Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[O:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]2[C:21]([O:22]C)=[CH:20][N:19]=[CH:18][C:17]=2[Cl:24])=[CH:10][CH:9]=[CH:8][N:7]=1.Cl.N1C=CC=CC=1.C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[O:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]2[C:21]([OH:22])=[CH:20][N:19]=[CH:18][C:17]=2[Cl:24])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: COc1cncc(Cl)c1CCCOc1cccnc1Oc1cccc(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: Oc1cncc(Cl)c1CCCOc1cccnc1Oc1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
2-(3-Chlorophenoxy)-3-[3-(3-chloro-5-methoxypyridin-4-yl)-propoxy]pyridine (8.5 g, 21 mmol) obtained in Example 72 and pyridine hydrochloride (100 g, 0.86 mol) are mixed, and the mixture is stirred for melting at 150° C. for one hour. To the mixture is added ice-water (300 ml), and the mixture is neutralized with sodium hydrogen carbonate, and extracted with ethyl acetate (100 ml×3). The organic layer is washed with a saturated aqueous sodium hydrogen carbonate solution (50 ml×2) and a saturated brine (50 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by basic silica gel column chromatography (eluent: ethanol/ethyl acetate), and further recrystallized from diethyl ether/diisopropyl ether to give the title compound (5.6 g) as colorless crystals, m.p. 95-96° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[OH:18][CH2:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.ClCCl.C(#N)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([C:24]4[CH:25]=[C:20]([CH2:19][OH:18])[CH:21]=[CH:22][CH:23]=4)=[CH:7][N:6]3[CH:8]=2)=[CH:12][CH:13]=1
Reactant: OCc1cccc(B(O)O)c1
Reactant: Clc1ccc(-c2cn3cc(Br)ccc3n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC#N
Solvent: ClCCl
Product: OCc1cccc(-c2ccc3nc(-c4ccc(Cl)cc4)cn3c2)c1
Yield: 76.6 %

Procedure:
Under a stream of nitrogen, 210 mg of 6-bromo-2-(4-chlorophenyl)imidazo[1,2-a]pyridine, 155 mg of 3-(hydroxymethyl)phenylboronic acid and 24 mg of tetrakis(triphenylphosphine)palladium are placed in a microwave tube containing 3 ml of toluene degassed beforehand under a stream of nitrogen, 3 ml of acetonitrile and 3 ml of a 2M solution of sodium carbonate. The tube is placed in a microwave apparatus and irradiated at 150° C. for 15 min. The organic phase is separated and dried and the filtrate is concentrated under reduced pressure. The residue obtained is taken up with dichloromethane. The precipitate is recovered by filtration, washed with dichloromethane and dried in a desiccator under reduced pressure. 175 mg of compound are obtained. Mp=181-182° C. 1H NMR (DMSO-d6, δ in ppm): 4.57 (d, J=5.5 Hz, 2H); 5.23 (t, J=5.6 Hz, 1H); from 7.28 to 7.71 (m, 8H); 7.97 (m, J=8.5 Hz, 2H); 8.41 (s, 1H); 8.84 (m, 1H). M+H=335.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]2[C:14](Br)=[N:15][CH:16]=[C:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCN2C=NC=C2C1)C1C=CC=CC=1.C([Li])CCC.[Br:39]Br>C1COCC1.O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]2[CH:14]=[N:15][C:16]([Br:39])=[C:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ncc2n1CCN(Cc1ccccc1)C2
Reactant: BrBr
Agent: [Li]CCCC
Agent: c1ccc(CN2CCn3cncc3C2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Brc1ncn2c1CN(Cc1ccccc1)CC2
Reaction time: 0.25 h
Yield: 18.2 %

Procedure:
