Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH:15]([CH3:17])[O:14][CH:13]([CH3:18])[CH2:12]2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O.[O:20]=[C:21](Cl)OC(Cl)(Cl)Cl>O1CCOCC1>[CH3:18][CH:13]1[O:14][CH:15]([CH3:17])[CH2:16][N:11]([C:8]2[CH:7]=[C:3]3[C:4]([O:6][C:21](=[O:20])[NH:1][C:2]3=[CH:10][CH:9]=2)=[O:5])[CH2:12]1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC1CN(c2ccc(N)c(C(=O)O)c2)CC(C)O1
Solvent: C1COCCO1
Solvent: O
Product: CC1CN(c2ccc3[nH]c(=O)oc(=O)c3c2)CC(C)O1

Procedure:
To the mixture of 8.9 g of 2-amino-5-(2,6-dimethylmorpholin-4-yl)benzoic acid in 60 ml of dioxane, under stirring and external cold water cooling 10 ml of diphosgene is added dropwise. The mixture is heated under reflux conditions for 4 hours. From the cold reaction mixture the solid material is filtered off, washed with 50 ml of ether. The product is stirred for 5 minutes in the mixture of 50 ml of methanol and 5 ml of triethylamine, then filtered off and washed with 30 ml of methanol. After drying 7 g of the title product is obtained (MH+: 277).
Reaction SMILES: [C:1]1([C:11]([O:13][C:14]([CH3:18])(C)[C:15]#[CH:16])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:19]1(C(O)=O)C2C(=CC=CC=2)C=CC=1.CC(O)(C)C#C>>[C:1]1([C:11]([O:13][CH:14]([CH2:15][CH3:16])[C:18]#[CH:19])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cccc2ccccc12
Reactant: C#CC(C)(C)OC(=O)c1cccc2ccccc12
Agent: C#CC(C)(C)O
Product: C#CC(CC)OC(=O)c1cccc2ccccc12

Procedure:
1,1-dimethyl-2-propynyl 1-naphthoate, nD20 =1.5765, is prepared from 1-naphthoic acid and 3-methyl-1-butyn-3-ol.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][CH2:8][C:9]1[CH:13]=[CH:12][S:11][CH:10]=1.CN(C)[CH:16]=[O:17].O>CCOCC>[CH3:6][O:7][CH2:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[CH:16]=[O:17]
Reactant: CN(C)C=O
Reactant: COCc1ccsc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: COCc1ccsc1C=O
Reaction time: 1 h
Yield: 62.4 %

