Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[N-:31]=[N+]=[N-].[Na+].O.CCOCC>CN1CCCC1=O>[CH:18]1([NH:17][C:13]2[N:12]=[C:11]([C:10]3[C:9]([C:23]4[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=4)=[N:8][N:7]4[C:2]([NH2:31])=[CH:3][CH:4]=[CH:5][C:6]=34)[CH:16]=[CH:15][N:14]=2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: COc1ccc(-c2nn3c(Cl)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: COc1ccc(-c2nn3c(N)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 80 °C
Yield: 52 %

Procedure:
To a solution of 4-[7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentylpyrimidin-2-amine (100 mg, 0.24 mmol) in 1-methyl-2-pyrrolidinone (3 mL) was added sodium azide (200 mg, 3.1 mmol). The resulting suspension was heated at 80° C. until the reaction was judged complete by thin layer chromatography. The mixture was cooled to room temperature and water and ether were added. The organic layer was washed with brine. The aqueous layer was extracted with ether and the combined organics were dried over sodium sulfate. Filtration and concentration followed by flash chromatography (2:1 to 1:1 hexanes-ethyl acetate) provided 3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine (50 mg, 52%) as a yellow powder. 1H NMR (CDCl3): δ 8.03 (d, 1 H), 7.87 (d, 1 H), 7.62 (d, 2 H), 7.27 (m, 1 H), 7.01 (d, 2 H), 6.37 (d, 1 H), 6.17 (d, 1 H), 5.39 (s, 2 H), 5.19 (d, 1 H), 4.39 (m, 1 H), 3.90 (s, 3 H), 2.10 (m, 2 H), 1.82–1.54 (m, 6 H); MS m/z 401(M+1).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[CH2:8][N:9]([C@@H:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH2:13][OH:14])[C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:25]=[N:26][N:27]([CH3:38])[C:28]=1B1OC(C)(C)C(C)(C)O1.C(N(CC)C(C)C)(C)C>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:23][C:24]1[CH:25]=[N:26][N:27]([CH3:38])[C:28]=1[C:2]1[N:7]=[C:6]2[CH2:8][N:9]([C@@H:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH2:13][OH:14])[C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1
Reactant: O=C1c2ccc(Br)nc2CN1[C@H](CO)Cc1cccc(F)c1
Reactant: Cn1ncc(Cl)c1B1OC(C)(C)C(C)(C)O1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cn1ncc(Cl)c1-c1ccc2c(n1)CN([C@H](CO)Cc1cccc(F)c1)C2=O
Yield: 70.3 %

Procedure:
In one 20 mL vial, a mixture of 2-bromo-6-[(1S)-1-(3-fluorobenzyl)-2-hydroxyethyl]-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (0.041 g, 0.11 mmol), 4-chloro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.0327 g, 0.135 mmol), bis(tri-t-butylphosphine)palladium (0.00574 g, 0.0112 mmol), and N,N-diisopropylethylamine (0.0587 mL, 0.337 mmol) in 1,4-dioxane (5 mL) was microwaved at 120° C. for 20 minutes. The resulting mixture was filtered through a pad of celite and concentrated, and the residue was purified by combi-flash chromatography using hexane/EtOAc/methanol to give 31 mg (68% yield) of the final product. LC/MS found: 401.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:15][CH2:14][CH2:13][C:7]=3[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1.[CH:16]([Sn](CCCC)(CCCC)CCCC)=[CH2:17]>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>[CH:16]([C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:15][CH2:14][CH2:13][C:7]=3[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1)=[CH2:17]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=c1[nH]c2cc(Br)ccc2c2c1CCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C=Cc1ccc2c3c(c(=O)[nH]c2c1)CCC3
Temperature: 110 °C
Yield: 87.8 %