7-Benzyl-3-bromo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine: The synthesis of 7-benzyl-3-bromo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine is described in PCT/IB03/00998 WO 03/076427 A1. A solution of 7-benzyl-5,6,7,8-tetrahydro imidazo[1,5-a]pyrazine (450 mg, 2.110 mmol) in THF was cooled in dry ice acetone bath. n-Butyllithium (0.928 mL, 2.321 mmol) was added dropwise. After 15 mins, bromine (0.120 mL, 2.321 mmol) was added dropwise. After 1 h, the solution was poured into H2O and extracted with DCM (3×). Purified by normal phase chromatography to afford 7-benzyl-1-bromo-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine (112 mg, 0.383 mmol, 18.2% yield) and 71A (260 mg, 0.890 mmol, 42.2% yield). 1H NMR (400 MHz, CDCl3) δ 7.18-7.44 (m, 5 H) 6.71 (s, 1 H) 3.78-3.95 (m, 2 H) 3.68 (s, 2 H) 3.60 (s, 2 H) 2.75-2.97 (m, 2 H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]([F:15])=[CH:13][N:12]=[C:11](Cl)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:17][O:18][C:19]([C:21]1[O:22][C:23]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][C:24]=2[CH:25]=1)=[O:20]>CO>[NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]([F:15])=[CH:13][N:12]=[C:11]([NH:30][C:27]3[CH:28]=[CH:29][C:23]4[O:22][C:21]([C:19]([O:18][CH3:17])=[O:20])=[CH:25][C:24]=4[CH:26]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: COC(=O)c1cc2cc(N)ccc2o1
Solvent: CO
Product: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4cccc(N)c4)n3)ccc2o1
Temperature: 100 °C

Procedure:
A mixture of N4-(3-aminophenyl)-2-chloro-5-fluoro-4-pyrimidineamine (10 mg, 0.06 mmol) and 2-methoxycarbonyl-5-aminobenzofuran (36 mg, 0.18 mmol) in dry MeOH (0.5 ml) was refluxed for 2 days (100° C. oil-bath temperature). The mixture was cooled to 22° C., concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel (CHCl3:Acetone, 9:1) to give N4-(3-aminophenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofurane-5-yl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 8.24 (s, 1H), 7.96 (dd, 1H, J=1.7, 3.5 Hz), 7.46–7.59 (m, 3H), 6.93–6.99 (m, 2H), 6.84 (d, 1H, J=8.2 Hz), 6.35 (m, 1H), 3.84 (s, 3H); LCMS purity: 97.8%; MS (ES) m/e 394.02 (M+, 70).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]([OH:7])=[O:6].[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1>[OH:3][CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: BrCc1ccccc1
Reactant: O=C(O)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(CO)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
NaH (6.31 g, 158 mmol) was suspended in dry THF (500 ml) and cooled to 0° C. 2-hydroxyacetic acid (12 g, 158 mmol) was added portion wise, and the mixture was stirred at RT for 1 hour. The solvent was removed, and the residue was suspended in DMF (500 ml); KI (2.488 g, 14.99 mmol) and benzyl bromide (18.77 ml, 158 mmol) were added; and the mixture was heated to 100° C. for 24 hours. The solvent was removed, and the crude was portioned between EtOAc (600 ml) and water (200 ml). The organic phase was washed with brine and dried over Na2SO4. The solvent was removed and the crude was purified by flash chromatography on silica gel (petroleum ether/EtOAc 80/20). Benzyl 2-hydroxyacetate was obtained (18.089 g, 69% yield).
Reaction SMILES: [NH2:1][CH:2]([CH3:11])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][N:5]=1.[C:12](=[O:15])([OH:14])[O-].[Na+].Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>C(Cl)Cl>[C:12]([C:8]1[C:7]([OH:10])=[CH:6][N:5]=[C:4]([CH2:3][CH:2]([NH2:1])[CH3:11])[C:9]=1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])([O:14][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:15]
Reactant: CC(N)Cc1ccc(O)cn1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(N)Cc1ncc(O)c(C(=O)OCc2ccccc2)c1C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
The starting material is prepared as follows: To the solution of 0.5 g of 2-(2-aminopropyl)-5-pyridinol, 10 ml of methylene chloride and 10 ml of saturated aqueous sodium bicarbonate, 1.04 g of benzyl chloroformate are added while stirring at room temperature. After 12 hours the organic phase is separated, dried, evaporated and the residue crystallized from diethyl ether-hexane, to yield the bis-carbobenzyloxy-2-(2-aminopropyl)-5-pyridinol melting at 63°-65°.
