Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH3:24])=[CH:15][N:14]([S:25]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)(=[O:27])=[O:26])[C:11]3=[N:12][CH:13]=2)=[CH:4][C:3]=1[C:35]([N:37]1[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]1)=[O:36].C(NC(C)C)(C)C.[C:51](Cl)(Cl)=[O:52].[NH:55]1[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1>ClCCl>[CH3:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]1[C:10]2[C:11](=[N:12][CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:51]([N:55]4[CH2:60][CH2:59][O:58][CH2:57][CH2:56]4)=[O:52])=[C:3]([C:35]([N:37]4[CH2:38][CH2:39][N:40]([CH3:43])[CH2:41][CH2:42]4)=[O:36])[CH:4]=3)[CH:9]=2)[N:14]([S:25]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH:15]=1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccc(N)c(C(=O)N4CCN(C)CC4)c3)cc12
Reactant: O=C(Cl)Cl
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccc(NC(=O)N4CCOCC4)c(C(=O)N4CCN(C)CC4)c3)cc12
Temperature: 0 °C
Reaction time: 15 h
Yield: 140 %

Procedure:
Crude {2-amino-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone (0.637 mmol) was dissolved in dichloromethane (7.0 mL) with di-iso-propylamine (266 μL, 1.91 mmol) and cooled to 0° C. Phosgene (20% w/v in toluene, 1.0 mL, 1.91 mmol) was added and after 1 minute, morpholine (557 μL, 6.37 mmol) was added rapidly. The mixture was stirred 15 h, washed with brine and dried over sodium sulfate to afford crude morpholine-4-carboxylic acid [4-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-(4-methyl-piperazine-1-carbonyl)-phenyl]-amide (632 mg, crude). MS: m/z 710 (M+H+).
Reaction SMILES: O=[C:2]([CH3:15])[CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:7]=[CH:8][CH:9]=1.[CH3:16][C@@H:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[C:18]1([C@H:17]([NH:24][C@H:2]([CH3:15])[CH2:3][C:4]2[CH:5]=[C:6]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:7]=[CH:8][CH:9]=2)[CH3:16])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: COC(=O)Cc1cccc(CC(C)=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)Cc1cccc(C[C@@H](C)N[C@H](C)c2ccccc2)c1
Yield: 41 %

Procedure:
A solution of methyl [3-(2-oxopropyl)phenyl]acetate (Preparation 90) (45.3 g, 236 mmol), (R)-α-methyl benzylamine (27.6 ml, 214 mmol), sodium triacetoxyborohydride (68.1 g, 321 mmol) and acetic acid (14.7 ml, 257 mmol) in dichloromethane (1500 ml) was stirred at room temperature for 18 hours. The reaction mixture was quenched by addition of saturated aqueous sodium bicarbonate (600 ml) and allowed to stir until effervescence ceased. The organic phase was separated and the aqueous phase extracted with further dichloromethane (2×100 ml). The combined organic extracts were washed with brine (100 ml), dried (sodium sulfate), filtered through celite and reduced in vacuo. The oil was dissolved in methanol (200 ml), treated with 1M hydrogen chloride in methanol (300 ml) and reduced in vacuo to give a 4:1 mixture of diastereomers (R,R major) as an off-white, hydrochloride salt. Two successive crystallisations (diisopropylether/methanol) gave the title compound (27.3 g) as a colourless crystalline solid.
Reaction SMILES: [OH-].[Na+].Cl.[C:4]([NH2:12])(=[NH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Br[CH:14]1[CH2:29][CH2:28][C:17]2=[C:18]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[S:19][C:20]([S:21][CH3:22])=[C:16]2[C:15]1=O>O.C(Cl)(Cl)Cl>[CH3:22][S:21][C:20]1[S:19][C:18]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:17]2[CH2:28][CH2:29][C:14]3[N:11]=[C:4]([C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)[NH:12][C:15]=3[C:16]=12
Reactant: CCOC(=O)c1sc(SC)c2c1CCC(Br)C2=O
Reactant: N=C(N)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)c1sc(SC)c2c1CCc1nc(-c3ccccc3)[nH]c1-2
Yield: 13.2 %