Procedure:
A solution of 2.0 g (7.6 mmol) of 7-bromo-1,2,3,5-tetrahydrocyclopenta[c]-quinolin-4-one, 2.6 ml (9.9 mmol) of vinyltributyltin and 0.44 g (0.38 mmol) of tetrakis(triphenylphosphine)palladium is degassed and aerated with nitrogen. After 6 hours of heating to 110° C., the batch is concentrated by evaporation and the residue is taken up on silica gel. Column chromatography on silica gel with hexane-ethyl acetate yields 1.41 g of product.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:45]([NH:48][C:49]2[S:53][N:52]=[CH:51][N:50]=2)(=[O:47])=[O:46])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=1[C:20]1[CH:21]=[N:22][N:23](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:24]=1[CH3:25])#[N:2]>Cl.O1CCOCC1>[C:1]([C:3]1[CH:4]=[C:5]([S:45]([NH:48][C:49]2[S:53][N:52]=[CH:51][N:50]=2)(=[O:47])=[O:46])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:12][C:11]=1[C:20]1[CH:21]=[N:22][NH:23][C:24]=1[CH3:25])#[N:2]
Reactant: Cc1c(-c2cc(C(F)(F)F)ccc2Oc2ccc(S(=O)(=O)Nc3ncns3)cc2C#N)cnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1[nH]ncc1-c1cc(C(F)(F)F)ccc1Oc1ccc(S(=O)(=O)Nc2ncns2)cc1C#N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-cyano-4-[2-(5-methyl-1-trityl-1H-pyrazol-4-yl)-4-(trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 428, 345 mg, 0.46 mmol) was dissolved in 4N HCl in 1,4-dioxane (5 ml) and stirred at room temperature for 3 hours before concentrating in vacuo. The residue obtained was purified using an ISCO™ (12 g SiO2) eluting with methanol:dichloromethane (gradient 0:1 to 1:9, by volume). The purified compound was triturated with dichloromethane (10 mL) to afford the title compound as a white solid (148 mg, 34%—isolated as the hydrochloride salt).
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:9]=[CH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)=[CH:19][C:18]=3[O:28][CH:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)[O:14][C:13](=[O:36])[C:12]=2[CH:37]=1.[Cl:38][C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][C:45]=1[Cl:46])[NH2:42]>>[Cl:38][C:39]1[CH:40]=[C:41]([NH:42][C:13](=[O:36])[C:12]2[CH:37]=[C:8]([F:7])[CH:9]=[CH:10][C:11]=2[NH:16][C:15](=[O:14])[C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)=[CH:19][C:18]=2[O:28][CH:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)[CH:43]=[CH:44][C:45]=1[Cl:46]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CN1CCC(Oc2cc(N3CCCC3)ccc2-c2nc3ccc(F)cc3c(=O)o2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CN1CCC(Oc2cc(N3CCCC3)ccc2C(=O)Nc2ccc(F)cc2C(=O)Nc2ccc(Cl)c(Cl)c2)CC1

Procedure:
Using methods substantially equivalent to those described in Example 91-G, except using potassium t-butoxide as the base; N-(3,4-dichlorophenyl)-5-fluoro-2-[2-(1-methylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)benzoylamino]benzamide was prepared from 6-fluoro-2-[2-(1-methylpiperidin-4-yloxy)-4-(pyrrolidin-1-yl)phenyl]-4H-3,1-benzoxazin-4-one and 3,4-dichloroaniline.
Reaction SMILES: [Li+].[OH-].[NH2:3][C:4]1[N:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]3[NH:22][CH:21]([CH2:23][C:24]([O:26]C)=[O:25])[C:20](=[O:28])[N:19]([CH2:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:18][C:17]=3[CH:37]=2)=[O:12])=[CH:6][CH:5]=1>C1COCC1.O>[NH2:3][C:4]1[N:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]3[NH:22][CH:21]([CH2:23][C:24]([OH:26])=[O:25])[C:20](=[O:28])[N:19]([CH2:29][CH2:30][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:18][C:17]=3[CH:37]=2)=[O:12])=[CH:6][CH:5]=1
Reactant: COC(=O)CC1Nc2ccc(C(=O)Nc3ccc(N)nc3)cc2CN(CCc2ccccc2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(NC(=O)c2ccc3c(c2)CN(CCc2ccccc2)C(=O)C(CC(=O)O)N3)cn1
Reaction time: 22.5 h
Yield: 86.1 %