Reaction SMILES: C(O[C@@H](C1C(C)=CC2N=C(N3C=CC=C(C4C=C5C(=CC=4)N(C)N=C5)C3=O)SC=2C=1C1C=CC(Cl)=CC=1)C(O)=O)(C)(C)C.[C:44]([O:48][C@@H:49]([C:54]1[C:79]([CH3:80])=[CH:78][C:57]2[N:58]=[C:59]([N:61]3[CH:66]=[C:65]([C:67]4[CH:68]=[C:69]5[C:73](=[CH:74][CH:75]=4)[N:72]([CH3:76])[N:71]=[CH:70]5)[CH:64]=[CH:63][C:62]3=[O:77])[S:60][C:56]=2[C:55]=1[C:81]1[CH:86]=[CH:85][C:84]([Cl:87])=[CH:83][CH:82]=1)[C:50]([O:52]C)=[O:51])([CH3:47])([CH3:46])[CH3:45]>>[C:44]([O:48][C@@H:49]([C:54]1[C:79]([CH3:80])=[CH:78][C:57]2[N:58]=[C:59]([N:61]3[CH:66]=[C:65]([C:67]4[CH:68]=[C:69]5[C:73](=[CH:74][CH:75]=4)[N:72]([CH3:76])[N:71]=[CH:70]5)[CH:64]=[CH:63][C:62]3=[O:77])[S:60][C:56]=2[C:55]=1[C:81]1[CH:82]=[CH:83][C:84]([Cl:87])=[CH:85][CH:86]=1)[C:50]([OH:52])=[O:51])([CH3:47])([CH3:45])[CH3:46]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-n3cc(-c4ccc5c(cnn5C)c4)ccc3=O)sc2c1-c1ccc(Cl)cc1
Agent: Cc1cc2nc(-n3cccc(-c4ccc5c(cnn5C)c4)c3=O)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Product: Cc1cc2nc(-n3cc(-c4ccc5c(cnn5C)c4)ccc3=O)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
Compound (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(5-(1-methyl-1H-indazol-5-yl)-2-oxopyridin-1(2H)-yl)benzo[d]thiazol-6-yl)acetic acid was prepared following the procedure used to (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-(1-methyl-1H-indazol-5-yl)-2-oxopyridin-1(2H)-yl)benzo[d]thiazol-6-yl)acetic acid of Example 27, except that (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(5-(1-methyl-1H-indazol-5-yl)-2-oxopyridin-1(2H)-yl)benzo[d]thiazol-6-yl)acetate was used instead of (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-(1-methyl-1H-indazol-5-yl)-2-oxopyridin-1(2H)-yl)benzo[d]thiazol-6-yl)acetate. 1H-NMR: 400 MHz, (CD3OD) δ 9.07 (d, J=2.8 Hz, 1H), 8.04 (s, 1H), 7.97 (s, 1H), 7.93 (dd, J=9.2, 2.4 Hz, 1H), 7.69-7.62 (m, 4H), 7.55-7.51 (m, 3H), 6.72 (d, J=9.6 Hz, 1H), 5.25 (s, 1H), 4.09 (s, 3H), 2.56 (s, 3H), 0.96 (s, 9H); LCMS-ESI+(m/z): [M+H]+ calcd for C33H30ClN4O4S: 613.17; Found: 613.2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([NH2:12])=[O:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[F:28])[CH2:23]Br>CC(CC)=O.O>[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[F:28])[CH2:23][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([NH2:12])=[O:11])=[CH:6][CH:7]=1
Reactant: Fc1ccc(CBr)cc1F
Reactant: NC(=O)CCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: NC(=O)CCc1ccc(OCc2ccc(F)c(F)c2)cc1
Reaction time: 24 h
Yield: 41.3 %

Procedure:
A mixture of 106 mg (0.64 mmol) 3-(4-hydroxy-phenyl)-propionamide, 178 mg (1.29 mmol) potassium carbonate and 140 mg (0.68 mmol) 3,4-difluorobenzyl bromide in 5 ml ethyl methyl ketone is hold at 50° C. for 24 hours. The reaction mixture is cooled, diluted with water and extracted with diethyl ether. Crystallization from n-hexane yields 77 mg (41%) of a colorless solid. MS: m/e=291.3 (M+).
