Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1(B(O)O)[CH2:3][CH2:2]1.C[O:8][C:9](=[O:34])[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:20][C:19]([C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=3)([C:21]([F:24])([F:23])[F:22])[O:18][N:17]=2)=[CH:12][C:11]=1Br>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH:1]1([C:11]2[CH:12]=[C:13]([C:16]3[CH2:20][C:19]([C:25]4[CH:26]=[C:27]([Cl:32])[CH:28]=[C:29]([Cl:31])[CH:30]=4)([C:21]([F:24])([F:22])[F:23])[O:18][N:17]=3)[CH:14]=[CH:15][C:10]=2[C:9]([OH:34])=[O:8])[CH2:3][CH2:2]1
Reactant: OB(O)C1CC1
Reactant: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
A solution of cyclopropyl boronic acid (0.67 g), 2-bromo-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-benzoic acid methyl ester (3 g) and Bis(triphenylphosphine)palladium(II) chloride (210 mg) were sequentially added to degassed toluene (38 ml). The reaction mixture was stirred for 30 min at room temperature then a degassed aqueous 2N solution of potassium phosphate (7 ml) was added and the resulting mixture was heated at 110° C. overnight. The reaction mixture was filtered over Hyflo and the resulting solution was concentrated in vacuo to give a yellow oil, which was poured into ethyl acetate. The organic phase was washed with water, dried over sodium sulfate, and the solvents were evaporated in vacuo. The product was used as such for the saponification step, as described in Example 17, Step E to afford the title acid compound (2.5 g) as a yellow solid. LCMS (Method F) 2.15 min M−H 442/444.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]([CH:20]3[CH2:24][CH2:23][N:22]([CH2:25][C:26](=[O:45])[N:27]4[CH2:32][CH2:31][N:30]([C:33]5[CH:38]=[CH:37][C:36]([C:39]6[N:44]=[CH:43][CH:42]=[CH:41][N:40]=6)=[CH:35][CH:34]=5)[CH2:29][CH2:28]4)[CH2:21]3)=[O:19])=[CH:14][CH:15]=2)[C:10]([NH2:46])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:47](Cl)(=[O:49])[CH3:48]>C(Cl)Cl.N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]([CH:20]3[CH2:24][CH2:23][N:22]([CH2:25][C:26](=[O:45])[N:27]4[CH2:28][CH2:29][N:30]([C:33]5[CH:34]=[CH:35][C:36]([C:39]6[N:40]=[CH:41][CH:42]=[CH:43][N:44]=6)=[CH:37][CH:38]=5)[CH2:31][CH2:32]4)[CH2:21]3)=[O:19])=[CH:14][CH:15]=2)[C:10]([NH:46][C:47](=[O:49])[CH3:48])=[N:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1nc(N)c2cc(NC(=O)C3CCN(CC(=O)N4CCN(c5ccc(-c6ncccn6)cc5)CC4)C3)ccc21
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1nn(C(=O)OC(C)(C)C)c2ccc(NC(=O)C3CCN(CC(=O)N4CCN(c5ccc(-c6ncccn6)cc5)CC4)C3)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 36 from Step 1 in CH2Cl2 (0.3 mL) and pyridine (0.3 mL) was added acetyl chloride (50 ul, 0.7 mmol) at rt. The crude was stirred at rt for 30 mins. The crude was quenched with sat. NaHCO3 at rt. The crude was partitioned between EtOAc and H2O. The organic layer was washed with H2O, brine, dried over MgSO4, filtered, and evaporated. The crude was chromatographed to give 20 mg of the product.
Reaction SMILES: Br[CH2:2][C:3]1[C:7]([Cl:8])=[CH:6][NH:5][N:4]=1.[CH3:9][C:10]1[N:15]=[C:14]([SH:16])[N:13]=[C:12]([OH:17])[CH:11]=1>>[Cl:8][C:7]1[C:3]([CH2:2][S:16][C:14]2[N:13]=[C:12]([OH:17])[CH:11]=[C:10]([CH3:9])[N:15]=2)=[N:4][NH:5][CH:6]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Clc1c[nH]nc1CBr
Product: Cc1cc(O)nc(SCc2n[nH]cc2Cl)n1