Procedure:
1.0 N LiOH (1.1 mL, 1.1 mmol) was added dropwise to a mixture of methyl (±)-7-[[(6-amino-3-pyridinyl)amino]carbonyl]-3-oxo-4-(2-phenylethyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (0.23 g, 0.48 mmol) in THF (12 mL) and H2O (17 mL) at RT. After 22.5 h, the dark reddish-brown reaction mixture was concentrated on the rotavap to remove excess THF. The resulting reddish solution was cooled in an ice-bath, and neutralized with 1.0 N AcOH (1.8 mL). The precipitate was collected by suction filtration, washed with water and ether, and air-dried to give the title compound (0.19 g, 86%) as a pinkish-purple solid: 1H NMR (400 MHz, DMSO-d6) δ9.55 (s, 1H), 6.40-8.29 (m, 7H), 5.69 (s, 2H), 5.42 (d, J=17 Hz, 1H), 5.09 (br, 1H), 3.95 (dd, J=17,1H), 3.59-3.65 (m, 2H), 2.51-2.82 (m, 4H); MS (ES) m/e 460.2 (M+H)+. Anal. Calcd for C25H25N5O4.9/4 H2O: C, 60.05; H, 5.98; N, 14.01. Found: C, 59.79; H, 5.92; N, 13.64.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:6][C@H:5]1B(O)O.[NH2:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15](Br)[C:12]=1[C:13]#[N:14]>>[NH2:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([C@@H:5]2[CH2:6][C@H:4]2[CH2:3][O:2][CH3:1])[C:12]=1[C:13]#[N:14]
Reactant: N#Cc1c(N)cccc1Br
Reactant: COC[C@@H]1C[C@H]1B(O)O
Product: COC[C@@H]1C[C@H]1c1cccc(N)c1C#N
Yield: 64 %

Procedure:
Prepared as in Example 270a from (±)-trans-2-(methoxymethyl)cyclopropylboronic acid (example 271b) and 2-amino-6-bromobenzonitrile in 64% yield as a yellowish brown waxy solid. 1H NMR (400 MHz, DMSO-d6) δ 0.932 (m, 2H), 1.341 (m, 1H), 1.879 (m, 1H), 2.324 (s, 3H), 3.351 (d, J=6 Hz, 2H), 5.896 (br. s, 2H), 6.148 (d, J=8 Hz, 1H), 6.550 (d, J=8 Hz, 1H), 7.130 (t, J=8 Hz, 1H).
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15](CC3C=CC(OC)=CC=3)CC3C=CC(OC)=CC=3)[N:9]=2)=[CH:6][CH:5]=[C:4]([O:34][CH2:35][CH2:36][O:37][CH3:38])[N:3]=1.[F:39][C:40]1[CH:41]=[C:42]([NH2:48])[CH:43]=[N:44][C:45]=1[O:46][CH3:47]>>[F:39][C:40]1[CH:41]=[C:42]([NH:48][C:2]2[C:7]([C:8]3[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[N:9]=3)=[CH:6][CH:5]=[C:4]([O:34][CH2:35][CH2:36][O:37][CH3:38])[N:3]=2)[CH:43]=[N:44][C:45]=1[O:46][CH3:47]
Reactant: COCCOc1ccc(-c2nc(C)nc(N(Cc3ccc(OC)cc3)Cc3ccc(OC)cc3)n2)c(F)n1
Reactant: COc1ncc(N)cc1F
Product: COCCOc1ccc(-c2nc(C)nc(N)n2)c(Nc2cnc(OC)c(F)c2)n1

Procedure:
The title compound was prepared in an analogous manner to that described in Example 254 using 4-(2-fluoro-6-(2-methoxyethoxy)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine and 5-fluoro-6-methoxypyridin-3-amine (Anichem), and was isolated as yellow amorphous powder (4.9%). m/z (ESI, +ve ion) 402.0 (M+H)+. 1H NMR (400 MHz, d4-MeOH) δ 12.15 (1H, br. s.); 8.77 (1H, d, J=8.6 Hz); 8.32 (1H, br. s.); 8.15 (1H, br. s.); 6.30 (1H, s); 3.98 (3H, s); 3.72 (2H, br. s.); 3.37 (4H, s); 2.44 (4H, s).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:9]=3[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28](O)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C(O)(=O)C>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([O:17][C:14]2[CH:15]=[CH:16][C:9]3[CH2:8][CH2:7][N:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:12][CH2:11][C:10]=3[CH:13]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Oc1ccc2c(c1)CCN(C1CCCC1)CC2
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)CCN(C2CCCC2)CC3)CC1

