Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[C:10]([I:23])=[C:11]([C:20](Cl)=[O:21])[C:12]([I:19])=[C:13]([C:17]=1[I:18])[C:14](Cl)=[O:15].[NH2:24][CH2:25][CH:26]([OH:29])[CH2:27][OH:28].[NH2:30][CH:31]([CH2:34][OH:35])[CH2:32][OH:33]>CC(N(C)C)=O.O>[NH2:8][C:9]1[C:10]([I:23])=[C:11]([C:20]([NH:24][CH2:25][CH:26]([OH:29])[CH2:27][OH:28])=[O:21])[C:12]([I:19])=[C:13]([C:17]=1[I:18])[C:14]([NH:30][CH:31]([CH2:34][OH:35])[CH2:32][OH:33])=[O:15]
Reactant: Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Reactant: NCC(O)CO
Reactant: NC(CO)CO
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Solvent: O
Product: Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NC(CO)CO)c1I
Temperature: -24 °C
Reaction time: 0.17 h
Yield: 57 %

Procedure:
At 2° C. a mantled reactor with mechanical stirrer, dropping funnel and inner thermometer was charged with DMA (640 ml), triethylamine (224 ml, 161.3 g, 1.59 mol) and 5-Amino-2,4,6-triiodo-isophthalic acid dichloride (320 g, 537 mmol). The mixture was stirred and cooled to −24° C. A solution of 1-amino-2,3-dihydroxypropane (49,92 g, 548 mmol) in DMA (160 ml) was added slowly to keep the inner temperature below −19° C. The mixture was stirred at a temperature gradient from −24° C. to 0° C. in 24 h. A solution of serinol (60 g, 658 mmol) in DMA (160 ml) was added slowly and the mixture was stirred at a temperature gradient from 0° C. to 40° C. in 20 h. The mixture was stirred at 22° C. for 1 day and precipitated triethylamine hydrochloride was filtered off. Evaporation at 60° C./25 mbar left a viscous liquid residue (586 g) which was diluted with water (350 ml). Salts and excess amines were removed by treatment with ion exchangers Amberlite200C (143 ml), IRA67 (148 ml) and IRA900 (56 ml) followed by filtration. The ion exchangers were washed with water (2×400 ml). Some seeding crystals were added to the combined aqueous phase and the solution was stirred slowly at 22° C. for 9 days. The precipitate was isolated by filtration. The filter cake was re-suspended in water (240 ml) and stirred for 1 day. The suspension was filtered and the filter cake was dried in air (216 g, 57% yield, 88.6% HPLC purity). The crude product was purified by preparative HPLC (column: selfpacked Luna C18, 10 μm 250×100 mm, solvents: A=water and B=acetonitrile; gradient 5-10% B over 10 min, hold 10 min; flow 350 ml/min, UV detection at 244 nm and 254 nm). Relevant fractions were combined and freeze dried to yield 5-amino-N1-(1,3-dihydroxypropan-2-yl)-N3-(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide.
Reaction SMILES: [C:1]([N:8]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)[CH2:9][CH2:10][CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[C:30]([N:37]([CH2:40][CH2:41][CH2:42]Br)[CH2:38][CH3:39])([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].O>O1CCOCC1>[CH2:38]([N:37]([C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[CH2:40][CH2:41][CH2:42][N:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:10][CH2:9][N:8]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)[C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:39]
Reactant: CC(C)(C)OC(=O)NCCCN(CCc1ccccn1)C(=O)OC(C)(C)C
Reactant: CCN(CCCBr)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCN(CCCN(CCCN(CCc1ccccn1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C