Reaction SMILES: [ClH:1].[O:2](CCCNC(C)(C)CC1C=CC(OC)=CC=1)[C:3]1C=CC=CC=1.Cl.O[C@H](COC1C=CC(C(C)(C)C)=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1.Cl.OC(COC1C2C(=CC=CC=2)C=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1.Cl.[OH:84][CH:85]([CH2:100][O:101][C:102]1[CH:107]=[CH:106][C:105]([O:108][CH3:109])=[CH:104][CH:103]=1)[CH2:86][NH:87][C:88]([CH3:99])([CH3:98])[CH2:89][C:90]1[CH:95]=[CH:94][C:93]([O:96][CH3:97])=[CH:92][CH:91]=1>>[ClH:1].[OH:84][CH:85]([CH2:100][O:101][C:102]1[CH:107]=[CH:106][C:105]([O:108][CH3:109])=[C:104]([O:2][CH3:3])[CH:103]=1)[CH2:86][NH:87][C:88]([CH3:99])([CH3:98])[CH2:89][C:90]1[CH:91]=[CH:92][C:93]([O:96][CH3:97])=[CH:94][CH:95]=1
Reactant: COc1ccc(CC(C)(C)NCCCOc2ccccc2)cc1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(OC)cc2)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2cccc3ccccc23)cc1
Agent: COc1ccc(CC(C)(C)NC[C@H](O)COc2ccc(C(C)(C)C)cc2)cc1
Agent: Cl
Product: COc1ccc(CC(C)(C)NCC(O)COc2ccc(OC)c(OC)c2)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 390 (M+, 0.0), 269 (17), 268 (100), 163 (6), 153 (5), 121 (21), 114 (17), 77 (5), 71 (19), 70 (17), 58 (7).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:4]=[C:5]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:6]3=[N:7][C:8]=2[N:9]=[CH:10][C:11]=1[C:12]#[N:13].[Cl:22][C:23]1[CH:29]=[C:28]([Cl:30])[C:27]([O:31][CH3:32])=[CH:26][C:24]=1[NH2:25].Cl.N1C=CC=CC=1>C(OCCO)C>[Cl:22][C:23]1[CH:29]=[C:28]([Cl:30])[C:27]([O:31][CH3:32])=[CH:26][C:24]=1[NH:25][C:2]1[C:3]2[CH:4]=[C:5]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:6]3=[N:7][C:8]=2[N:9]=[CH:10][C:11]=1[C:12]#[N:13]
Reactant: COc1cc(N)c(Cl)cc1Cl
Reactant: COc1cc2cc3c(Cl)c(C#N)cnc3nc2cc1OC
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc(Nc2c(C#N)cnc3nc4cc(OC)c(OC)cc4cc23)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 37.8 %

Procedure:
A mixture of 4-chloro-7.8-dimethoxybenzo[b][1,8]naphthyridine-3-carbonitrile (150 mg, 0.50 mmol), 2,4-dichloro-5-methoxyaniline (160 mg, 0.83 mmol) and pyridine hydrochloride (70 mg, 0.60 mmol) in 15 mL of 2-ethoxyethanol is heated at reflux for 25 minutes then cooled to room temperature. The solution is partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is partitioned between ethyl acetate and an aqueous solution of sodium hydroxide and sodium bicarbonate (pH 14). The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. Diethyl ether is added to the residue and the resultant bright orange solid is collected to provide 86 mg (38%) of 4-(2,4-dichloro-5-methoxyanilino)-7,8-dimethoxybenzo[b][1,8]naphthyridine-3-carbonitrile, mp 297° C. dec.
Reaction SMILES: C(O)(C(F)(F)F)=O.COC1C=CC(C[N:15]2[C:19]3=[N:20][CH:21]=[C:22]([C:37]([F:40])([F:39])[F:38])[C:23]([N:24]4[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]4)=[C:18]3[CH:17]=[N:16]2)=CC=1.C(Cl)[Cl:44]>>[ClH:44].[ClH:44].[N:24]1([C:23]2[C:22]([C:37]([F:39])([F:40])[F:38])=[CH:21][N:20]=[C:19]3[NH:15][N:16]=[CH:17][C:18]=23)[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]1
Reactant: ClCCl
Reactant: COc1ccc(Cn2ncc3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(C(F)(F)F)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: FC(F)(F)c1cnc2[nH]ncc2c1N1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
TFA (0.5 mL) was added to a solution of tert-butyl 4-(1-(4-methoxybenzyl)-5-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.114 g, 0.232 mmol) in DCM (2 mL) and stirred at room temperature for 1 hour. The reaction was then concentrated to dryness. The resulting residue was dissolved in TFA (1.79 mL, 23.2 mmol) and heated at 65° C. for 2 hours. The reaction was again concentrated to dryness. The resulting residue was dissolved in DCM (0.5 mL), and HCl in ether (2 mL, 2N) was added. The resulting solid was collected by filtration to give 4-(piperazin-1-yl)-5-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine dihydrochloride (0.075 g, 94%). MS APCI (+) m/z 272.0 detected.