Procedure:
Reaction of 3-bromomethylthiophene with sodium methoxide in methanol provided 3-methoxymethylthiophene (84%). n-Butyl lithium (30 ml, 1.5 M, 45 mmol) was slowly added to 3-methoxymethylthiophene (5.0 g, 39 mmol) in dry ether (100 ml) at 25° C. After stirring for 1 h, N,N-dimethylformamide (5.7 g, 78 mmol) in dry ether (200 ml) was added dropwise and the resultant solution was stirred for an additional 18 h at 20° C. Water (5 ml) was added and the organic phase washed with 5% hydrochloric acid (100 ml) followed by water (100 ml) and dried. The solvent was removed to yield the crude product (5.2 g, 85%) which was essentially pure by n.m.r. Distillation afforded the title compound (3.80 g, 62%) as a colourless oil, b.p. 73°-75° C. at 0.25 mmHg (Found M+ : 156.0256. C7H8O2S requires M, 156.0245) which showed νmax (film) 667m, 1107m, 1200w, 1426m, 1662s, 2930w and 3100w cm-1 ; δH (CCl4) 3.35 (3H, s), 4.66 (2H, s), 7.05 (1H, d, J 5 Hz), 7.49 (1H, d, J 5 Hz), 9.87 (1H, s); m/z 156 (M+), 141 (M+ -CH3).
Reaction SMILES: C[O:2][C:3](=[O:38])[CH:4]([NH:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[NH:29][C:28]2=[O:37])[CH2:23][CH2:22]1)=[O:20])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([CH2:15][CH3:16])[CH:14]=1)[NH:11][N:10]=[C:9]2[CH3:17].O1CCCC1.CO.O.[OH-].[Li+]>O>[CH2:15]([C:13]1[CH:14]=[C:6]([CH2:5][CH:4]([NH:18][C:19]([N:21]2[CH2:22][CH2:23][CH:24]([N:27]3[CH2:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[NH:29][C:28]3=[O:37])[CH2:25][CH2:26]2)=[O:20])[C:3]([OH:38])=[O:2])[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[CH3:17])[CH3:16]
Reactant: CCc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)OC)cc2c(C)n[nH]c12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)O)cc2c(C)n[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
A suspension of (±)-3-(7-ethyl-3-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid methyl ester (0.94 g, 1.81 mmol) in 1:1 tetrahydrofuran/methanol (30 mL) at room temperature was treated with a solution of lithium hydroxide monohydrate in water (10 mL). The solution was stirred at room temperature for 1 hand the solvents evaporated. The resultant residue was diluted with water (10 mL) and the pH adjusted to ca. 1 with 1N hydrochloric acid. The resultant white suspension was stored at 4° C. overnight and the product was collected by filtration, washed by a small amount of water and dried in vacuo for several hours to give 0.82 g (90%) of the desired product. LC/MS: tR=1.57 min, 505.29 (MH)+.
Reaction SMILES: [O:1]=[S:2]1(=[O:29])[C:11]2[C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=O)=[CH:15][CH:14]=3)=[N:9][C:8]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.C(Cl)CCl.C1C=[CH:36][C:37]2N(O)N=[N:40][C:38]=2C=1.C(N)CC>CN(C=O)C.C(OCC)(=O)C>[O:1]=[S:2]1(=[O:29])[C:11]2[C:10]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([CH2:19][C:20]([NH:40][CH2:38][CH2:37][CH3:36])=[O:22])=[CH:17][CH:18]=3)=[N:9][C:8]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[N:7][C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: O=C(O)Cc1ccc(Nc2nc(-c3ccccc3)nc3c2S(=O)(=O)CCC3)cc1
Reactant: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCNC(=O)Cc1ccc(Nc2nc(-c3ccccc3)nc3c2S(=O)(=O)CCC3)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.2 %

Procedure:
To a solution of 2-(4-((5,5-dioxido-2-phenyl-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetic acid (0.115 g, 0.28 mmol) in DMF (4 mL) was added EDC (0.107 g, 0.56 mmol), HOBT (0.076 g, 0.56 mmol) and n-propylamine (0.12 mL, 1.4 mmol). The mixture was stirred at rt for 16 h. The mixture was diluted with ethyl acetate and then washed with water. The organic layer were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by column chromatography (silica, dichloromethane/methanol) to afford the desired product (0.110 g, 87%) as a white solid. MW=450.55. 1H NMR (DMSO-d6, 500 MHz) δ 8.74 (s, 1H), 8.29-8.25 (m, 2H), 8.05-7.99 (m, 1H), 7.63-7.49 (m, 5H), 7.33 (d, J=8.5 Hz, 2H), 3.76-3.71 (m, 2H), 3.42 (s, 2H), 3.10-2.99 (m, 4H), 2.42-2.35 (m, 2H), 1.45-1.38 (m, 2H), 0.85 (t, J=7.5 Hz, 3H); APCI MS m/z 451 [M+H]+.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C@H:9]([C:16]1[CH:28]=[CH:27][C:19]([C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Br)=[CH:32][CH:31]=1>>[CH3:1][C@H:2]1[CH2:7][N:6]([CH2:34][C:33]2[CH:36]=[CH:37][C:30]([F:29])=[CH:31][CH:32]=2)[C@H:5]([CH3:8])[CH2:4][N:3]1[C@H:9]([C:16]1[CH:17]=[CH:18][C:19]([C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])=[CH:27][CH:28]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CCN(CC)C(=O)c1ccc([C@H](c2ccccc2)N2C[C@@H](C)NC[C@@H]2C)cc1
Product: CCN(CC)C(=O)c1ccc([C@H](c2ccccc2)N2C[C@@H](C)N(Cc3ccc(F)cc3)C[C@@H]2C)cc1