Procedure:
This example was synthesized from 3-(bromomethyl)-4-chloro-1H-pyrazole and 6-methyl-2-sulfanylpyrimidin-4-ol following general procedure as described in the last step of Example 22. The title compound was obtained as a white solid (500 mg, 20% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.21 (s, 3H), 3.17 (s, 1H), 4.40 (s, 2H), 6.00 (bs, 1H), 7.93 (s, 1H); M+ 257.
Reaction SMILES: [NH2:1][C:2](=[S:17])[CH2:3][N:4]1[C:8]([CH3:9])=[C:7]([C:10]([O:12]C(C)(C)C)=[O:11])[CH:6]=[N:5]1.Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=1)=O>>[CH3:9][C:8]1[N:4]([CH2:3][C:2]2[S:17][CH:19]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:30])([F:31])[F:32])[CH:23]=3)[N:1]=2)[N:5]=[CH:6][C:7]=1[C:10]([OH:12])=[O:11]
Reactant: O=C(CBr)c1cccc(OC(F)(F)F)c1
Reactant: Cc1c(C(=O)OC(C)(C)C)cnn1CC(N)=S
Product: Cc1c(C(=O)O)cnn1Cc1nc(-c2cccc(OC(F)(F)F)c2)cs1
Yield: 74.6 %

Procedure:
A reaction similar to Example 1c was performed using the compound (200 mg, 0.783 mmol) obtained in Example 11b and 2-bromo-1-[3-(trifluoromethoxy)phenyl]ethanone (222 mg, 0.783 mmol). As a result, the title compound (224 mg, 74%) wherein tert-butyl ester was hydrolyzed by hydrobromic acid produced under the reaction conditions was obtained as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](O)=[C:8]([C:17]#[N:18])[C:7]1=[O:19])[CH3:2].O=P(Cl)(Cl)[Cl:22]>O>[Cl:22][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]([CH2:5][CH2:4][O:3][CH2:1][CH3:2])[C:7](=[O:19])[C:8]=1[C:17]#[N:18]
Reactant: CCOCCn1c(=O)c(C#N)c(O)c2ccccc21
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCOCCn1c(=O)c(C#N)c(Cl)c2ccccc21
Temperature: 100 °C

Procedure:
To 1-(2-Ethoxy-ethyl)-4-hydroxy-2-oxo-1,2-dihydro-quinoline-3-carbonitrile (1 eq, 0,150 g, 0.58 mmole) was added POCl3 neat. The resulting solution was heated to 100° C. for 8 hours. Reaction mixture was added dropwise to water (20 mL) which had been heated to 80° C. then cooled to RT and extracted with ethyl acetate (25 mL×3). Combined, organic phase was Washed consecutively with water, brine before drying over sodium sulfate. Organic phase was evaporated and the residue was purified by flash chromatography to afford 4-Chloro-1-(2-ethoxy-ethyl)-2-oxo-1,2-dihydro-quinoline-3-carbonitrile as a yellow solid (0.109 g, 68%. LCMS calc M+H 277, obs M+H 277).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH:21]([C:30](=O)[C:31]#[C:32][CH:33]1[CH2:36][CH:35]([CH2:37][CH:38]([CH2:41][CH3:42])[CH2:39][CH3:40])[CH2:34]1)[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.S([O-])([O-])(=O)=O.[Na+].[Na+].[Cl-].[CH3:54][O:55][NH3+:56]>N1C=CC=CC=1>[Si:1]([O:18][CH2:19][CH2:20][CH:21]([C:30](=[N:56][O:55][CH3:54])[C:31]#[C:32][CH:33]1[CH2:36][CH:35]([CH2:37][CH:38]([CH2:39][CH3:40])[CH2:41][CH3:42])[CH2:34]1)[CH2:22][C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(CC)CC1CC(C#CC(=O)C(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC(=O)OC(C)(C)C)C1
Reactant: CO[NH3+]
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Product: CCC(CC)CC1CC(C#CC(=NOC)C(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
tert-Butyl 3-[2-(tert-butyldiphenylsilanyloxy)ethyl]-6-[3-(2-ethylbutyl)cyclobutyl]-4-oxo-5-hexynoate (9.70 g) and methanol (70 mL) were mixed. To the mixture were added sodium sulfate (4.57 g), pyridine (7.0 mL) and O-methylhydroxylammonium chloride (2.69 g). The mixture was stirred at RT overnight and filtered. The filtrate was concentrated in vacuo. The resultant residue was purified by silica gel column chromatography (Eluent: ethyl acetate/hexane=1/30→1/20) to give the title compound (7.85 g).
Reaction SMILES: [O:1]([C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]2)=[N:15][CH:16]=1)=O)C1C=CC=CC=1.O.[NH2:29][NH2:30].O>O1CCOCC1>[NH:29]([C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]2)=[N:15][CH:16]=1)=[O:1])[NH2:30]
Reactant: NN
Reactant: CCOC(=O)N1CCN(c2ccc(NC(=O)Oc3ccccc3)cn2)CC1
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)N1CCN(c2ccc(NC(=O)NN)cn2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 67 %