Procedure:
3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E4) (1.1 g, 4.8 mmol), 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (1.15 g, 5.7 mmol), di-tert-butyl azodicarboxylate (1.31 g, 5.7 mmol) and triphenylphosphine (1.5 g, 5.7 mmol) were stirred at room temperature for 16 hours in tetrahydrofuran (20 ml). The mixture was acidified with acetic acid and applied to a SCX ion exchange cartridge (Varian bond-elute, 10 g) and washed with methanol and then a mixture of 0.880 ammonia:methanol (1:9). The combined basic fractions were concentrated in vacuo and the resulting residue was purified by column chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (1:9:90) to afford the title product (E5a); MS (ES+) m/e 415 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:7]2[C:12]([N:13]=[C:14]3[C:19]=1[CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].[CH2:20]([O:22][C:23](=[O:27])[C@H:24]([CH3:26])[NH2:25])[CH3:21].C(Cl)(Cl)Cl>O>[CH2:20]([O:22][C:23](=[O:27])[C@H:24]([CH3:26])[NH:25][CH2:2][C:3]([NH:5][C:6]1[C:7]2[C:12]([N:13]=[C:14]3[C:19]=1[CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4])[CH3:21]
Reactant: O=C(CCl)Nc1c2c(nc3ccccc13)CCCC2
Reactant: CCOC(=O)[C@H](C)N
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)[C@H](C)NCC(=O)Nc1c2c(nc3ccccc13)CCCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
To 5 g of 9-chloroacetylamino-1,2,3,4-tetrahydroacridine, was added 22 g of L-alanine ethyl ester and the reaction was continued for 30 minutes at 100° C. After cooled to room temperature, the reaction mixture was added with 100 ml of chloroform and 100 ml of water and stirred. The chloroform layer was dried over anhydrous sodium sulfate and purified by silica gel column chromatography (chloroform-methanol), followed by recrystallization from chloroform-n-hexane to obtain 5.9 g of the titled compound having the melting point of 101° to 102° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.C([O-])(O)=O.[Na+].[CH2:17](O)[CH3:18]>OS(O)(=O)=O>[CH2:17]([O:9][C:8]([C:5]1[CH:4]=[C:3]([CH3:11])[C:2]([Br:1])=[CH:7][N:6]=1)=[O:10])[CH3:18]
Reactant: Cc1cc(C(=O)O)ncc1Br
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1cc(C)c(Br)cn1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
To a suspension of crude 5-bromo-4-methyl-pyridine-2-carboxylic acid (10.9 g, approximately 35.5 mmol) in ethanol (120 mL), H2SO4 (0.5 mL) is added. The mixture is stirred at 70° C. for 18 h. The pH of the clear solution is adjusted to pH 9 by adding sat. aq. NaHCO3-solution and the mixture was extracted with diethyl ether (3×300 mL). The combined org. extracts are dried over MgSO4, filtered and concentrated to give 5-bromo-4-methyl-pyridine-2-carboxylic acid ethyl ester (8.20 g) as a green oil; LC-MS: tR=0.87 min, [M+1]+=243.91.
Reaction SMILES: [F:1][C:2]1([CH3:12])[CH2:5][C:4]([CH3:11])([C:6]([O:8]CC)=[O:7])[CH2:3]1.[OH-].[Na+]>C(O)C>[F:1][C:2]1([CH3:12])[CH2:5][C:4]([CH3:11])([C:6]([OH:8])=[O:7])[CH2:3]1
Reactant: CCOC(=O)C1(C)CC(C)(F)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(F)CC(C)(C(=O)O)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 57 %