Procedure:
To a solution of 1.85 g (5.1 mmol) of N,N'-di-BOC-N-[2-(2-pyridyl)-ethyl]-1,3-propanediamine in 20 ml of dioxane there are added, with stirring, 0.4 g (10 mmol) of sodium hydride dispersion (approximately 60% in oil; Fluka, Buchs, Switzerland) and, after 20 minutes, a solution of 1.23 ; (6 mmol) of N-BOC-N-ethyl-3-bromo-propylamine in 2 ml of dioxane. The reaction mixture is stirred at 50° C. for 18 hours, a further 0.4 g (10 mmol) of sodium hydride dispersion (approximately 60%) and 1.23 g (6 mmol) of N-BOC-N-ethyl-3-bromo-propylamine are added at 25° C., the mixture is stirred at 50° C. for a further 18 hours and is then coded to room temperature, 50 ml of water are added, and the reaction mixture is extracted with methylene chloride. The methylene chloride extract is dried over sodium sulfate and concentrated by evaporation. and the residue is purified by flash chromatography on silica gel having a particle size of 0.04-0.063 mm using tert-butyl methyl ether. After concentration of the product-containing fractions by evaporation, the title compound is obtained in the form of an oil, Rf value=0.37 (silica gel/tert-butyl methyl ether).
Reaction SMILES: O[C@@H:2]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])/[CH:3]=[CH:4]/[C:5]1[CH2:6][CH2:7][C:8](=[O:19])[C:9]=1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17].C(OC=C(OC(C)=COC(C)C)C)(C)C.P(Cl)(Cl)(Cl)=O>C(Cl)Cl.CCOCC>[O:19]=[C:8]1[CH2:7][CH2:6][C:5](/[CH:4]=[CH:3]/[CH2:2][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: CCCCC[C@H](O)/C=C/C1=C(CCCCCCC(=O)O)C(=O)CC1
Agent: CC(=COC(C)C)OC(C)=COC(C)C
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCCCC/C=C/C1=C(CCCCCCC(=O)O)C(=O)CC1

Procedure:
To a 250 ml roundbottom borosilicate flask containing 0.4 g of 15(S)-hydroxy-9-oxo-8(12),13-trans-prostadienoic acid in 15 ml of methylene chloride is added 5 ml of isopropoxyisopropenyl ether and 0.01 ml of phosphorus oxychloride and the flask's contents allowed to react at 20° C. for 36 hours. Next the reaction product is diluted with 25 ml of ether and washed with 50% brine and saturated brine until the solution is neutral. Next, the residue is extracted with methylene chloride, filtered, and freed of solvent under reduced pressure, dried over anhydrous magnesium sulfate, to give 15(S)-(dimethyl' isopropoxy' methyloxy)-9-oxo-8(12),13-trans-prostadienoic acid.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[OH-:12].[Na+].[C:14]([C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20])(=O)[CH3:15]>O>[C:19]([C:18]1[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=1[C:14]1[CH:15]=[C:4]([C:2]([OH:12])=[O:3])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:1]=1)([OH:21])=[O:20]
Reactant: CC(=O)c1ccccc1C(=O)O
Reactant: O=C1Nc2ccccc2C1=O
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccccc1-c1cc(C(=O)O)c2ccccc2n1
Temperature: 90 °C
Yield: 33.6 %

Procedure:
In 15 ml of water were dissolved 14.7 g (0.1 mol) of isatin and 8 g (0.2 mol) of sodium hydroxide. Then, 16.4 g (0.1 mol of 2-acetylbenzoic acid was added thereto and the resulting mixture was heated at 90° C. under reflux. When the reaction became mild, the mixture was heated at 115° C. for an additional 1 hour. After allowing to cool to room temperature, it was poured into 300 g of water cooled with ice. The aqueous layer was washed with ether and acidified with 2M hydrochloric acid. The precipitate thus formed was collected by filtration to thereby give 9.85 g of 2-(2-carboxyphenyl)-4-quinolinecarboxylic acid. NMR (270 MHz, CD3COCD3): δ 7.70-8.70 (m,9H).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:16]3[C:11](=[C:12]([NH2:17])[CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][N:8]=2)=[CH:4][C:3]=1[C:20]([F:23])([F:22])[F:21].[Cl:24][C:25]1[C:30]([C:31](O)=[O:32])=[C:29]([F:34])[C:28]([CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:27][CH:26]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:24][C:25]1[C:30]([C:31]([NH:17][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:11]=2[N:10]=[CH:9][N:8]=[C:7]3[O:6][C:5]2[CH:18]=[CH:19][C:2]([F:1])=[C:3]([C:20]([F:23])([F:21])[F:22])[CH:4]=2)=[O:32])=[C:29]([F:34])[C:28]([CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:40])([CH3:39])[CH3:41])=[CH:27][CH:26]=1
Reactant: Nc1cccc2c(Oc3ccc(F)c(C(F)(F)F)c3)ncnc12
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Oc4ccc(F)c(C(F)(F)F)c4)ncnc23)c1F
Yield: 39.4 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 4-(4-fluoro-3-(trifluoromethyl)phenoxy)quinazolin-8-amine (Intermediate-45, 60 mg, 0.18 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 80 mg, 0.27 mmol), oxalyl chloride (52 mg, 0.41 mmol), DMF (1 drop) and DIPEA (70 mg, 0.54 mmol) in CH2Cl2 (2 mL) to afford 42 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.93 (s, 1H), 8.91 (d, J=7.8 Hz, 1H), 8.80 (s, 1H), 8.17 (d, J=7.2 Hz, 2H), 7.96 (t, 1H), 7.85 (m, 2H), 7.69 (t, J=9.6 Hz, 1H), 7.37 (m, 2H), 4.31 (d, J=5.4 Hz, 2H), 1.14 (s, 9H); MS (m/z): 593.10 (M+H)+.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.I[CH:13]([CH3:15])[CH3:14].[OH:16][C@@H:17]([CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:18][CH2:19][C@@H:20]([O:29][CH2:30][CH:31]1[CH2:35][CH2:34][C:33](=[O:36])[NH:32]1)[C:21]1[S:25][C:24]([C:26]([OH:28])=[O:27])=[CH:23][CH:22]=1>CC(C)=O>[CH:13]([O:28][C:26]([C:24]1[S:25][C:21]([C@H:20]([O:29][CH2:30][CH:31]2[CH2:35][CH2:34][C:33](=[O:36])[NH:32]2)[CH2:19][CH2:18][C@@H:17]([OH:16])[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:22][CH:23]=1)=[O:27])([CH3:15])[CH3:14]
Reactant: CC(C)I
Reactant: CCCCC[C@H](O)CC[C@@H](OCC1CCC(=O)N1)c1ccc(C(=O)O)s1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(C)=O
Product: CCCCC[C@H](O)CC[C@@H](OCC1CCC(=O)N1)c1ccc(C(=O)OC(C)C)s1
Reaction time: 120 h
Yield: 85.7 %