Procedure:
A mixture of ethyl 4-[5-[(phenoxycarbonyl)amino]-2-pyridinyl]-1-piperazinecarboxylate (0.3 mol crude residue) and hydrazine hydrate (1.5 mol) in 1,4-dioxane (1100 ml) was stirred for 6 hours at room temperature. The reaction mixture was poured into water (4000 ml) and the resulting precipitate was filtered. The filtrate was extracted three times with CH2Cl2 (700 ml each time). The separated organic layer was washed with water, dried, filtered and the solvent was evaporated. The residue was stirred in DIPE. The precipitate was filtered and dried (25° C.; 20 hours), yielding 62 g (67%) of ethyl 4-[5-[(hydrazinocarbonyl)amino]-2-pyridinyl]-1-piperazinecarboxylate (interm. 9).
Reaction SMILES: [C:1]1([CH:11]2[C:16](=[O:17])[NH:15][C:14](=[O:18])[NH:13][C:12]2=[O:19])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[BrH:20].BrBr>C(O)C>[Br:20][C:11]1([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[C:16](=[O:17])[NH:15][C:14](=[O:18])[NH:13][C:12]1=[O:19]
Reactant: Br
Reactant: O=C1NC(=O)C(c2cccc3ccccc23)C(=O)N1
Agent: BrBr
Solvent: CCO
Product: O=C1NC(=O)C(Br)(c2cccc3ccccc23)C(=O)N1
Temperature: 0 °C

Procedure:
A suspension of 5-naphtylbarbituric acid (0.2 g) in 1.5 ml of 95% ethanol, cooled at 0° C. and kept under stirring, is added dropwise with 48% hydrobromic acid (0.5 ml) and successively with 4.4 μl of bromine. After 4 hours under stirring at room temperature the solid is filtered and washed with water, then it is dried under vacuum at 40° C. overnight. 0.25 g of the product are obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]3([CH2:27][O:26][C:25]4[CH:28]=[C:29]5[C:33](=[CH:34][C:24]3=4)[CH2:32][CH2:31][O:30]5)[C:16]2=[O:35])[CH2:9]1)C1C=CC=CC=1.C(OCC)(=O)C>CO.[OH-].[OH-].[Pd+2]>[CH3:1][N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]3([CH2:27][O:26][C:25]4[CH:28]=[C:29]5[C:33](=[CH:34][C:24]3=4)[CH2:32][CH2:31][O:30]5)[C:16]2=[O:35])[CH2:9]1
Reactant: O=C1N(CC2CN(Cc3ccccc3)CCO2)c2ccccc2C12COc1cc3c(cc12)CCO3
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN1CCOC(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)C1
Yield: 9.3 %