Procedure:
A solution of sodium hydroxide (1.65 g) in water (3 ml) was added to a solution of benzamidine hydrochloride (5.38 g) in water (2 ml) at room temperature; a solution of ethyl 5-bromo-4,5,6,7-tetrahydro-3-methylthio-4-oxobenzo[c]thiophene-1-carboxylate (2.00 g) in chloroform (30 ml) was further added. The reaction mixture was refluxed under heating for 3 days, after which it was poured over water and extracted with ethyl acetate. The organic layer was washed with water and dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:2, v/v) to yield ethyl 4,5-dihydro-8-methylthio-2-phenylthieno[3,4-e]benzimidazole-6-carboxylate (0.28 g, 13.2%), which was then recrystallized from ethyl acetate-ethanol. Brown prisms. Melting point 218-219° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[C:14]3[C:15](=[O:23])[O:16][C:17]([CH3:22])([C:19](O)=[O:20])[CH2:18][C:13]=3[N:12]=[CH:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:24][N:25](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)[CH3:26].[B-](F)(F)(F)F.Cl.CNC.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH3:24][N:25]([CH3:26])[C:19]([C:17]1([CH3:22])[O:16][C:15](=[O:23])[C:14]2[N:10]([C:4]3[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[CH:3]=3)[CH:11]=[N:12][C:13]=2[CH2:18]1)=[O:20]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC1(C(=O)O)Cc2ncn(-c3ccc(C#N)c(Cl)c3)c2C(=O)O1
Agent: CNC
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)C(=O)C1(C)Cc2ncn(-c3ccc(C#N)c(Cl)c3)c2C(=O)O1
Reaction time: 48 h
Yield: 40 %

Procedure:
To 50 mg (0.15 mmol) of 44 in 2 mL of DMF is added 58 mg (0.18 mmol) of TBTU, 15 mg (0.18 mmol) of dimethylamine hydrochloride and 0.03 mL (0.2 mmol) of iPr2NEt. The mixture is stirred for 48 h, diluted with 50 mL of EtOAc, and washed twice with 20 mL of H2O and once with 20 mL of brine. The organic phase is dried with MgSO4, filtered, concentrated, and purified twice by preparative TLC (100% EtOAc) to give 22 mg (0.06 mmol) of 46.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[N:25]1([CH:30]2[CH:39]3[CH:34]([CH2:35][CH2:36][CH2:37][NH:38]3)[CH2:33][CH2:32][CH2:31]2)[CH2:29][CH2:28][CH2:27][CH2:26]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:38]2[CH:39]3[CH:34]([CH2:33][CH2:32][CH2:31][CH:30]3[N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:35][CH2:36][CH2:37]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C1CNC2C(C1)CCCC2N1CCCC1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCCC2CCCC(N3CCCC3)C21
Reaction time: 4 h

Procedure:
A solution of 1.98 g of 3,4-dichlorophenyl acetic acid and 1.56 g of carbonyldiimidazole in 17 ml of tetrahydrofuran was stirred at 20° to 22° C. for one hour and the, 1.679 g of [4aRS(4aα, 8α, 8aβ)](±)-decahydro-8-(1-pyrrolidinyl)-quinoline (preparation given at the end of Example (4) were added in solution in 5 ml of tetrahydrofuran. The solution was stirred for 4 hours at 20° to 22° C. and the tetrahydrofuran was eliminated under reduced pressure at less than 45° C. The residue was triturated in 15 ml of ether and in 5 ml of a saturated solution of sodium bicarbonate, then separated and rinsed, first with water then with ether. After drying under reduced pressure, 2.320 g of [4aRS(4aα, 8α, 8aβ)](±)-decahydro-1-[(3,4-dichlorophenyl)-acetyl]-8-(1-pyrrolidinyl)-melting at 138° C. were obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[CH:14]=[CH:15][CH2:16][CH2:17][OH:18])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.CS(C)=O.[NH4+].[Cl-]>C(Cl)Cl.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[CH:14]=[CH:15][CH2:16][CH:17]=[O:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1C=CCCO
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)c1ccc([N+](=O)[O-])cc1C=CCC=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
4-(2-tert-Butyl-5-nitro-phenyl)-but-3-en-1-ol (1.024 g) was dissolved in 10 ml of CH2Cl2 and added dropwise over 5 min to a −78° C. mix of oxalyl chloride (0.645 ml), DMSO (0.583 ml), and 10 ml CH2Cl2. The reaction was stirred at −78° C. for 1 h, then treated with a solution of TEA (1.52 ml) in 7 ml CH2Cl2 and stirred at −78° C. for an additional 25 min, then warmed to −30° C. for 35 min. The reaction was treated with 50 ml of saturated aqueous NH4Cl, diluted with H2O and extracted with EtOAc. The organic layer was brine-washed, dried over Na2SO4, filtered, and concentrated in vacuo to yield a yellow oil which was used as is in Preparation LXXXVIII.
Reaction SMILES: [Cl:1][C:2]1=[C:3]([Cl:9])[C:4]([O:6][C:7]1=O)=[O:5].Cl.[CH3:11][NH2:12].C(O)(=O)C.C[O-].[Na+]>O>[Cl:1][C:2]1[C:7](=[O:6])[N:12]([CH3:11])[C:4](=[O:5])[C:3]=1[Cl:9]
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Reactant: CN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CN1C(=O)C(Cl)=C(Cl)C1=O
Temperature: 10 °C
Reaction time: 24 h

