Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:5])[CH3:4].[CH:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(O)(=O)C>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][NH:1][CH2:2][C@H:3]([OH:5])[CH3:4])=[CH:8][CH:9]=1
Reactant: COc1ccc(C=O)cc1
Reactant: C[C@@H](O)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(CNC[C@@H](C)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.7 %

Procedure:
A solution of (R)-(−)-1-amino-2-propanol (9.00 g, 0.12 mol) in tetrahydrofuran (40 ml) and acetic acid (5 ml) was added dropwise to a solution of p-anisaldehyde (5.45 g, 0.04 mol) in tetrahydrofuran (40 ml), and once addition was complete, the solution was stirred at room temperature for 2 hours. The solution was cooled in an ice-bath, and sodium triacetoxyborohydride (9.50 g, 0.0.045 mol) was added portionwise, and then the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between dichloromethane (150 ml) and sodium hydroxide solution (150 ml, 0.5N). The layers were separated and the aqueous phase was saturated with sodium chloride, then extracted with further dichloromethane (3×30 ml). The combined organic solutions were dried (MgSO4) and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (gradient elution 98:2:0.2 to 97:3:0.3 dichloromethane:methanol:0.88 NH3) to afford an orange oil (4.9 g). 1H-NMR (CDCl3, 400 MHz) δ: 1.12 (d, 3H), 2.39 (dd, 1H), 2.70 (dd, 1H), 3.62-3.79 (m, 6H), 6.82 (d, 2H), 7.19 (d, 2H). LRMS: m/z (ES+) 196 [MH+].
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]([CH2:13][CH2:14][CH2:15][O:16][C:17]2[N:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[S:19][N:18]=2)[CH3:12])=[CH:5][CH:4]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29].C(=O)([O-])[O-].[Na+].[Na+]>N1C=CC=CC=1>[NH:2]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][N:11]([CH2:13][CH2:14][CH2:15][O:16][C:17]2[N:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[S:19][N:18]=2)[CH3:12])=[CH:7][CH:8]=1)[C:28]([CH3:29])=[O:30]
Reactant: CC(=O)OC(C)=O
Reactant: CN(CCCOc1nsc(-c2ccccc2)n1)CCc1ccc(N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(CCN(C)CCCOc2nsc(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
300 mg of 3-{3-[N-(2-(4-aminophenyl)-ethyl)-N-methylamino]-propyloxy}-5-phenyl-1,2,4-thiadiazole (for preparation, see Example 62) were dissolved in 4 ml pyridine. 1 ml of acetic acid anhydride was added to the solution and the reaction mixture was stirred for 2 hours at room temperature. For workup, it was poured over ice and the mixture made alkaline by adding sodium carbonate solution. Then extraction was performed with ethyl acetate, the organic phase was separated, and concentrated to dryness. The crude oily title compound obtained was purified by medium-pressure chromatography over fine-grained silica gel (Lichroprep Si 60®) using 95:5 ethyl acetate/methanol as the eluent. 0.12 g of the title compound were obtained as an oil.
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[CH3:27])[N:11]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.C(C1C=CC(OC)=C(B(O)O)C=1)#N>>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([CH:10]2[C:5]3[N:6]([CH:7]([CH3:9])[CH3:8])[C:2]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[O:29][CH3:28])=[CH:3][C:4]=3[C:12](=[O:13])[N:11]2[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[C:21]([CH3:27])[CH:22]=1
Reactant: Cc1cc(Cl)ccc1C1c2c(cc(Br)n2C(C)C)C(=O)N1C1CCOCC1
Reactant: COc1ccccc1B(O)O
Agent: COc1ccc(C#N)cc1B(O)O
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: COc1ccccc1-c1cc2c(n1C(C)C)C(c1ccc(Cl)cc1C)N(C1CCOCC1)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described for Example 17 but 2-bromo-6-(4-chloro-2-methyl-phenyl)-1-isopropyl-5-(tetrahydro-pyran-4-yl)-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Intermediate AK) and 2-methoxyphenylboronic acid were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 5-cyano-2-methoxyphenylboronic acid respectively. The title compound was obtained as a white solid. tR: 7.52 min (HPLC 2); ESI-MS: tR=1.25 min, [M+H]+479/481 (LC-MS 1); TLC: Rf=0.36 (EtOAc).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:29])[C:8](CC)=[C:9]([C:25]#[N:26])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14](OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=1)=[O:5])[CH3:2].Br[C:31]1[C:36]2[S:37][CH:38]=[CH:39][C:35]=2[CH:34]=[CH:33][CH:32]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:29])[CH:8]=[C:9]([C:25]#[N:26])[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([C:31]2[C:36]3[S:37][CH:38]=[CH:39][C:35]=3[CH:34]=[CH:33][CH:32]=2)=[CH:15][CH:16]=1)=[O:5])[CH3:2]
Reactant: Brc1cccc2ccsc12
Reactant: CCOC(=O)c1c(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2)c(C#N)c(CC)n1C
Product: CCOC(=O)c1c(-c2ccc(-c3cccc4ccsc34)cc2)c(C#N)cn1C