Procedure:
1′-[(4-Benzylmorpholin-2-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.19 g, 0.41 mmol) was suspended in methanol (20 mL) and ethyl acetate (20 mL) in a steel bomb, then 20% palladium hydroxide on carbon (0.03 g, 0.04 mmol) was added. Hydrogenation was done at 120 psi in the steel bomb for 16 h. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated to dryness. The residue was purified by column chromatography (ethyl acetate/methanol/ammonia, 10:1:0.1) to afford 1′-[(4-methylmorpholin-2-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1H)-one (0.015 g, 10%) as a colorless foam as the first fraction: 1H NMR (300 MHz, CDCl3) δ7.34-7.25 (m, 1H), 7.17-6.99 (m, 3H), 6.48 (s, 0.5H), 6.44 (s, 0.5H), 6.39 (s, 1H), 4.94-4.88 (m, 1H), 4.69-4.63 (m, 1H), 4.52 (t, J=8.7 Hz, 2H), 4.00-3.55 (m, 5H), 2.97 (t, J=8.7 Hz, 2H), 2.76 (d, J=8.4 Hz, 1H), 2.60 (d, J=8.4 Hz, 1H), 2.26 (s, 3H), 2.18-1.88 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 178.1, 178.0, 161.8, 161.7, 161.2, 161.18, 142.7, 142.67, 132.7, 132.6, 128.7, 128.6), 123.7, 123.6, 123.3, 123.2, 120.4, 120.3, 119.8, 119.7, 118.9, 118.8, 109.6, 109.4, 93.2, 93.16, 80.5, 80.4, 73.7, 73.6, 72.3, 66.8, 66.6, 58.3 58.0, 57.6, 54.7, 54.6, 46.4, 46.3, 43.2, 43.17, 29.0; MS (ES+) m/z 393.0 (M+1), and 1-(morpholin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.04 g, 26%) as a colorless foam as the second fraction: MS (ES+) m/z 379.0 (M+1).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@:32]2([CH3:33])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:34])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:27])[CH2:18][CH2:19][C:20]([F:26])([F:25])[C:21]([OH:24])([CH3:23])[CH3:22])[CH2:8][C@@H:7]([O:35][C:36](=[O:38])[CH3:37])[CH2:6]1)(=[O:3])[CH3:2].C(=O)(O)[O-].[Na+].[Br:44]N1C(C)(C)C(=O)N(Br)C1=O>CCCCCC>[C:1]([O:4][C@@H:5]1[C@@:32]2([CH3:33])[C:9](=[CH:10][CH:11]([Br:44])[C@@H:12]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:34])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:27])[CH2:18][CH2:19][C:20]([F:26])([F:25])[C:21]([OH:24])([CH3:23])[CH3:22])[CH2:8][C@@H:7]([O:35][C:36](=[O:38])[CH3:37])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCC(F)(F)C(C)(C)O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Product: CC(=O)O[C@@H]1CC2=CC(Br)[C@H]3[C@@H]4CC[C@H]([C@H](C)CCC(F)(F)C(C)(C)O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Temperature: 80 °C

Procedure:
A mixture of 1.05 g (0.0019 mol) of [1α,3β]-24,24-difluorocholest-5-en-1,3,25-triol 1,3-diacetate, 0.84 g of sodium bicarbonate, 0.357 g (0.0012 mol) of 1,3-dibromo-5,5-dimethylhydantoin and 40 mL of hexane was heated at reflux (80° C.) for 1 hr and cooled. The mixture was filtered and the solids were triturated with hexane and filtered. The filtrates were evaporated to dryness to yield [1α,3β,7ξ]-7-bromo-24,24-difluorocholest-5-en-1,3,25-triol 1,3-diacetate.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([O:17][CH:18]([CH3:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])[CH2:13][CH2:14][CH2:15][CH3:16].O.Cl>N1C=CC=CC=1>[CH2:12]([O:17][CH:18]([CH3:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCOC(C)CCCCCO
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCCCOC(C)CCCCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.9 %

Procedure:
A solution of 2.26 g of p-toluenesulfonic acid chloride in 5 ml of pyridine was gradually added dropwise to a cooled solution of 2.04 g of 6-pentyloxyheptanol in 8 ml of pyridine for 7 min. below 5° C. After stirring for 5 hours at room temperature, the reaction mixture was injected into 150 ml of cold water and, after being acidified to pH 3 with 6N-hydrochloric acid, was extracted with ethyl acetate. The resultant solution was washed with water and dried with anhydrous magnesium sulfate, followed by distilling-off of the solvent to obtain 2.98 g of (6-pentyloxyheptyl)-p-toluenesulfonate.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][N:11]=[CH:12][CH:13]=2)[N:8]2[N:15]=[N:16][N:17]=[C:7]2[C:6]=1[N+:18]([O-])=O.S.[Na]>C(O)(=O)C.O>[CH3:1][CH:2]([CH3:21])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][N:11]=[CH:12][CH:13]=2)[N:8]2[N:15]=[N:16][N:17]=[C:7]2[C:6]=1[NH2:18]
Reactant: CC(C)CNc1c([N+](=O)[O-])c2nnnn2c2cnccc12
Agent: S
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)CNc1c(N)c2nnnn2c2cnccc12
Yield: 90.8 %