Procedure:
A 3L-three-necked flask fitted with a magnetic stir bar, digital thermocouple/thermometer, nitrogen purge and solid addition funnel was charged with 450 g (269.5 mol) of dichloromaleic anhydride, 191 g (282.8 mol) of methylamine hydrochloride and 1.6 L of acetic acid. The reaction mixture was then cooled to 10° C., and 160 g NaOMe added from the solid addition funnel over 1 hour while keeping the temperature between 10°-12° C. The reaction mixture was allowed to stir at room temperature for 42 hours (24 hours is sufficient) then heated to 100° C. for 3 hours. HPLC analysis at this time indicated that all the starting material had disappeared. The reaction was cooled to room temperature and 2L water was added. The mixture was then cooled to 3°-10° C. for 1 hour and filtered at 4° C. The solids were then rinsed with 2L of cold deionized water. The pale yellow solid dried in an air oven overnight to afford 360 g (75%) yield of the titled compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.O[CH2:13][C@@H:14]([NH:16][C:17](=[O:23])OC(C)(C)C)[CH3:15].[C:24]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[C:17]([NH:16][C@@H:14]([CH3:15])[CH2:13][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)(=[O:23])[CH3:24]
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(O)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(OC[C@H](C)NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of methyl 4-hydroxybenzoate (4.77 g), tert-butyl [(1S)-2-hydroxy-1-methylethyl]carbamate (5.00 g) and triphenylphosphine (11.2 g) in THF (70 mL) was added dropwise a toluene solution (2.2 M, 20 mL) of diethyl azodicarboxylate, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate). Using the obtained residue, and in the same manner as in Example 1, step D, the title compound (3.80 g) was obtained.
Reaction SMILES: [OH:1][CH:2]([C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[C:25](=[O:29])[O:24][C@H:23]([CH3:30])[CH2:22]2)[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12]C(C)(C)C)=[O:11])[CH2:6][C@H:5]1[CH2:17][OH:18].FC(F)(F)C(O)=O.C(N(CC)CC)C.ClC(O[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=O>C(Cl)Cl>[OH:1][CH:2]([C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[C:25](=[O:29])[O:24][C@H:23]([CH3:30])[CH2:22]2)[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[O:11])[CH2:6][C@H:5]1[CH2:17][OH:18]
Reactant: C[C@@H]1Cc2cc(C(O)CN3CCN(C(=O)OC(C)(C)C)C[C@H]3CO)ccc2C(=O)O1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1Cc2cc(C(O)CN3CCN(C(=O)OCc4ccccc4)C[C@H]3CO)ccc2C(=O)O1