Procedure:
Prepare the title compound in the manner analogous to the procedure set fourth in example E-222 using 4-cyano-5-ethyl-1-methyl-3-(4-trifluoromethanesulfonyloxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester (prepared in example E-97a or 97b) and 7-bromo-benzo(b)thiophene. Purify the material by silica gel chromatography (Chromatotron™ eluting with methylene chloride/ethyl acetate 4:1 to provide the title compound a white solid. Mass spectrum (m/e): 413.2 (M*−1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[O:14][N:13]=[C:12]([NH2:15])[N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[K+].[I:18]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C>[I:18][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:10]3[O:14][N:13]=[C:12]([NH2:15])[N:11]=3)[CH:5]=2)[NH:1][CH:2]=1
Reactant: II
Reactant: Nc1noc(-c2ccc3[nH]ccc3c2)n1
Agent: O=S([O-])([O-])=S
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1noc(-c2ccc3[nH]cc(I)c3c2)n1
Reaction time: 0.17 h
Yield: 54.8 %

Procedure:
To a solution of 5-(1H-indol-5-yl)-[1,2,4]oxadiazol-3-ylamine (0.225 g, 1.12 mmol) in DMF (1 mL) was added KOH pellets (0.189 g, 3.36 mmol) at 0-5° C. The reaction was stirred for 10 min then I2 (0.567 g, 2.24 mmol) was added portionwise. The reaction was stirred another 2 h at RT then treated with saturated aq sodium thiosulphate (100 mL) to obtain a brownish precipitate. The precipitate was filtered and dried under vacuum. The crude was further treated with petroleum ether to give 5-(3-iodo-1H-indol-5-yl)-1,2,4-oxadiazol-3-amine (0.2 g, 54%) as off white solid. MS (ESI, pos. ion) m/z: 326.9 (M+1).
Reaction SMILES: Cl.Cl.Cl.Cl.[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[CH:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:19][CH2:18]3)=[O:14])=[CH:8][C:7]=1[NH:30][C:31]1[N:36]=[C:35]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)[CH:34]=[CH:33][N:32]=1.C(N(CC)CC)C.[C:50](Cl)(=[O:52])[CH3:51]>CN(C=O)C>[C:50]([N:27]1[CH2:26][CH2:25][N:24]([CH:20]2[C:21]3[C:17](=[CH:16][C:15]([C:13]([NH:12][C:9]4[CH:10]=[CH:11][C:6]([CH3:5])=[C:7]([NH:30][C:31]5[N:36]=[C:35]([C:37]6[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=6)[CH:34]=[CH:33][N:32]=5)[CH:8]=4)=[O:14])=[CH:23][CH:22]=3)[CH2:18][CH2:19]2)[CH2:29][CH2:28]1)(=[O:52])[CH3:51]
Reactant: Cc1ccc(NC(=O)c2ccc3c(c2)CCC3N2CCNCC2)cc1Nc1nccc(-c2cccnc2)n1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(C2CCc3cc(C(=O)Nc4ccc(C)c(Nc5nccc(-c6cccnc6)n5)c4)ccc32)CC1
Reaction time: 0.33 h
Yield: 54.8 %