Procedure:
4-((alpha-S)-alpha-((2S,5R)-2,5-Dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)benzyl)-N,N-diethylbenzamide was prepared from 4-((alpha-S)-alpha-((2S,5R)-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-diethylbenzamide (Example 1) and 4-fluorobenzyl bromide by a procedure similar to that described in Example 1. Calc. for C31H38FN3O: C, 76.35; H, 7.85; N, 8.62; F, 3.90. Found C, 76.32; H, 7.86; N, 8.60; F, 3.95% 1H NMR (CDCl3, 600 MHz); δ 1.07 (d, J=6.2 Hz, 3H); 1.10 (d, J=6.3 Hz, 3H, partially overlapped by br m, 3H); 1.23 (br m, 3H); 1.93 (m, 1H); 1.98 (dd, J=11.1, 8.3 Hz, 1H); 2.54 (br m, 2H); 2.65 (m, 2H); 3.14 (d, J=13.1 Hz, 1H); 3.28 (br m, 2H); 3.54 (br m, 2H); 3.86 (d, J=13.1 Hz, 1H); 5.15 (s, 1H); 6.90 (t, J=8.2 Hz, 2H); 7.20 (d, J=7.3 Hz, 2H); 7.24 (m, 2H); 7.27 (m, 1H; partially overlapped by CHCl3); 7.29 (d, J=9.4 Hz, 2H); 7.33 (m, 2H); 7.46 (d, J=8.1 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=3)[N:10]([S:21]([C:24]3[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH:9]=2)[C:5]([C:31]#[N:32])=[CH:4][N:3]=1.CC(C)([O-])C.[K+].[CH2:39]([O:41][P:42](Cl)([O:44][CH2:45][CH3:46])=[O:43])[CH3:40].C([O-])(O)=O.[Na+]>C1COCC1>[P:42]([O:44][CH2:45][CH3:46])([O:41][CH2:39][CH3:40])([O:1][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([C:17]([F:18])([F:20])[F:19])[CH:15]=3)[N:10]([S:21]([C:24]3[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH:9]=2)[C:5]([C:31]#[N:32])=[CH:4][N:3]=1)=[O:43]
Reactant: CCOP(=O)(Cl)OCC
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(O)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)Oc1ncc(C#N)c(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(C(F)(F)F)cc23)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 58.4 %

Procedure:
2-hydroxy-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile (87% pure, 1.23 g, 2.329 mmol) in dry THF (24.60 mL) was stirred at −25° C. and treated with potassium t-butoxide (2.795 mL of 1.0 M, 2.795 mmol) in THF. The reaction mixture was warmed up to 0° C. for 20 minutes, cooled to −50° C. and treated with diethylchlorophosphate (482.3 mg, 403.9 μL, 2.795 mmol). The reaction mixture was stirred at −40° C. for 20 minutes and at room temperature for 2 hours. The reaction mixture was diluted with ice cold ethyl acetate (60 mL), cooled in ice and shaken quickly with ice cold water containing 1M HCl (2.8 mL, 2.8 mmol), basified with aqueous NaHCO3 and extracted into ethyl acetate. The organic extracts were dried over magnesium sulfate and concentrated to give a pale yellow solid which was triturated with ether and filtered to give a pale yellow solid (810 mg). The mother liquors were concentrated in vacuo and the residue purified on silica gel by flash column chromatography to afford a colourless solid (219 mg) (total: 1.029 g, 74% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:9]=1.[Br:26][C:27]1[N:32]=[C:31]([C:33](O)=[O:34])[CH:30]=[CH:29][CH:28]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN1C(=O)CCC1>[Br:26][C:27]1[N:32]=[C:31]([C:33]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C:8]2[N:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[N:11]=[C:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])[CH:9]=2)=[O:34])[CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(-c2ccncc2N)nc(C(F)(F)F)n1
Reactant: O=C(O)c1cccc(Br)n1
Agent: On1nnc2cccnc21
Solvent: CN1CCCC1=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)Nc1cc(-c2ccncc2NC(=O)c2cccc(Br)n2)nc(C(F)(F)F)n1
Yield: 95 %