Procedure:
DBU (9 μL, 0.06 mmol) and 2-iodopropane (62 μL, 0.62 mmol) were added to a solution of acid 6 (12 mg, 0.031 mmol) in acetone (0.3 mL) at room temperature under nitrogen. After 5 days at room temperature, the solvent was removed under a stream of nitrogen. The residue was acidified with 1 N HCl (2 mL) and extracted with EtOAc (3×10 mL). The combined extracts were washed with brine (5 mL) then dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica (CH2Cl2→10% MeOH/CH2Cl2) afforded 11.3 mg (85%) of the title compound.
Reaction SMILES: [ClH:1].C(OCC)C.C([NH:14][CH2:15][C:16](=[O:36])[CH2:17][CH2:18][C:19]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:20])(OC(C)(C)C)=O>C(OCC)(=O)C>[ClH:1].[NH2:14][CH2:15][C:16](=[O:36])[CH2:17][CH2:18][C:19]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:20]
Reactant: CC(C)(C)OC(=O)NCC(=O)CCC(=O)OCCCCCCCCCCCC(=O)O
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: NCC(=O)CCC(=O)OCCCCCCCCCCCC(=O)O
Reaction time: 120 h

Procedure:
A 1.0 M solution of HCl in diethyl ether (5.0 mL; 5.0 mmol) was added to a stirred solution of the product of 14c (0.95 g; 2.2 mmol) in ethyl acetate (10 mL) at ambient temperature under argon. After 5 days, the mixture was filtered and the residue was triturated with diethyl ether (2×5 mL). The residue was dried overnight at 40° C. and 15 mm Hg to give 0.11 g white solid. The combined ether extracts were evaporated. LC-MS analysis indicated that the product contained ca. 25% 5-amino-4-oxopentanoic acid; the combined crops were purified by flash chromatography on a 150×25 mm silica gel 60 column eluted sequentially with 3% methanol in acetonitrile (1000 mL), 6% methanol in acetonitrile (1000 mL), then 9% methanol in acetonitrile (2000 mL), collecting 56×50 mL fractions. Fractions containing the product were evaporated and the residue was dissolved in water (10 mL). The solution was freeze-dried overnight, and 0.06 g (7.5%) product obtained (white solid, mp 110-115° C. (softens, no sharp mp)).
Reaction SMILES: N1C2C(=CC=CC=2)C[C:2]1=[O:10].Br[C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])/[C:15]/2=[N:22]\[C:23]1[CH:28]=[CH:27][CH:26]=[C:25](C(F)(F)F)[CH:24]=1.C(N(CC)CC)C.[C:40]1(B(O)O)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:2][O:10][C:28]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:22]=[C:15]1[C:14]2[C:18](=[CH:19][CH:20]=[CH:12][CH:13]=2)[N:17]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:16]1=[O:21]
Reactant: O=C1Cc2ccccc2N1
Reactant: O=C1Nc2ccc(Br)cc2/C1=N/c1cccc(C(F)(F)F)c1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1N=C1C(=O)N(c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 20 %