Procedure:
N-(4-Methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl)-1-piperazin-1-yl-2,3-dihydro-1H-indene-5-carboxamide tetrahydrochloride (100 mg, 0.15 mmol) was dissolved in DMF (2 mL), and triethylamine (101 mg, 1 mmol) was added followed by acetyl chloride (16 mg, 0.2 mmol) while being cooled in an ice bath. After being stirred for 20 minutes, the solution obtained was purified by high performance liquid chromatography at pH=10 to obtain 45 mg (55% yield) of the title compound. MS (+1)=548.27. 1HNMR (DMSO-d6, ppm): δ 10.15 (s, 1H); 9.26 (s, 1H); 8.99 (s, 1H); 8.66 (d, J=4.8 Hz, 1H); 8.49 (d, J=5.2 Hz, 1H); 8.45 (d, J=8.4 Hz); 8.05 (s, 1H); 7.79 (s, 1H); 7.76 (d, J=8.0 Hz, 1H); 7.50 (dd, J=8.0 & 4.8 Hz, 1H); 4.37 (t, J=7.0 Hz, 1H); 3.42 (m, 1H); 3.40 (m, 3H); 2.91 (m, 1H); 2.83 (m, 1H); 2.2-2.5 (m, 4H); 2.20 (s, 3H); 2.06 (m, 2H); 1.95 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26])#[CH:18]>>[F:26][C:25]([F:27])([F:28])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:17]#[C:18][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2
Reactant: C#Cc1ccccc1C(F)(F)F
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Product: O=c1[nH]c2nccc(C#Cc3ccccc3C(F)(F)F)c2c2ccccc12
Yield: 11.5 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 160 using 83 (100 mg, 0.43 mmol) and 2-ethynyl-α,α,α-trifluorotoluene (0.09 mL, 0.65 mmol) to provide 254 (18 mg, 12% yield) as a tan solid. LC-MS (M+H=365 obsd.=365). 1H NMR (400 MHz, d6-DMSO): δ 9.62 (d, 1H), 8.50 (d, 1H), 8.41 (dd, 1H), 8.08 (d, 1H), 7.95 (d, 1H), 7.86 (m, 2H), 7.74 (m, 2H), 7.39 (d, 1H).
Reaction SMILES: O.O.O.O.O.[OH-].C[N+](C)(C)C.CN(C=O)C.[C:17]([OH:20])(=[O:19])[CH3:18].[CH2:21]([O:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]Br)=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)=[O:25])[CH3:22]>CCOCC>[CH2:21]([O:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][O:20][C:17](=[O:19])[CH3:18])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)=[O:25])[CH3:22]
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCCCCCCCCBr)cc2)cc1
Reactant: CC(=O)O
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(-c2ccc(OCCCCCCCCCCOC(C)=O)cc2)cc1
Reaction time: 1 h
Yield: 69.8 %

Procedure:
60 m moles(10.9 g) of tetramethylammonium hydroxide pentahydrate was added to a DMF solution of 60 m moles(3.6 g) of acetic acid, and stirred for one hour, then 50 m moles(23.1 g) of the above 4'-(10-bromodecyloxy)biphenyl-4-carboxylic acid ethyl ester was added thereto, and stirred for 12 hours. The reaction solution was ether extracted and concentrated, and then purified by column chromoatography, to obtain 15.4 g of 4'-(10-acetyloxydecyloxy)biphenyl-4-carboxylic acid ethyl ester. (yield: 70%)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[C:11]([Br:13])[CH:12]=2)[C:5]([C:14]#[N:15])=[C:4](S(C)=O)[N:3]=1.[CH3:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][OH:27])=[N:24][CH:25]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[C:11]([Br:13])[CH:12]=2)[C:5]([C:14]#[N:15])=[C:4]([O:27][CH2:26][C:23]2[CH:22]=[CH:21][C:20]([CH3:19])=[CH:25][N:24]=2)[N:3]=1
Reactant: Cc1ccc(CO)nc1
Reactant: CS(=O)c1nc(N)nc(-c2cc(Br)co2)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Cc1ccc(COc2nc(N)nc(-c3cc(Br)co3)c2C#N)nc1