Procedure:
To a solution of Intermediate 307A (85 mg, 0.360 mmol) in ethanol (2 mL) was added NaOH (0.144 mL, 0.719 mmol, 5M aq. solution) and the reaction mixture was stirred at RT for 12 h. The volatiles were removed under reduced pressure, and the residue was diluted with water (15 mL) and extracted with diethyl ether (1×25 mL). The aqueous layer was then acidified with a 1.5N aq. solution of HCl and extracted with EtOAc (2×25 mL). The combined organic layer was dried over Na2SO4, filtered and the filtrate concentrated to afford Intermediate 307B as a pale yellow liquid (30 mg, 43%). 1H NMR (300 MHz, DMSO-d6) δ ppm 12.29 (br. s., 1H), 2.60-2.53 (m, 1H), 2.37-2.22 (m, 3H), 1.44 (d, J=18 Hz, 3H), 1.36 (s, 3H).
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([C:16]2[CH:32]=[CH:31][C:19]3[NH:20][C:21]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)=[N:22][C:18]=3[CH:17]=2)[CH:10]=1)C1C=CC=CC=1>CCO.[Pd]>[OH:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([C:16]2[CH:32]=[CH:31][C:19]3[NH:20][C:21]([C:23]4[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=4)=[N:22][C:18]=3[CH:17]=2)[CH:10]=1
Reactant: COc1ccc(-c2nc3cc(-n4ccc(=O)c(OCc5ccccc5)c4)ccc3[nH]2)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(-c2nc3cc(-n4ccc(=O)c(O)c4)ccc3[nH]2)cc1
Temperature: 60 °C

Procedure:
3-(Benzyloxy)-1-[2-(4-methoxyphenyl)-1H-benzimidazol-5-yl]pyridin-4(1H)-one (912 mg, 10 mmol) and 10% Pd/C (100 mg) in EtOH (300 mL) was stirred under an H2 balloon for 3 hours. After this time, LCMS indicated that the reaction was complete. After evacuation and purge with N2 (3×), the EtOH solution was heated at 60° C. for 1 h, filtered, and the catalyst was washed with EtOH (4×50 mL). The combined EtOH solution was concentrated to provide the desired product 3-hydroxy-1-[2-(4-methoxyphenyl)-1H-benzimidazol-5-yl]pyridin-4(1H)-one as a slightly yellow solid. ′H NMR (500 MHz, DMSO): δ 13.05 (s, broad, 1H); 8.15 (d, J=8.3 Hz, 2H); 7.89 (d, J=6.9 Hz, 1H); 7.71 (m, 3H); 7.34 (d, J=7.9 Hz, 1H); 7.13 (d, J=8.6 Hz, 2H); 6.32 (d, J=7.3 Hz, 1H); 3.85 (s, 3H); LCMS (M+H)+ 334; HRMS Calcd for (C19H15N3O3+H)+ 334.1 186. found 334.1188.
Reaction SMILES: [CH2:1]([C:3]([OH:25])([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13]Br)=[CH:6][CH:5]=1)[CH3:2].[CH2:26]([NH:29][CH2:30][CH2:31][CH3:32])[CH2:27][CH3:28]>>[CH2:1]([C:3]([OH:25])([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][N:29]([CH2:30][CH2:31][CH3:32])[CH2:26][CH2:27][CH3:28])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCCNCCC
Reactant: CCC(O)(c1ccc(OCCCBr)cc1)c1cccc(C(F)(F)F)c1
Product: CCCN(CCC)CCCOc1ccc(C(O)(CC)c2cccc(C(F)(F)F)c2)cc1
Reaction time: 6 h