Procedure:
(3Z)-5-BROMO-1-PHENYL-3-{[3-TRIFLUOROMETHYL)PHENYL]IMINO}-1,3-DIHYDRO-2H-INDOL-2-ONE: A mixture of (3Z)-5-bromo-3-{[3-(trifluoromethyl)phenyl]imino}-1,3-dihydro-2H-indol-2-one (100 mg, 0.272 mmol), copper (II) acetate (54 mg, 0.33 mmol), triethylamine (82.8 mg, 0.817 mmol), and benzene boronic acid (40 mg, 0.325 mmol) in 5 mL of CH2Cl2 was stirred at room temperature for 12 h. The crude mixture was concentrated in vacuo and purified by preparative TLC using EtOAc:hexane (3:7, 1% triethylamine), giving the desired product (22 mg, 20%).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[C:5]([CH3:12])[CH:4]=1)#[N:2].S(Cl)([Cl:15])=O.CN(C)C=O>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:15])=[O:8])=[C:5]([CH3:12])[CH:4]=1)#[N:2]
Reactant: Cc1cc(C#N)ccc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1cc(C#N)ccc1C(=O)Cl
Yield: 100 %

Procedure:
To a solution of A-4 (4-cyano-2-methylbenzoic acid) (20 g, 0.124 mol) in toluene (200 mL) was added thionyl chloride (18 mL, 0.248 mol), and catalytic amount of dimethylformamide (0.5 mL). The resultant mixture was stirred at 70° C. for 14 h, and concentrated under reduced pressure to give A-5 (4-cyano-2-methylbenzoyl chloride) (24 g, yield 100%), which was used in the next step without further purification.
Reaction SMILES: NC(N)=[S:3].[ClH:5].Cl.[CH3:7][C:8]1[CH:24]=[CH:23][C:11]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][Cl:22])[CH2:15][CH2:14]2)=[CH:10][CH:9]=1.C(N(CC)CC)C.[OH-].[Na+]>O.C(O)C>[ClH:22].[ClH:5].[CH3:7][C:8]1[CH:24]=[CH:23][C:11]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][SH:3])[CH2:15][CH2:14]2)=[CH:10][CH:9]=1
Reactant: NC(N)=S
Reactant: Cc1ccc(CN2CCN(CCCCl)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccc(CN2CCN(CCCS)CC2)cc1
Yield: 71.8 %

Procedure:
The procedure described in Example 1(b) was followed, using 7.7 g of thiourea, 23.0 g of 1-(4-methylbenzyl)-4-(3-chloropropyl)piperazine dihydrochloride, 6.5 g of triethylamine and 250 ml of reagent ethanol. The hydrolysis was effected with 6.0 g of sodium hydroxide in 40 ml of water. Work-up, as described above, gave 16.4 g (72% of theory) of 3-[4-(4-methylbenzyl)piperazin-1-yl]propanethiol dihydrochloride as a white crystalline solid, M.p. 273°-277° C. (dec.).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)(=O)=O)=CC=1.[C:19]([O-:22])(=[S:21])[CH3:20].[K+]>CN(C=O)C.C(OCC)(=O)C>[O:14]1[CH2:15][CH2:16][CH2:17][CH2:18][C@H:13]1[CH2:12][S:21][C:19](=[O:22])[CH3:20]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCCO2)cc1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)SC[C@@H]1CCCCO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 111.1 %