Procedure:
From 2-amino-4-(4-bromo-furan-2-yl)-6-methanesulfinyl-pyrimidine-5-carbonitrile, 5-methyl-2-pyridinemethanol and DBU in DME. ES-MS m/e (%): 388 (M{81Br}+H+, 100), 386 (M{79Br}+H+, 95).
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[C:8]([Cl:12])[N:9]=[C:10](Cl)[C:5]=2[S:4][CH:3]=1.CO.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[Br:1][C:2]1[C:6]2[N:7]=[C:8]([Cl:12])[N:9]=[C:10]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:5]=2[S:4][CH:3]=1
Reactant: C1COCCN1
Reactant: Clc1nc(Cl)c2scc(Br)c2n1
Solvent: CO
Product: Clc1nc(N2CCOCC2)c2scc(Br)c2n1
Reaction time: 1.5 h
Yield: 35.9 %

Procedure:
7-Bromo-2,4-dichlorothieno[3,2-d]pyrimidine (2.9 g, 10.0 mmol) was dissolved in methanol (100 mL, 2000 mmol) and added morpholine (2 mL, 22 mmol) and let the reaction mixture stir for 1.5 h. Complete reaction confirmed by LCMS. Concentrated in vacuo and diluted with water. Extracted with DCM and concentrated in vacuo again. The product was purified by silica gel chromatography (0 to 100% ethyl acetate/heptanes) on the CombiFlash® Rf system and concentrated in vacuo to give 4-(7-bromo-2-chlorothieno[3,2-d]pyrimidin-4-yl)morpholine (1.2 g, 35% yield). 1H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 4.01 (m, 4H), 3.85 (m, 4H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:18][O:19][C:20](=[O:31])[C@H:21]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[NH2:22]>>[CH3:18][O:19][C:20](=[O:31])[C@H:21]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=1)[NH:22][C:15](=[O:17])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-tyrosine methyl ester (Bachem), the title compound was prepared as a solid (mp=85-88° C.). The reaction was monitored by tlc (Rf=0.27 in 50% EtOAc/hexanes) and the product was purified by silica gel column chromatography.
Reaction SMILES: [CH:1]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH:19]=O.[CH3:21][C:22]([NH2:27])([CH2:25][OH:26])[CH2:23][OH:24].C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH3-]C#N.[Na+].CC1C(Br)=C(O)C(Br)=CC=1C1(C2C=C(Br)C(O)=C(Br)C=2C)OS(=O)(=O)C2C=CC=CC1=2.[ClH:74]>CCO.CCOCC.O.C1(C)C=CC=CC=1>[ClH:74].[CH3:21][C:22]([NH:27][CH2:19][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[CH:1]=1)([CH2:25][OH:26])[CH2:23][OH:24]
Reactant: O=Cc1ccc2c3ccccc3c3ccccc3c2c1
Reactant: CC(N)(CO)CO
Agent: Cc1c(C2(c3cc(Br)c(O)c(Br)c3C)OS(=O)(=O)c3ccccc32)cc(Br)c(O)c1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(CO)(CO)NCc1ccc2c3ccccc3c3ccccc3c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 1 L Erlenmeyer flask was added 2-triphenylenecarbaldehyde 5.13 g, (20 mmol), 2-methyl-2-amino-1,3-propanediol (Aldrich, 2.2 g, 21 mmol), p-toluenesulfonic acid.H2O (Eastman Kodak Co., Rochester, NY, 14650, 0.1 g, 0.5 mmol), and PhCH3 (250 mL). The mixture was warmed to reflux for a few minutes and H2O (2-3 mL) was driven off. The resulting golden colored solution was allowed to cool to RT, diluted with absolute EtOH (250 mL) and stirred overnight. NaBH3CN (Aldrich, 95%, 0.63 g, 10 mmol) was added to the reaction. After the NaBH3CN dissolved, an indicator (bromocresol green, Eastman, 5 mg) was added. To the resulting blue solution was added 5 drops of 1M solution of HCl gas in absolute EtOH every 15 minutes. After 3 days the indicator turned green then yellow and voluminous white precipitate was present in the flask. To the flask was then added 1M gas HCl (10 mL) in absolute EtOH. The reaction was diluted to 2 L with absolute ether and stirred for 1 h. The precipitate was then collected by filtration through a medium porosity glass fritted funnel and pressed dry. The filter cake was washed thoroughly with 20% HCL (2×250 mL), pressed dry and then washed with CH2Cl2 (4×500 mL), pressed and sucked dry. The crude off-white solid was then recrystallized (EtOH/Et2O) 3× to give after drying (100°) 3.34 g (43%) of 2-methyl-2-((2-triphenylenylmethyl)amino)-1,3-propanediol hydrochloride.1/2H2O mp 207°-208.5° (dec), (C, H, Cl, N).
Reaction SMILES: Cl[CH:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1)[C:3]#[N:4].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>C(OCC)(=O)C.CCCCCC>[CH3:14][O:13][C:7]1[CH:6]=[C:5]([CH:2]([S:22][C:19]2[CH:20]=[CH:21][C:16]([CH3:15])=[CH:17][CH:18]=2)[C:3]#[N:4])[CH:10]=[CH:9][C:8]=1[O:11][CH3:12]
Reactant: COc1ccc(C(Cl)C#N)cc1OC
Reactant: Cc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ccc(C(C#N)Sc2ccc(C)cc2)cc1OC
Yield: 65.4 %