Procedure:
Method 27 was followed using tert-butyl 6-(3-aminopyridin-4-yl)-2-(trifluoromethyl)pyrimidin-4-ylcarbamate (1.0 equiv.), 6-bromopicolinic acid (1.0 equiv.), EDC (1.0 equiv.), and HOAt (1.0 equiv.) in NMP yielding tert-butyl 6-(3-(6-bromopicolinamido)pyridin-4-yl)-2-(trifluoromethyl)pyrimidin-4-ylcarbamate>95% yield. LCMS (m/z): 539/541 (MH+); LC Rt=3.97 min.
Reaction SMILES: C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[CH:14]1[C:19]2[N:20]=[C:21]3[C:33]4[C:25]([C:26]5[C:31]([N:32]=4)=[CH:30][CH:29]=[CH:28][CH:27]=5)=[CH:24][CH:23]=[C:22]3[C:18]=2[CH:17]=[CH:16][CH:15]=1.[C:34]1([C:47]2[CH:48]=[C:49](Br)[CH:50]=[CH:51][CH:52]=2)[C:46]2[NH:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:38]=2[CH:37]=[CH:36][CH:35]=1.CC(C)([O-])C.[Na+]>C1(C)C(C)=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[C:34]1([C:47]2[CH:48]=[CH:49][C:50]([N:20]3[C:21]4[C:22](=[CH:23][CH:24]=[C:25]5[C:26]6[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=6[NH:32][C:33]5=4)[C:18]4[C:19]3=[CH:14][CH:15]=[CH:16][CH:17]=4)=[CH:51][CH:52]=2)[C:46]2[NH:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:38]=2[CH:37]=[CH:36][CH:35]=1
Reactant: Brc1cccc(-c2cccc3c2[nH]c2ccccc23)c1
Reactant: c1ccc2c(c1)N=c1c-2ccc2c1=Nc1ccccc1-2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1C
Solvent: O
Product: c1ccc2c(c1)[nH]c1c(-c3ccc(-n4c5ccccc5c5ccc6c7ccccc7[nH]c6c54)cc3)cccc12
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 46.7 %

Procedure:
In a 100-ml three-necked flask that had been deaerated and filled with nitrogen was placed a solution of 0.21 g (0.94 millimole) of palladium(II) acetate, 0.76 g (3.8 millimoles) of tri-tert-butylphosphine was added, and the mixture was heated at 60° C. with stirring for 30 minutes. The resulting solution was transferred under nitrogen flow to a solution heated at 60° C. of 4.6 g (18.0 millimoles) of indolo[2,3-a]carbazole, 5.8 g (18.0 millimoles) of 3-carbazolylbromobenzene, and 7.7 g (80.0 millimoles) of sodium tert-butoxide in 180 ml of xylene. The solution was then heated to 130° C., and heated with stirring at this temperature for 5 hours. The solution was cooled to room temperature and 200 ml of water was added. The mixture was subjected to oil-water separation, and the organic layer was concentrated under reduced pressure to give a crude product. The crude product was purified by crystallization from dichloromethane and ethanol, the solvent was stripped off under reduced pressure, and 4.2 g (8.4 millimoles, 47% yield) of 11-(4-carbazolylphenyl)indolo[2,3-a]carbazole was obtained.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[Cl:7][C:8]1[C:13]([N:14]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([F:25])[CH:21]=3)[N:16]=[C:15]2[CH:26]=CN(C)C)=[CH:12][CH:11]=[CH:10][N:9]=1>O1CCCC1>[Cl:7][C:8]1[C:13]([N:14]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([F:25])[CH:21]=3)[N:16]=[C:15]2[CH:26]=[O:2])=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: CN(C)C=Cc1nc2ccc(F)cc2c(=O)n1-c1cccnc1Cl
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1nc2ccc(F)cc2c(=O)n1-c1cccnc1Cl
Reaction time: 1 h
Yield: 98 %