Procedure:
To a solution of 3.90 g (14.41 mmol) of (2S)-oxan-2-ylmethyl 4-methylbenzene-1-sulfonate in DMF (40 mL) are added 3.29 g (28.83 mmol) potassium thioacetate at room temperature. After complete addition, the reaction is stirred at room temperature for 18 h, then heated to 50° C. for further 20 h. The reaction mixture is diluted with ethyl acetate (250 mL) and washed with saturated aqueous NaHCO3 solution (2×100 mL) and water (2×100 mL). The organic layer is dried (MgSO4), filtered and the filtrate is concentrated under reduced pressure to afford 2.79 g of 1-{[(2S)-oxan-2-ylmethyl]sulfanyl}ethan-1-one. Yield: 93%; ES-MS: m/z 175 [M+H]; 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.17-1.36 (2H, m), 1.42-1.59 (2H, m), 1.63-1.72 (1H, m), 1.79-1.88 (1H, m), 2.34 (3H, s), 2.84-2.93 (1H, m), 3.10 (1H, dd, J=13.73, 4.27 Hz), 3.30-3.47 (2H, m), 3.98 (1H, dt, J=11.41, 2.08 Hz).
Reaction SMILES: Cl.[O:2]1[C:6]2([CH2:11][CH2:10][CH:9]([CH:12]([NH2:15])[CH2:13][CH3:14])[CH2:8][CH2:7]2)[O:5][CH2:4][CH2:3]1.[CH3:16][N:17]([CH3:21])[C:18](Cl)=[O:19]>ClCCl>[O:2]1[C:6]2([CH2:11][CH2:10][CH:9]([CH:12]([NH:15][C:18]([N:17]([CH3:21])[CH3:16])=[O:19])[CH2:13][CH3:14])[CH2:8][CH2:7]2)[O:5][CH2:4][CH2:3]1
Reactant: CCC(N)C1CCC2(CC1)OCCO2
Reactant: CN(C)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: CCC(NC(=O)N(C)C)C1CCC2(CC1)OCCO2
Temperature: 0 °C

Procedure:
Into a 50 mL round-bottom flask was placed a solution of 1-1,4-dioxaspiro[4.5]decan-8-ylpropan-1-amine hydrochloride (as prepared in Example 104 Step B) (50 mg, 0.21 mmol, 1.00 equiv) in dichloromethane (10 mL) and TEA (42.8 mg, 0.42 mmol, 2.00 equiv). This was followed by the addition of dimethylcarbamic chloride (27.5 mg, 0.25 mmol, 1.20 equiv) dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with 2×20 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The title compound was obtained as a yellow oil.
Reaction SMILES: [I-].[K+].C([N:5]([CH2:8]C)[CH2:6][CH3:7])C.[CH:10]1[N:18]2[C:19]3[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=3[CH:21]=[CH:22][C:16]3=[C:17]2[C:12](=[CH:13][CH:14]=[CH:15]3)[CH:11]=1.C1O[C:30]([CH2:32][CH2:33][CH2:34]Cl)([CH3:31])[O:29]C1>O.CN(C=O)C>[CH2:26]1[CH:19]2[CH:20]([CH:21]=[CH:22][C:16]3[C:17]4[N:18]2[C:10]2[CH:7]=[CH:6][N:5]=[CH:8][C:11]=2[C:12]=4[CH2:13][CH2:14][CH:15]=3)[CH2:23][CH:24]([CH2:34][CH2:33][CH2:32][C:30](=[O:29])[CH3:31])[CH2:25]1
Reactant: CCN(CC)CC
Reactant: CC1(CCCCl)OCCO1
Reactant: C1=Cc2cccc3ccn(c23)-c2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)CCCC1CCC2C(C=CC3=CCCc4c3n2c2ccncc42)C1
Temperature: 62 °C

Procedure:
3.6 grams of potassium iodide and 12 ml. of triethylamine were added to a solution of 5.5 grams of (±)-trans-1,2,3,4,4a,8,9,14a-octahydropyrido[4',3':2,3]=indolo[1,7-ab][1]benzazepine in 50 ml. DMF, followed by addition of 3.7 grams of 5-chloro-2-pentanone ethylene ketal. The mixture was heated at approximately 62° C for 20 hours. The mixture was then poured into water, extracted with benzene, and chromatographed through basic alumina to eliminate remaining benzazepine starting material. The resulting ketal was dissolved in ether. HCl gas was bubbled through this solution to precipitate the hydrochloride salt of the title compound. Recrystallization from ethanol yielded 350 mg. of the title compound, hydrochloride salt, m.p. 258°-259° C(dec).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[C:7]3[C:13]([C:14]#[N:15])=[CH:12][N:11](S(C4C=CC(C)=CC=4)(=O)=O)[C:8]3=[N:9][CH:10]=[C:5]2[CH:4]=[N:3]1.C1C(=O)N([Br:33])C(=O)C1.CN(C=O)C>O>[Br:33][C:12]1[NH:11][C:8]2=[N:9][CH:10]=[C:5]3[CH:4]=[N:3][N:2]([CH3:1])[C:6]3=[C:7]2[C:13]=1[C:14]#[N:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(S(=O)(=O)n2cc(C#N)c3c2ncc2cnn(C)c23)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncc2cnc3[nH]c(Br)c(C#N)c3c21
Temperature: 150 °C
Reaction time: 2 h
Yield: 43.5 %