Procedure:
A mixture of 4.12 g of α-chloro-3,4-dimethoxybenzeneacetonitrile (U.S. Pat. No. 4,833,162), 2.48 g of p-thiocresol, 2.76 g of potassium carbonate and 100 mL of acetonitrile is stirred at 65° C. overnight. After filtering off the salts, the reaction mixture is concentrated in vacuo leaving a golden oil. The oil is dissolved in a minimum amount of ethyl acetate and diluted with 3 volumes of hexane. Seeding gives 3.81 g of the desired compound as light yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH:5]([NH:10][C:11](=[O:29])[C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][CH:21]([CH:24](OC)[O:25]C)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]>C(Cl)Cl.FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4](=[O:30])[C@H:5]([NH:10][C:11](=[O:29])[C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH2:19][CH2:20][CH:21]([CH:24]=[O:25])[CH2:22][CH2:23]2)=[CH:16][CH:17]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)NC(=O)c1ccc(N2CCC(C(OC)OC)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@@H](CC(C)C)NC(=O)c1ccc(N2CCC(C=O)CC2)cc1

Procedure:
A solution of (2S)-2-{{[4-(4-(dimethoxymethyl)piperidin-1-yl)benzoyl]-amino}-4-methylpentanoic acid ethyl ester (0.163 g, 0.4 mmol) in methylene chloride (3 mL) and trifluoroacetic acid (0.210 mL) was stirred at ambient temperature for 2 hours. The reaction mixture was diluted with methylene chloride and washed with saturated sodium bicarbonate, brine, and dried (Na2SO4). Removal of solvent in vacuo afforded the crude aldehyde which was used directly in the following step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.CO[CH:10](OC)[N:11]([CH3:13])[CH3:12]>>[CH3:10][N:11]([CH3:13])[CH:12]=[N:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1cnccn1
Reactant: COC(OC)N(C)C
Product: CN(C)C=Nc1cnccn1