Procedure:
To the solution of (3S)-tert-butyl 4-(2-hydroxy-2-((R)-3-methyl-1-oxoisochroman-6-yl)ethyl)-3-(hydroxymethyl)piperazine-1-carboxylate (2630 mg, 6.25 mmol) in methylene chloride (10 mL) was added trifluoroacetic acid (10 mL, 130 mmol) at rt for 1 h. After removing the volatile the residue was dissolved in methylene chloride (100 mL). To the above solution was added triethylamine (4.36 mL, 31.3 mmol) and benzyl chloroformate (0.986 mL, 6.56 mmol) at 0° C. for 0.5 h. The reaction was quenched by water followed by addition of saturated sodium carbonate. The mixture was extracted with methylene chloride, dried over sodium sulfate, concentrated and the residue was purified on Biotage using 40-100% EtOAc/hexane to give the title compound: LC/MS: (M+1)+: 455.10.
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20](O)([C:23]2[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20]([F:7])([C:23]2[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ncccc2Cl)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(F)(c2ncccc2Cl)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7.1 %

Procedure:
To a solution of DAST (0.837 mL, 6.3 mmol) in DCM (20 mL) at −78° C. a solution of 3-chloro-4′-hydroxy-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (1.8 g, 5.8 mmol) in DCM (50 mL) was slowly added and allowed to warm to room temperature. Further DAST (0.6 mL) was added at 0° C. and stirred at room temperature for 30 minutes. Sodium hydrogen carbonate (sat.aq.) and DCM were added, the organics separated, dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was purified by flash chromatography on silica eluting with 20% ethyl acetate/cyclohexane. The fractions containing the desired product were concentrated under vacuum to give the title compound as a white solid (0.13 g).
Reaction SMILES: O.[OH-].[Li+:3].[Cl:4][C:5]1[C:13]2[O:12][CH:11]([C:14]([O:16]CC)=[O:15])[O:10][C:9]=2[CH:8]=[C:7]([CH:19]=[O:20])[C:6]=1[Cl:21].C(OC(C)C)(C)C>CO>[Cl:4][C:5]1[C:13]2[O:12][CH:11]([C:14]([O-:16])=[O:15])[O:10][C:9]=2[CH:8]=[C:7]([CH:19]=[O:20])[C:6]=1[Cl:21].[Li+:3]
Reactant: CCOC(=O)C1Oc2cc(C=O)c(Cl)c(Cl)c2O1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC(C)OC(C)C
Product: O=Cc1cc2c(c(Cl)c1Cl)OC(C(=O)[O-])O2
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.2 %

Procedure:
1.03 g of lithium hydroxide monohydrate are added to a solution of 7.0 g of ethyl 4,5-dichloro-6-formyl-1,3-benzodioxole-2-carboxylate in methanol under ice-cooling and the mixture is stirred at room temperature for 4 hours. Isopropyl ether is added to the reaction mixture and the resultant powdery materials are collected by filtration to give 6.48 g of lithium 4,5-dichloro-6-formyl-1,3-benzodioxole-2-carboxylate.
Reaction SMILES: CS(O[CH:6]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:7][CH2:8][CH2:9][CH2:10]C)(=O)=O.[C-]#[N:18].[K+].C1O[CH2:36][CH2:35]OCCOCCOCCOCCOC1.[OH-].[Na+]>C(#N)C>[CH2:12]([CH:6]([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:35][C:36]#[N:18])[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: CCCCCC(CCCCC)OS(C)(=O)=O
Reactant: [C-]#N
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CCCCCC(CC#N)CCCC