Reaction SMILES: [N:1]([N:3]1[C:8]([CH3:10])([CH3:9])[CH2:7][S:6](=[O:12])(=[O:11])[CH2:5][C:4]1([CH3:14])[CH3:13])=O>C(O)(=O)C.O.[Zn]>[NH2:1][N:3]1[C:4]([CH3:13])([CH3:14])[CH2:5][S:6](=[O:12])(=[O:11])[CH2:7][C:8]1([CH3:10])[CH3:9]
Reactant: CC1(C)CS(=O)(=O)CC(C)(C)N1N=O
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)CS(=O)(=O)CC(C)(C)N1N
Temperature: 50 °C
Reaction time: 3 h

Procedure:
22.0 g (0.1 mole) of 1-nitroso-2,2,6,6-tetramethyl-1-aza-4-thiacyclohexane-4,4-dioxide is suspended in a mixture of 150 ml of glacial acetic acid and 100 ml of water. Within 3 hours, 40 g of zinc dust is introduced in small portions, the temperature being maintained between 30° and 35° C. The reaction mixture is subsequently fully stirred for 5 hours at 50° C; the zinc sediment is filtered off hot, and the cooled filtrate rendered alkaline with sodium hydroxide solution. It is extracted with ether, the ether solution dried over sodium sulphate, and the solvent evaporated off. Crystallisation of the residue from ligroin yields 1-amino-2,2,6,6-tetramethyl-1-aza-4-thiacyclohexane-4,4-dioxide (10), M.P. 122° C.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](Cl)=[C:5]([Cl:12])[N:4]=1)#[N:2].[CH2:13]([SH:15])[CH3:14].N1C=CC=CC=1>CC(C)=O.O>[C:9]([C:8]1[C:3]([C:1]#[N:2])=[N:4][C:5]([Cl:12])=[C:6]([S:15][CH2:13][CH3:14])[N:7]=1)#[N:10]
Reactant: N#Cc1nc(Cl)c(Cl)nc1C#N
Reactant: CCS
Solvent: O
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CCSc1nc(C#N)c(C#N)nc1Cl
Yield: 29.4 %

Procedure:
2,3-Dicyano-5,6-dichloropyrazine (1.00 g; 0.005 mole) and 0.47 g of ethanethiol were dissolved in 50 ml of acetone. The solution was cooled to -15° to -10° C., and a solution of 0.40 g (0.005 mole) of pyridine in 40 ml of water was added dropwise over the period of 30 minutes. The mixture was worked up in the same way as in Example 26 to afford 0.33 g (yield 29%) of 2,3-dicyano-5-chloro-6-ethylthiopyrazine.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])[CH:18]=2)[N:9]=1.[CH2:32]=O>CO.C(Cl)Cl>[CH3:32][N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C@H:24]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH3:25])[CH:18]=2)[N:9]=1
Reactant: CC(Nc1cc(-c2cc3nccn3c(N3CC4CC3CN4)n2)ccn1)c1ccccc1
Reactant: C=O
Solvent: CO
Solvent: ClCCl
Product: C[C@H](Nc1cc(-c2cc3nccn3c(N3C[C@@H]4C[C@H]3CN4C)n2)ccn1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 96 mg (0.23 mmol) {4-[5-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-imidazo[1,2-c]pyrimidin-7-yl]-pyridin-2-yl}-(1-phenyl-ethyl)-amine in 3 mL methanol was treated with 0.17 mL (2.3 mmol) formaldehyde (37% in water) and 150 mg (0.70 mmol) NaBH3(CN). The mixture was stirred at ambient temperature for 1 h when MS showed that all starting materials had converted to product. The reaction mixture was diluted with 50 mL DCM, washed with 50 mL satd. NaHCO3, and dried over anhydrous Na2SO4. After purification by HPLC, the title compound was obtained. MS (ES+): 426 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])[CH:5]=[CH:4][CH:3]=1.[CH3:19][C:20](=O)[CH2:21][CH2:22][C:23](=O)[CH3:24].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:18][C:16]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([NH:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([N:1]3[C:23]([CH3:24])=[CH:22][CH:21]=[C:20]3[CH3:19])[N:7]=2)[CH:17]=1
Reactant: CC(=O)CCC(C)=O
Reactant: Nc1cccc(Nc2cc(Cl)ccc2C(=O)O)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: Cc1ccc(C)n1-c1cccc(Nc2cc(Cl)ccc2C(=O)O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
A slurry of 2-(6-amino-pyridin-2-ylamino)-4-chlorobenzoic acid (2.4 g) and 2,5-hexanedione (1.04 g) and p-toluenesulfonic acid (0.15 g) was heated at reflux in a Dean-Stark trap for 24 h. The resulting mixture was cooled to RT and filtered, then stirred with H2O (50 mL) overnight, filtered, and dried to yield 4-chloro-2-[6-(2,5-dimethyl-pyrrol-1-yl)-pyridin-2-ylamino]-benzoic acid (2.4 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1.[CH3:19][O-:20].[Na+].Cl>CO>[CH3:19][O:20][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc(OCCCCCCBr)cc1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COCCCCCCOc1ccc(C(=O)OC)cc1

Procedure:
A solution of methyl 4-(6-bromo-n-hexyloxy)benzoate (186 g) in methanol (1 L) was treated with 28% sodium methoxide in methanol (340 ml) and the solution refluxed for 2 hours. After cooling, the stirred solution was adjusted to pH 2 with 1M-hydrochloric acid then extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, filtered and evaporated to give a crude oil. This oil was purified on a silica gel column (2 kg, 9:1 hexane-ethyl acetate elution) to give methyl 4-(6-methoxy-n-hexyloxy)benzoate (127 g) as an oil.
