed only partial reaction, so further hydrochloric acid (1.872 mL, 7.49 mmol) 4M in dioxane was added and the reaction stirred for 21 h. The reaction mixture was then concentrated under vacuum to give the title compound (2.448 g) as a pale yellow solid.