Procedure:
Sodium borohydride (0.55 g, 14.6 mmol) was added to a solution of 6-undecanone (1.66 g, 9.8 mmol) in 50 ml methanol, and the mixture was stirred at room temperature 2 hours. Solvent was evaporated and water was added to the residue which was extracted with CH2Cl2. The extracts were dried over anhydrous potassium carbonate, filtered, and the solvent was evaporated to leave crude 6-undecanol. The procedure of example 13 a. was followed but the crude 6-undecanol was substituted in place of 9-dodecyn-1-ol to obtain crude 6-undecanyl methanesulfonate. The crude 6-undecanyl methanesulfonate was dissolved in 20 ml acetonitrile and 1 g potassium cyanide were added, as well as 50 mg 18-crown-6, and 100 mg Et4NCN. The mixture was stirred and heated at reflux for 4 days. The mixture was cooled, poured into 5% aqueous NaOH, and extracted with CH2Cl2. The extracts were dried over Na 2 SO4. The extracts were filtered, and the solvent was evaporated. The residue was chromatographed on silica gel eluting with EtOAc-hexanes (2:98) to obtain crude 3-pentylheptanenitrile in low yield. This nitrile was dissolved in 30 ml THF, 1 ml 1M BH3 -THF solution was added, and the mixture was stirred at reflux for 4 hours. Water and 1N NaOH were added. The mixture was concentrated and water was added. The mixture was extracted with CH2Cl2. The extracts were dried over Na2SO4, filtered, and the solvent was evaporated to leave the title compound as an oil (57 mg, 3% yield overall): C12H27N (185.36); 1H-NMR (CDCl3) δ2.64 (d,2), 1.28 (m,17), 0.89 (t,6).
Reaction SMILES: C1(C)C=CC(S([CH2:10][N+:11]#[C-])(=O)=[O:8])=CC=1.CC(C)([O-])C.[K+].C(O[CH2:24][CH:25]=[C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][C:27]1=[O:35])(=O)C>O1CCCC1>[O:35]=[C:27]1[C:26]2[NH:11][CH:10]=[CH:24][C:25]=2[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[NH:28]1.[CH2:26]([C:27]([O-:35])=[O:8])[CH3:34]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CC(=O)OCC=C1C(=O)Nc2ccccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCC(=O)[O-]
Product: O=c1[nH]c2ccccc2c2cc[nH]c12
Yield: 91.8 %

Procedure:
18.3 g (93.6 mmol) of p-toluenesulfonylmethyl isonitrile followed by a solution of 54 mL (93.6 mmol) of a 20% solution of potassium tert-butoxide in tetrahydrofuran in 700 mL of anhydrous tetrahydrofuran are added to a solution of 20.3 g (93.6 mmol) of (2-oxo-1,2-dihydro-indol-3-ylidene)-ethyl ethanoate dissolved in 340 mL of anhydrous tetrahydrofuran (time of addition 90 minutes). The reaction mixture is refluxed for 1 hour then the solid is filtered. The filtrate is poured into a mixture of ice and water (about 1 L) and the solution is acidified with acetic acid until the pH is 4. The solvents are concentrated by evaporation under vacuum then the solid is filtered and then recrystallized from acetic acid to give 11.05 g (37%) of 4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate cocrystallized with one equivalent of acetic acid in the form of a white solid.
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([NH:20][CH3:21])=[O:19])=[CH:16][CH:15]=2)[O:11][CH3:12])=[O:9])[C:4](=[O:24])O1.[CH2:26]=O.[NH2:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>CO>[CH3:12][O:11][N:10]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:18](=[O:19])[NH:20][CH3:21])=[CH:22][CH:23]=1)[C:8]([C:7]1[CH2:26][N:28]([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[C:4](=[O:24])[C:5]=1[OH:6])=[O:9]
Reactant: CNC(=O)c1ccc(CN(OC)C(=O)C=C2OC(C)(C)OC2=O)cc1
Reactant: NCCN1CCOCC1
Reactant: C=O
Solvent: CO
Product: CNC(=O)c1ccc(CN(OC)C(=O)C2=C(O)C(=O)N(CCN3CCOCC3)C2)cc1
Yield: 41 %

Procedure:
Reaction 4-({[2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl]-methoxy-amino}-methyl)-N-methyl-benzamide (0.053 g, 0.15 mmol) with the paraformaldehyde-N-(2-aminoethyl)morpholine adduct in methanol using a procedure similar to the one described in the preparation of compound 13 gave 0.034 g (41% yield) of the title compound as a white solid after chromatography on reversed phase silica gel. 1HNMR 400 MHz (DMSO-d6) δ (ppm); (TFA salt) 2.77 (3H, d, J=4.65 Hz, NCH3), 3.1 (2H, broad m, NCH2), 3.4–3.8 (8H, broad m, 2×NCH2 and 2×OCH2), 3.75 (3H, s, OCH2), 3.98 (2H, broad, NCH2), 4.24 (2H, s, NCH2), 4.94 (2H, s, NCH2), 7.39 (2H, d, J=8.4 Hz, aromatics), 7.80 (2H, d, J=8.4 Hz, aromatic), 8.41 (1H, q, J=4.5 Hz, NH). HRMS (FAB+) calculated for C21H29N4O6: [M+H]+: 433.208710. found: 433.209419.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH:17]=O)[CH2:11][CH2:10]1.[CH2:19]([NH:22][CH:23]1[CH2:31][CH2:30][C:26]2[N:27]=[CH:28][S:29][C:25]=2[CH2:24]1)[CH2:20]C>>[CH2:19]([N:22]([CH2:17][CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:10][CH2:11]1)[CH:23]1[CH2:31][CH2:30][C:26]2[N:27]=[CH:28][S:29][C:25]=2[CH2:24]1)[CH3:20]
Reactant: COc1ccccc1N1CCN(CCC=O)CC1
Reactant: CCCNC1CCc2ncsc2C1
Product: CCN(CCCN1CCN(c2ccccc2OC)CC1)C1CCc2ncsc2C1
Yield: 10 %