Procedure:
To a mixture of sodium periodate (1.9 g, 8.7 mmol) in tetrahydrofuran (10 mL) and aqueous pH 7 buffer (15 mL) was added 3-(2-chloro-pyridin-3-yl)-6-fluoro-2-(2-dimethylamino-vinyl)-3,4-dihydro-quinazolin-4-one (1.0 g, 2.90 mmol) all at once. The reaction was stirred for 1 hour. The precipitate was collected, washed well with water and dried under a nitrogen stream to afford 0.863 g (92%) of 3-(2-chloro-pyridin-3-y)-6-fluoro-3,4-dihydro-quinazolin-4-one-2-carboxaldehyde as a yellow solid which was about a 25:1 mixture of hydrate to free aldehyde. The product was characterized as follows: mp 160-164° C.; 1H NMR (DMSOd6) δ (hydrate) 8.51 (dd, J=2, 5 Hz, 1H), 8.08 (dd, J=2, 8 Hz, 1H), 7.87-7.78 (m, 3H), 7.60 (dd, J=5, 8 Hz, 1H), 6.64 [ABq, Dn1-3=18 Hz, J=7 Hz, 2H (hydrate OHs], 5.27 [br s 1H (hydrate methine CH]. Addition of D2O to the NMR sample caused the multiplet at 6.64 ppm to disappear and sharpened up the singlet at 5.27 ppm. The presence of free aldehyde was demonstrated by a minor singlet at 9.51 ppm.
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[N+:17]([O-:19])=O)([C:3](OCC)=[O:4])=[O:2]>CN(C)C=O.[Pt]>[OH:19][N:17]1[C:10]2[C:9](=[CH:14][C:13]([O:15][CH3:16])=[CH:12][CH:11]=2)[NH:8][C:1](=[O:2])[C:3]1=[O:4]
Reactant: CCOC(=O)C(=O)Nc1cc(OC)ccc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)[nH]c(=O)c(=O)n2O
Yield: 42 %

Procedure:
0.21 g (0.8 mmol) N-ethoxalyl-5-methoxy-2-nitroaniline in 10 ml dimethylformamide was hydrogenated at atm. pressure by using 10 mg 5% Pt-C as a catalyst. The reaction mixture was filtered and 5 drops of 25% aqueous ammonia was added to the filtrate. The precipitate was filtered off, and the filter cake was washed several times with 1N aqueous potassium hydroxide. The filtrate was acidified with concentrated hydrochloric acid, and the precipitate was filtered off, washed with water, ethanol and ether to give 0.07 g (44%) of 1-hydroxy-6-methoxyquinoxaline-2,3(1H,4H)-dione. M.p. decomp. 1H-NMR (DMSO-d ) 12.1 (1H, broad s), 7.6-6.6 (3H, m), 3.8 (3H, s). MS (m/e): 208 (M+, 50%), 163 (100%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:13])[C:9]([O:11]C)=[O:10])=[CH:4][CH:3]=1.CC([NH:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)=O.C(=O)([O-])[O-].[K+].[K+]>[Cu]>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:13])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=2)=[CH:19][CH:20]=1
Reactant: CC(=O)Nc1ccc(Cl)cc1
Reactant: COC(=O)C(C)c1ccc(I)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C(=O)O)c1ccc(Nc2ccc(Cl)cc2)cc1