Procedure:
A 10 mL microwave reaction vial was charged with 1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine-8-carbonitrile (0.011 g, 0.30 mmol, prepared using General Procedure AK from Preparation #1, Step D with NBS, General Procedure AE), NBS (0.012 g, 0.66 mmol) and DMF (2 mL). The suspension was heated in a microwave at about 150° C. for about 30 min (250 psi maximum pressure, 2 min ramp, 300 max watts). Additional NBS (134 mg, 0.754 mmol) was added and mixture was stirred at rt for about 2 h. To the reaction mixture was added water (4 mL) and the solid was collected by filtration and washed with water (5 mL). The solid was dried in a vacuum oven at about 70° C. for about 40 min to give 7-bromo-1-methyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine-8-carbonitrile (0.036 g, 43%): LC/MS (Table 2, Method c) Rt=1.25 min; MS m/z: 276 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]2[CH:12]=[N:13][NH:14][C:3]1=2.[H-].[Na+].[H][H].[C:19](Cl)(=[O:21])[CH3:20]>C1COCC1>[C:19]([N:13]1[CH:12]=[C:4]2[O:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:2]([CH3:1])[C:3]2=[N:14]1)(=[O:21])[CH3:20]
Reactant: CN1c2ccccc2Oc2cn[nH]c21
Reactant: [H][H]
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)n1cc2c(n1)N(C)c1ccccc1O2

Procedure:
A solution of 7.5 g (40 mmols) of 9-methylpyrazolo[4,3-b][1,4]benzoxazine in 50 ml of absolute THF is added dropwise to a suspension of 1.8 g of sodium hydride (55-60% dispersion in oil) in 10 ml of absolute THF. After completion of evolution of hydrogen, 3.14 ml of acetyl chloride were added dropwise to the reaction mixture and the mixture was boiled under reflux for 3 hours. The solvent is removed in vacuo, the residue is taken up in water and the product is extracted at pH 7 with dichloromethane. The organic phase is evaporated and the residue is chromatographed on silica gel with ethyl acetate (dichloromethane (1:1).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:17])=O>C(Cl)Cl>[ClH:17].[CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][Cl:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1nccn1Cc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cl
Product: ClCc1nccn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 1-benzyl-2-hydroxymethyl-imidazole (6 g, 32 mmol) in methylenechloride is slowly added thionylchloride (3.5 ml, 48 mmol) and after stirring at ambient temperature for 4 hours the reaction mixture is concentrated in vacuo yielding 1-benzyl-2-chloromethyl-imidazole, hydrochloride.
Reaction SMILES: [C:1]([C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].Cl.CC1C=C(C=CC=1)CC1(CO)CCNCC1.Cl.[CH3:36][C:37]1[CH:51]=[CH:50][CH:49]=[CH:48][C:38]=1[CH2:39][C:40]1([CH2:46][OH:47])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[OH:47][CH2:46][C:40]1([CH2:39][C:38]2[CH:48]=[CH:49][CH:50]=[CH:51][C:37]=2[CH3:36])[CH2:45][CH2:44][N:43]([C:13]([C:12]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:17][CH:16]=3)[CH:9]=[N:10][CH:11]=2)=[O:15])[CH2:42][CH2:41]1
Reactant: N#Cc1ccc(Cn2cncc2C(=O)O)cc1
Reactant: Cc1ccccc1CC1(CO)CCNCC1
Agent: Cc1cccc(CC2(CO)CCNCC2)c1
Agent: Cl
Product: Cc1ccccc1CC1(CO)CCN(C(=O)c2cncn2Cc2ccc(C#N)cc2)CC1

Procedure:
The title compound was prepared as white solid according to the procedure described in Example 38, Step A-B substituting 1-(4-cyanobenzyl)imidazole-5-acetic acid-lithium chloride with 1-(4-cyanobenzyl)imidazole-5-carboxylic acid and 4-(3-methylbenzyl)-4-hydroxymethylpiperidine hydrochloride salt with 4-(2-methylbenzyl)-4-hydroxymethylpiperidine hydrochloride salt (Example 35) in Step B. The crude product was purified with column chromatography on silica gel eluting with 2-5% methanol in chloroform.