Procedure:
Compound 29 is prepared from 29B and 1C as described for 1. The salt of maleic acid is crystallized from ethanol/diethylether.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[I:11]N1C(=O)CCC1=O.C(Cl)(Cl)Cl.O>CN(C=O)C>[Cl:1][C:2]1[C:7]2[C:8]([I:11])=[CH:9][NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc2[nH]ccc12
Reactant: O=C1CCC(=O)N1I
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: Clc1nccc2[nH]cc(I)c12
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.9 %

Procedure:
4-Chloro-1H-pyrrolo[3,2-c]pyridine (247 mg) synthesized by the method disclosed in WO2007/095223 was dissolved in DMF (7.0 ml). After cooling to 0° C., N-iodosuccinimide (382 mg) was added thereto. The resulting mixture was stirred at room temperature for 1 hour, and then chloroform and water were added thereto to separate the organic layer. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a dark-brown solid (455 mg). Physical properties: m/z [M+H]+ 279.1
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[Li+].[Cl-].C([Cu])#N.[F:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1>C1COCC1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][C:7]=1[C:19]([C:18]1[CH:22]=[CH:23][C:15]([F:14])=[CH:16][CH:17]=1)=[O:20]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Clc1ccc(Cl)nn1
Agent: N#C[Cu]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(c1ccc(F)cc1)c1cc(Cl)nnc1Cl
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
3,6-Dichloropyridazine (3) (149 mg, 1.0 mmol) in THF (2 mL) was added to a solution of TMPZnCl.LiCl (2) (1.3 M in THF, 0.85 mL, 1.1 mmol) at 25° C. and the reaction mixture was then stirred at this temperature for 30 min according to TP 2. After cooling down to −20° C., CuCN.2LiCl (1.0 M in THF, 1.1 mmol, 1.1 equiv) was added and the resulting mixture was stirred for 30 min at this temperature. 4-Fluorobenzoyl chloride (317 mg, 2.0 mmol) was then slowly added and the resulting mixture was allowed to warm up slowly to 10° C. The reaction mixture was quenched with a sat. aq. NH4Cl solution (20 mL), extracted with diethyl ether (3×50 mL) and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated in vacuo. Purification by flash-chromatography (CH2Cl2/n-pentane, 1:1) furnished compound 5b (259 mg, 96%) as a white solid.
Reaction SMILES: [NH3:1].Br[CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[C:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:5]>>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]2[NH:6][C:4](=[O:5])[CH2:3][N:1]=[C:14]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[C:8]=2[CH:9]=1
Reactant: O=C(CBr)Nc1ccc(Cl)cc1C(=O)c1ccc(O)cc1
Reactant: N
Product: O=C1CN=C(c2ccc(O)cc2)c2cc(Cl)ccc2N1
Yield: 67 %

Procedure:
To 350 ml of liquid ammonia was added 60 g (0.163 mole) of 2-bromo-4'-chloro-2'-(4-hydroxybenzoyl)acetanilide. After refluxing for 3 hr, the ammonia was allowed to evaporate. The residue was heated to reflux in 400 ml of ethanol for 3 hr. Ethanol was evaproated, and 800 ml of acetone was added. This suspension was heated and filtered to remove inorganic salts. Concentration of acetone filtrate gave 31.5 g (67%) of product, mp 271°-272°.