Procedure:
Methyl 2-(4-iodophenyl)propionate (2 g.), acet-p-chloroanilide (1.17 g.), potassium carbonate (0.62 g.) and copper powder (0.1 g.) were heated at 165°C. for 7.5 hours. The cooled solid was triturated with methylene chloride, filtered, and the filtrate evaporated to dryness. The residue was refluxed for 1.5 hours with ethanol (7 ml.) and 2.5N sodium hydroxide (14 ml.); ethanol was distilled in vacuo and the residue diluted with water, washed with ether and acidified with dilute hydrochloric acid. The resulting oil was isolated in ether and evaporated to dryness. The resulting gum was purified by preparative layer chromatography using 5% acetic acid/petroleum ether b.p. 62°-68°C. and eluting with ethyl acetate; recrystallization from benzene/petroleum ether b.p. 62°-68°C. and from petroleum ether b.p. 80°-100°C. gave 2-[4-(4-chloroanilino)-phenyl]propionic acid, m.p. 106-109°C.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[O:11][N:10]=[C:9]([O:12][CH2:13][CH:14]([NH:18][CH:19]=O)[CH2:15][O:16][CH3:17])[C:8]=2[CH:21]=1.Cl.[OH-].[Na+]>O1CCCC1.CC(O)C.O1CCOCC1.O.C(OCC)(=O)C.CO>[ClH:3].[CH3:19][NH:18][CH:14]([CH2:15][O:16][CH3:17])[CH2:13][O:12][C:9]1[C:8]2[CH:21]=[C:4]([Cl:3])[CH:5]=[CH:6][C:7]=2[O:11][N:10]=1
Reactant: COCC(COc1noc2ccc(Cl)cc12)NC=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CNC(COC)COc1noc2ccc(Cl)cc12

Procedure:
Under a nitrogen stream, 0.27 g of sodium borohydride and 0.86 ml of a boron trifluoride-diethyl ether complex salt are added to a solution of 0.40 g of 5-chloro-3-(2-formylamino-3-methoxypropoxy)-1,2-benzoisoxazole in 6 ml of tetrahydrofuran at -45° to -40° C. The temperature is elevated to 20°-25° C., and then, they are subjected to reaction at the same temperature for two hours. To the reaction mixture is added 15 ml of methanol with ice-cooling, and then, 0.58 ml of a dioxane solution (2.2N) of hydrogen chloride is added, after which they are stirred for ten minutes. Thereafter, the solvent is removed by distillation under reduced pressure. To the residue obtained are added ethyl acetate and water, and the pH is adjusted to 9 with a 10% (w/w) aqueous sodium hydroxide solution, after which the organic layer is separated. The separated organic layer is washed with a saturated saline solution and dried over anhydrous magnesium sulfate, after which the solvent is removed by distillation under reduced pressure. The residue obtained is dissolved in 8 ml of 2-propanol, and to this solution is added 0.70 ml of a dioxane solution (2.2N) of hydrogen chloride, after which the crystals precipitated are collected by filtration, to obtain 0.25 g of colorless, crystalline 3-(2-methylamino-3-methoxypropoxy)-5-chloro-1,2-benzoisoxazole hydrochloride having a melting point of 197°-198° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[N:19]1([CH2:24][C:25]2[S:29][C:28]([C:30](O)=[O:31])=[N:27][CH:26]=2)[CH:23]=[CH:22][N:21]=[CH:20]1>>[N:19]1([CH2:24][C:25]2[S:29][C:28]([C:30]([NH:1][C@@H:2]([CH3:18])[CH2:3][N:4]3[CH:8]=[CH:7][C:6]([C:9]4[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=4)=[N:5]3)=[O:31])=[N:27][CH:26]=2)[CH:23]=[CH:22][N:21]=[CH:20]1
Reactant: O=C(O)c1ncc(Cn2ccnc2)s1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1ncc(Cn2ccnc2)s1
Yield: 4.8 %