Procedure:
A solution of 2-aminopyrazine (16.45 g) in dimethylformamide dimethylacetal (22.4 g) was refluxed at 85° C. for 3 h, evaporated under reduced pressure, and used in the next step without further purification.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)[CH:12]=1.O.O.O.C([O-])(=O)C.[Na+]>ClCCCl.O>[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([CH:3]=[O:4])=[CH:18]2)[CH:12]=1
Reactant: c1cncc(-n2ccc3ccccc32)c1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: O=Cc1cn(-c2cccnc2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 2.12 ml of N,N-dimethylformamide in 20 ml of 1,2-dichloroethane is cooled to 0° and 3.1 ml of phosphorus oxychloride is added dropwise. The reaction is stirred for 10 minutes at 15° and recooled to 0° before a solution of 4.85 g of N-(3-pyridyl)indole in 10 ml of 1,2-dichloroethane is added. After 2 hours at 5°, the reaction mixture is refluxed for 15 minutes, cooled to room temperature and a solution of 18.75 g of sodium acetate trihydrate in 25 ml of water is added. After an additional 15 minutes at reflux, the organic phase is separated, washed with sodium bicarbonate and water, and dried over magnesium sulfate. Filtration, evaporation and recrystallization of the residue from methylene chloride-methanol yields N-(3-pyridyl)-indole-3-carboxaldehyde, m.p. 148°-150°.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[CH:10]=[CH:9][C:8]([F:12])=[CH:7][C:6]=2[C:5]2[C:13](CC#N)=[N:14][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:16](=[O:17])[C:4]1=2)[CH3:2].Cl.[C:28]([OH:31])(=[O:30])[CH3:29]>O>[CH2:1]([N:3]1[C:11]2[CH:10]=[CH:9][C:8]([F:12])=[CH:7][C:6]=2[C:5]2[C:13]([CH2:29][C:28]([OH:31])=[O:30])=[N:14][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:16](=[O:17])[C:4]1=2)[CH3:2]
Reactant: CCn1c2ccc(F)cc2c2c(CC#N)nn(-c3ccccc3)c(=O)c21
Reactant: CC(=O)O
Agent: Cl
Solvent: O
Product: CCn1c2ccc(F)cc2c2c(CC(=O)O)nn(-c3ccccc3)c(=O)c21

Procedure:
A solution of 5.8 g (16.8 mmol) of 5-ethyl-8-fluoro-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetonitrile in 200 ml of a 1/1 mixture of concentrated hydrochloric acid and of glacial acetic acid is heated at reflux for 2 h. The solution is cooled, 100 ml of water are added and the insoluble material is collected by filtration and washed copiously with water and with ether on sintered glass. After drying in an oven, 5.2 g (15 mmol) of a white solid are obtained, which solid is used as is in the following stage.
Reaction SMILES: [OH:1][C:2]1[C:12](I)=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.CN(C=O)C.[CH:19](B(O)O)=[CH2:20].C(=O)([O-])[O-].[Na+].[Na+]>O>[OH:1][C:2]1[C:12]([CH:19]=[CH2:20])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cnc(O)c(I)c1
Reactant: C=CB(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1cc(C(=O)OCC)cnc1O
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 72.1 %

Procedure:
Ethyl 6-hydroxy-5-iodonicotinate (200 mg, 0.682 mmol) was added with N,N′-dimethylformamide (4.1 mL) and water (1.4 mL). The resultant mixture was then added with tetrakis triphenylphosphine palladium (79 mg, 0.0682 mmol), vinylboronic acid (417 μL, 2.46 mmol) and sodium carbonate (433 mg, 4.09 mmol), and stirred at 80° C. for 20 minutes. Subsequently, the resultant mixture was further added with tetrakis triphenylphosphine palladium (79 mg, 0.0682 mmol) and vinylboronic acid (417 μL, 2.46 mmol), and stirred at 80° C. for 20 minutes. The reaction solution was filtered using celite and extracted with ethyl acetate. Subsequently, the organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The obtained residue was purified using column chromatography (chloroform/acetone) and concentrated in vacuo. Ethyl 6-hydroxy-5-vinylnicotinate (95 mg, yield 72%) was obtained as a yellow oil.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.C(OCC)(=[O:21])C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([OH:21])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: CCOC(C)=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the alcohol produced in Example VIII in dry CH2Cl2 at 0 degree C. there were added triethylamine, p-toluenesulfonyl chloride and N,N-dimethyl-4-aminopyridine (catalytic amount). The mixture was stirred overnight at room temperature, and then diluted with ethyl acetate. The reaction mixture was washed with H2O, saturated aqueous NaHCO3 and brine solution, dried over Na2SO4, and concentrated in vacuo to a yellow oil. Purification by SiO2 column chromatography yielded the p-toluenesulfonate.