Procedure:
N5-(2-Methylpropyl)-4-nitrotetrazolo[1,5-a][1,7]naphthyridin-5-amine (1.5 g, 5.22 mmol) was suspended in acetic acid (75 mL). An excess of sodium hydrogen sulfide was dissolved in a minimum of water and added to the suspension. The reaction mixture turned red and all of the material went into solution. The reaction mixture was extracted twice with dichloromethane (150 mL). The extracts were combined, washed with water, dried over magnesium sulfate, filtered and concentrated under vacuum to provide 1.22 g of N5-(2-methylpropyl)tetrazolo[1,5-a][1,7]naphthyridin-4,5-diamine as a light yellow solid, m.p. 203-204.5° C. Analysis: Calculated for: C12H15N7: % C, 56.02; % H, 5.88; % N, 38.11; Found: % C, 55.68; % H, 5.81; % N, 37.74.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH2:15][CH2:14][NH:13][CH2:12][C:11]=2[CH:10]=[C:9]1[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].F[C:32]1[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][CH:33]=1.O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH2:15][CH2:14][N:13]([C:32]3[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][CH:33]=3)[CH2:12][C:11]=2[CH:10]=[C:9]1[C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1
Reactant: COc1ccc(-c2cc3c(n2-c2ccccc2Cl)CCNC3)cc1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc3c(n2-c2ccccc2Cl)CCN(c2ccc(C#N)cc2)C3)cc1
Temperature: 130 °C
Reaction time: 48 h
Yield: 43.1 %

Procedure:
To a suspension of 1-(2-chlorophenyl)-2-(4-methoxyphenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine (Example 2, 80.0 mg, 0.236 mmol) and K2CO3 (97.9 mg, 0.708 mmol) in 2 mL DMF was added 4-fluorobenzonitrile (86.0 mg, 0.472 mmol) under argon. The mixture was heated at 130° C. with stirring for 48 h. The mixture was cooled to rt, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over Na2SO4 and evaporated under reduced pressure. The crude product was purified on silica gel eluting with 1:3 EtOAc/hexanes to give a solid (44.7 mg, 43%): Rf=0.32 (1:2 EtOAc/hexanes).
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[N:9]=1.[F:19][C:20]([F:29])([F:28])[CH:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1>CCCCCC>[CH3:6][O:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:24]3([OH:27])[CH2:23][CH2:22][CH:21]([C:20]([F:28])([F:29])[F:19])[CH2:26][CH2:25]3)[CH:14]=2)[N:9]=1
Reactant: O=C1CCC(C(F)(F)F)CC1
Reactant: COc1ccc2cc(Br)ccc2n1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc2cc(C3(O)CCC(C(F)(F)F)CC3)ccc2n1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a cold (−78° C.) anhydrous THF solution of 2-methoxy-6-bromoquinoline (1.16 g, 4.89 mmol) was added w-BuLi (2.05 mL of a 2.5 M solution in hexane, 5.13 mmol). The mixture was stirred at −78° C. under a nitrogen atmosphere for 15 min and 4-(trifluoromethyl)cyclohexanone (0.81 g, 4.89 mmol) was added slowly to the reaction. After addition was complete, the bath was allowed to warm to room temperature. The reaction mixture was quenched with saturated NH4Cl (aq) and extracted with EtOAc/hexanes. The organic layer was dried over Na2SO4 and evaporated in vacuo and the resultant residue was purified by flash chromatography on silica gel using gradient elution (0% to 20% EtOAc/hexanes, 150 mL; 20% to 35% EtOAc/hexanes, 204 mL; 35% to 75% EtOAc/hexanes, 381 mL) to provide Isomer A as the faster-moving isomer and Isomer B as the slower-moving isomer.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([C@@H:12]1[CH2:17][C@@H:16]2[C@@H:14]([CH2:15]2)[NH:13]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:18]([C:21]1[C:29]2[C:24](=[CH:25][N:26]=[CH:27][CH:28]=2)[N:23]([CH2:30][C:31](O)=[O:32])[N:22]=1)(=[O:20])[CH3:19].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:2]([O:9][C:10]([C@@H:12]1[CH2:17][C@@H:16]2[C@@H:14]([CH2:15]2)[N:13]1[C:31](=[O:32])[CH2:30][N:23]1[C:24]2=[CH:25][N:26]=[CH:27][CH:28]=[C:29]2[C:21]([C:18](=[O:20])[CH3:19])=[N:22]1)=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1C[C@H]2C[C@H]2N1
Reactant: CC(=O)c1nn(CC(=O)O)c2cnccc12
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: CN(C)C=O
Product: CC(=O)c1nn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)OCc2ccccc2)c2cnccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (1R,3S,5R)-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid benzyl ester hydrochloride (2.98 g, 9.06 mmol), (3-acetyl-pyrazolo[3,4-c]pyridin-1-yl)-acetic acid (prepared as described in Part A, 3.2 g, 9.06 mmol) and HBTU (5.15 g, 13.59 mmol) in DMF (30.2 mL) was added DIPEA (4.75 mL, 27.2 mmol). The reaction mixture was stirred for 16 h at RT under a nitrogen atmosphere. DMF was evaporated. The residue was diluted in EtOAc and washed with aq. HCl 1N then with NaHCO3 (5% in water). The organic layer was dried (Phase separator) and concentrated. The residual oil was purified by flash column chromatography on silica gel (c-hexane/EtOAc 10:0 to 0:10) to give the title compound. TLC, Rf (EtOAc)=0.33; MS (UPLC-MS): 419 [M+H]+; tR (HPLC conditions d): 2.97 min.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[C:12]([O:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(O)cccc1C(=O)O
Product: CC(=O)Oc1cccc(C(=O)O)c1C