Reaction SMILES: [CH2:1]([Zn]CC)C.FC(F)(F)C(O)=O.ICI.[Si:16]([O:23][C@H:24]1[CH2:33][C:32]([CH3:35])([CH3:34])[CH2:31][C:30]2[N:29]=[C:28]([C:36]([CH3:38])=[CH2:37])[C:27]3[C@@H:39]([C:47]4[CH:52]=[CH:51][C:50]([C:53]([F:56])([F:55])[F:54])=[CH:49][CH:48]=4)[O:40][C:41]4([CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)[C:26]=3[C:25]1=2)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>ClCCl>[Si:16]([O:23][C@H:24]1[CH2:33][C:32]([CH3:35])([CH3:34])[CH2:31][C:30]2[N:29]=[C:28]([C:36]3([CH3:1])[CH2:38][CH2:37]3)[C:27]3[C@@H:39]([C:47]4[CH:52]=[CH:51][C:50]([C:53]([F:56])([F:54])[F:55])=[CH:49][CH:48]=4)[O:40][C:41]4([CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)[C:26]=3[C:25]1=2)([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:18])[CH3:17]
Reactant: C=C(C)c1nc2c(c3c1[C@@H](c1ccc(C(F)(F)F)cc1)OC31CCOCC1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Reactant: CC[Zn]CC
Solvent: ICI
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)Cc2nc(C3(C)CC3)c3c(c2[C@@H](O[Si](C)(C)C(C)(C)C)C1)C1(CCOCC1)O[C@@H]3c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
536 μl Diethylzinc (1 M in n-hexane) are dissolved in 5 ml dichloromethane, cooled to 0° C. and treated dropwise with a solution of 41 μl trifluoroacetic acid in 5 ml dichloromethane. The mixture is stirred for 20 minutes and then 41 μl diiodomethane in 2.5 ml dichloromethane are added dropwise. After stirring for further 20 minutes a solution of 150 mg (3R,9S)-9-(tert-butyldimethylsilyloxy)-7,7-dimethyl-4-(prop-1-en-2-yl)-3-(4-(trifluoromethyl)phenyl)-2′,3′,5′,6,6′,7,8,9-octahydro-3H-spiro[furo[3,4-c]quinoline-1,4′-pyran] in 2.5 ml dichloromethane are added dropwise. The mixture is then allowed to warm to room temperature and is stirred for 4 hours. Then it is partitioned between saturated solution of sodium bicarbonate in water and dichloromethane. The aqueous phase is twice extracted with dichloromethane. The combined organic phases are dried with sodium sulphate and the solvents are evaporated in vacuo. The residue is chromatographed on silica gel (petrole ether/ethylacetate 100:0 to 85:15).
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[C:1]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Oc1cccc([N+](=O)[O-])c1)c1ccccc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1cccc(OC(=O)c2ccccc2)c1
Temperature: 100 °C
Yield: 100 %

Procedure:
3-Nitrophenyl benzoate (2.7080 g, 11.144 mmol) and tin (II) chloride dihydrate (12.564 g, 55.720 mmol) were dissolved in 60 mL of ethanol and heated at 100° C. for 1 hour. The reaction crude was allowed to cool to room temperature, and an aqueous solution of sodium carbonate was added until pH 8. The crude material was extracted with dichloromethane (3×50 mL), magnesium sulfate was added to the organic phase, filtered and the solvent was removed under reduced pressure, thus affording 2.374 g (11.143 mmol, yield=100%) of 3-aminophenyl benzoate.