Procedure:
20.8 g. of α-ethyl-α-(3-trifluoromethylphenyl)-4-(3-bromopropoxy)-benzylalcohol and 41 ml. of dipropyl amine are slightly refluxed with stirring for 6 hours. After cooling, the reaction mixture is evaporated under reduced pressure. To the residue water is added and it is extracted with benzene. The benzene phase is washed with water, dried over anhydrous potassium carbonate and evaporated. The residue is fractionated in vacuo to yield 17.2 g. of the desired compound, boiling at 176° to 178° C./6.6 Pa.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:32])[CH:28]([CH3:31])[CH:29]=[CH2:30])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].I[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:32])[CH:28]([CH3:31])/[CH:29]=[CH:30]/[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: C=CC(C)C(O)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1
Reactant: Ic1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)C(C)/C=C/c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 59, Step 1, using 1-{4′-[4-(1-hydroxy-2-methyl-but-3-enyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and iodobenzene.
Reaction SMILES: [Na].Cl[CH2:3][CH2:4][CH:5]([CH3:20])[C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:13]=1[C:14]#[N:15])=[O:7]>C(O)C>[C:14]([C:13]1[C:12]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:11][S:10][C:9]=1[N:8]1[CH2:3][CH2:4][CH:5]([CH3:20])[C:6]1=[O:7])#[N:15]
Reactant: CC(CCCl)C(=O)Nc1scc(C(C)(C)C)c1C#N
Agent: [Na]
Solvent: CCO
Product: CC1CCN(c2scc(C(C)(C)C)c2C#N)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
To a solution of 0.21 g of sodium dissolved in 10 ml of ethanol was added 2.75 g of 4-chloro-N-[3-cyano-4-(1,1-dimethylethyl)-2-thienyl]-2-methylbutanamide dissolved in 35 ml ethanol dropwise. The mixture was allowed to stir at room temperature for about one hour and the solvent was removed in vacuo. The residue was combined with 10 ml ethanol and 250 ml water and the precipitate was collected by filtration. The collected solid was recrystallized from hexane to afford 1.8 g of N-[3-cyano-4-(1,1-dimethylethyl)-2-thienyl]-3-methyl-2-pyrrolidinone. Yield 75%. mp=92°-94° C.
Reaction SMILES: C([O-])(=O)C.[CH3:5][O:6][C:7]1[CH:23]=[CH:22][C:10]([CH2:11][C@H:12]2[C:21]3[CH:16]([CH2:17][CH2:18][CH2:19][CH:20]=3)[CH2:15][CH2:14][NH2+:13]2)=[CH:9][CH:8]=1.[OH-].[Na+]>O>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][C@H:12]2[C:21]3[CH:16]([CH2:17][CH2:18][CH2:19][CH:20]=3)[CH2:15][CH2:14][NH:13]2)=[CH:22][CH:23]=1
Reactant: COc1ccc(C[C@@H]2[NH2+]CCC3CCCC=C32)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(C[C@@H]2NCCC3CCCC=C32)cc1
Yield: 97.3 %

Procedure:
A solution of 31.7 g of (S)-1-(4-methoxybenzyl)-octahydroisoquinolinium acetate in 250 ml of water is brought by addition of concentrated sodium hydroxide solution to pH 12. The free base is extracted twice with 150 ml of diethyl ether each time. Washing of the combined extracts with water, drying over sodium sulfate and removal of the solvent in vacuo leaves 25.0 g (97.3% of theory) of (S)-1-(4-methoxybenzyl)-octahydroisoquinoline.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:14]=3)[CH:9]=[C:10]([CH2:11][OH:12])[N:6]2[N:5]=[CH:4][N:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[NH2:1][C:2]1[C:7]2=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:14]=3)[CH:9]=[C:10]([CH:11]=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnn2c(CO)cc(-c3cccc(OCc4ccccc4)c3)c12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Nc1ncnn2c(C=O)cc(-c3cccc(OCc4ccccc4)c3)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 35 %

Procedure:
To a solution of {4-amino-5-[3-(benzyloxy)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}methanol (300 mg, 0.87 mmol) in dichloromethane (5 mL) was added Dess-Martin Periodinane (492 mg, 1.13 mmol). The mixture was stirred (rt) for 4 h. The reaction was quenched with the addition of a 1:1 mixture of saturated, aqueous NaHCO3 and saturated aqueous Na2S2O3 solutions (5 mL) and the mixture was allowed to stir at it for 1 h. The mixture was extracted with dichloromethane (3×5 mL) and the combined organics were washed with brine, dried (Na2SO4) and concentrated to afford 105 mg (35%) of the desired product, which was used without further purification. ES-MS m/z 345.2 [M+H]+, HPLC RT (min) 3.12.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH2:4]([O:6][C:7]([C:9]1[S:10][C:11](S(C)(=O)=O)=[C:12]([C:21]#[N:22])[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=1)=[O:8])[CH3:5]>C1COCC1>[CH2:4]([O:6][C:7]([C:9]1[S:10][C:11]([N:2]([CH3:3])[CH3:1])=[C:12]([C:21]#[N:22])[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=1)=[O:8])[CH3:5]
Reactant: CCOC(=O)c1sc(S(C)(=O)=O)c(C#N)c1-c1ccc(I)cc1
Reactant: CNC
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(N(C)C)c(C#N)c1-c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
Add 3 mL of 2N dimethylamine in THF to 3-(4-iodophenyl)-4-cyano-5-methanesulfonyl-thiophene-2-carboxylic acid ethyl ester (0.23 mmol) and stir under nitrogen at room temperature for 2 h. Evaporate to dryness to provide the title compound which is used without further purification. Yield 95%. MS (ES+, m/e)=427 (M++1).