Procedure:
WO 95/09843 describes a multistage process for the preparation of 3-acetoxy-2-methylbenzoic acid. This process starts from 3-methoxybenzoyl chloride. The 3-methoxybenzoyl chloride is reacted with aniline to give 3-methoxy-N-phenylbenzamide. In a second step, the 3-methoxy-N-phenylbenzamide is reacted with 2 equivalents of n-butyllithium and then alkylated using methyl iodide. 3-Methoxy-2-methyl-N-phenylbenzamide is formed here, which is then reacted with aqueous hydrochloric acid and aqueous hydrogen bromide in boiling acetic acid with hydrolysis of the amide group and cleavage of the methoxy group to give 3-hydroxy-2-methylbenzoic acid. The 3-hydroxy-2-methylbenzoic acid must be acylated with acetic anhydride in order to obtain the 3-acetoxy-2-methyl-benzoic acid. The individual reaction steps are described in greater detail in WO 95/09843 under Preparation 9 A, B and C and Example 81.
Reaction SMILES: C([CH:5]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([C:18]2[S:19][CH:20]=[C:21]([S:23]([CH3:25])=[O:24])[N:22]=2)[C:10]1=[O:26])[C:6]([O-:8])=[O:7])(C)(C)C.C(Cl)Cl>C(O)(C(F)(F)F)=O>[CH3:25][S:23]([C:21]1[N:22]=[C:18]([N:11]2[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:9]([CH2:5][C:6]([OH:8])=[O:7])[C:10]2=[O:26])[S:19][CH:20]=1)=[O:24]
Reactant: CS(=O)c1csc(-n2c(=O)n(C(C(=O)[O-])C(C)(C)C)c3ccccc32)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)c1csc(-n2c(=O)n(CC(=O)O)c3ccccc32)n1

Procedure:
(±)-tert-Butyl{3-[4-(methylsulfinyl)-1,3-thiazol-2-yl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}acetate from Step D (100 mg, 0.254 mmol) was dissolved in TFA (3 mL) and CH2Cl2 (3 mL) and the mixture was stirred at ambient temperature for 3 h, then concentrated in vacuo to give the title compound. MS: m/z=338 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[N:9]2)[N:5]=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:3]=1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.Cl>CN1CCCC1=O>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:4]2[CH:3]=[C:2]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:7]=[C:6]([N:8]3[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[N:9]3)[N:5]=2)=[CH:17][CH:18]=1
Reactant: C1COCCN1
Reactant: Cc1cc(C)n(-c2nc(Cl)cc(Nc3ccc(Cl)cc3)n2)n1
Agent: Cl
Solvent: CN1CCCC1=O
Product: Cc1cc(C)n(-c2nc(Nc3ccc(Cl)cc3)cc(N3CCOCC3)n2)n1
Temperature: 110 °C
Reaction time: 1 h
Yield: 64.6 %

Procedure:
A mixture of [6-chloro-2-(3,5-dimethyl-pyrazol-1-yl)-pyrimidin-4-yl]-(4-chlorophenyl)-amine (125 mg, 0.37 mmol) and morpholine (0.32 mL, 3.74 mmol) in 1-methyl-2-pyrrolidinone (4 mL) was stirred for one hour at 110° C. The reaction mixture was allowed to cool down to room temperature, acidified with aqueous hydrochloric acid (1 M) and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulphate, filtrated and concentrated in vacuo. The crude product was purified by flash chromatography (dichloromethane/methanol as eluent) to give (4-chloro-phenyl)-[2-(3,5-dimethyl-pyrazol-1-yl)-6-morpholin-4-yl-pyrimidin-4-yl]-amine (92 mg, 64%) as a white solid. Mp. 186-187° C.