Procedure:
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (157 mg, 0.60 mmol) was coupled with 5-((1H-imidazol-1-yl)methyl)thiazole-2-carboxylic acid (0.60 mmol) using the method of Example 34(d). Crude product was purified twice by CombiFlash (1st column: C-18, eluent: 0-100% MeCN in water; 2nd column: silica, eluent: 0-8% MeOH in DCM) to yield 13 mg (5%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.18 (d, 2H), 4.29-4.52 (m, 3H), 5.36 (s, 2H), 6.92 (s, 1H), 6.94 (dd, 1H), 7.22 (s, 1H), 7.71 (s, 1H), 7.75 (s, 1H), 7.83 (d, 1H), 7.90 (dd, 1H), 7.96 (d, 1H), 8.04 (d, 1H), 8.83 (d, 1H).
Reaction SMILES: [CH2:1]([S-])[CH3:2].[Na+].Cl[C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11]1[N:24]([CH3:25])[C:14]2=[N:15][CH:16]=[C:17]([S:19][C:20]([F:23])([F:22])[F:21])[CH:18]=[C:13]2[N:12]=1.CN1C(=O)CCC1>O>[CH2:1]([C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:11]1[N:24]([CH3:25])[C:14]2=[N:15][CH:16]=[C:17]([S:19][C:20]([F:23])([F:22])[F:21])[CH:18]=[C:13]2[N:12]=1)[CH3:2]
Reactant: Cn1c(-c2sccc2Cl)nc2cc(SC(F)(F)F)cnc21
Reactant: CC[S-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCc1ccsc1-c1nc2cc(SC(F)(F)F)cnc2n1C
Temperature: 70 °C
Reaction time: 4 h
Yield: 81.8 %

Procedure:
0.32 g of sodium ethanethiolate was added to a mixture of 0.71 g of 2-(3-chloro-thiophen-2-yl)-3-methyl-6-trifluoromethylthio-3H-imidazo[4,5-b]pyridine and 4 ml of NMP, under ice cooling, and the mixture was stirred at 70° C. for 4 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, then concentrated under reduced pressure and applied to a silica gel column chromatography to obtain 0.57 g of 2-(3-ethylthiophen-2-yl)-3-methyl-6-trifluoromethylthio-3H-imidazo[4,5,b]pyridine (Compound of Present Invention (3)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][Mg]Cl.[I:12][C:13]1[CH:24]=[CH:23][C:16]([C:17](N(OC)C)=[O:18])=[CH:15][CH:14]=1>>[I:12][C:13]1[CH:14]=[CH:15][C:16]([C:17](=[O:18])[CH:6]([C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:23][CH:24]=1
Reactant: COc1cccc(C[Mg]Cl)c1
Reactant: CON(C)C(=O)c1ccc(I)cc1
Product: COc1cccc(CC(C(=O)c2ccc(I)cc2)c2cccc(OC)c2)c1

Procedure:
The title compound was prepared from (3-methoxybenzyl)magnesium chloride and 4-iodo-N-methoxy-N-methylbenzamide following the procedure outlined for Intermediate 1. 1H NMR (400 MHz, DMSO-d6): δ 7.84 (d, 2H), 7.77 (d, 2H), 7.17 (t, 1H), 7.10 (t, 1H), 6.88-6.83 (m, 2H), 6.77-6.65 (m, 4H), 5.17 (t, 1H), 3.68 (s, 3H), 3.66 (s, 3H), 3.38 (dd, 1H), 2.96 (dd, 1H).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:37])[NH:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:14]=[C:15]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][C@H:30]4[CH3:35])[C:16]4[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][C:17]=4[N:18]=3)=[C:9]([F:36])[CH:8]=2)[CH2:3][CH2:2]1.[ClH:38]>CO.O1CCOCC1>[ClH:38].[CH:1]1([NH:4][C:5]([NH:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:14]=[C:15]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][C@H:30]4[CH3:35])[C:16]4[CH2:21][NH:20][CH2:19][C:17]=4[N:18]=3)=[C:9]([F:36])[CH:8]=2)=[O:37])[CH2:2][CH2:3]1
Reactant: C[C@@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C[C@@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CNC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (R)-tert-butyl 2-(4-(3-cyclopropylureido)-2-fluorophenyl)-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (1.1 g, 2.1 mmol) in methanol (15 ml) was added 4M HCl in dioxane (4 ml) and the reaction was stirred at RT overnight. The reaction was concentrated in vacuo to yield the titled compound as a yellow solid which was used without further purification.