Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.[C:6](#[N:8])[CH3:7].C[O:10][C:11]([CH:13]1[CH2:16][C:15]([O:19][CH3:20])([O:17][CH3:18])[CH2:14]1)=O.C(#N)C.C(=O)=O>C1COCC1>[CH3:18][O:17][C:15]1([O:19][CH3:20])[CH2:16][CH:13]([C:11](=[O:10])[CH2:7][C:6]#[N:8])[CH2:14]1
Reactant: CC#N
Reactant: COC(=O)C1CC(OC)(OC)C1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC1(OC)CC(C(=O)CC#N)C1
Reaction time: 1 h

Procedure:
To 200 mL of THF at −78° C. was added n-BuLi (207.0 mL, 517.0 mmol, 2.5 M in hexanes). After the reaction temperature equilibrated (˜15 min), a solution of acetonitrile (27.0 mL, 517.0 mmol in 100 mL of THF) was added dropwise via addition funnel over a 20 min period. The resulting milky white slurry was allowed to stir one hr before a solution of 3,3-dimethoxy-cyclobutanecarboxylic acid methyl ester (45.0 g, 258.6 mmol in 150 mL of THF) was added down the side of the flask over a 20 min period. After one hr, the reaction was warmed to −45° C. (acetonitrile/CO2), and allowed to stir for two hr. The reaction was quenched cold by the dropwise addition of 2 N HCl (˜260 mL), pH=7 and then diluted with EtOAc (1 L). The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×600 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to yield the title compound (quantitative yield) as a yellow oil that was used with out further purification. Rf 0.32 (40% EtOAc/hexanes). m/z (APCI+) 182 (M−1).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][Si](C=[N+]=[N-])(C)C.[BrH:21].CC(O)=O.N#N>C(Cl)Cl>[Br:21][CH2:14][C:6]([C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1)=[O:7]
Reactant: Br
Reactant: Cc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: N#N
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1ccc(C(=O)CBr)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
To a stirred solution of 4-methyl-3-nitrobenzoyl chloride (Sigma-Aldrich, 2.0 g, 10 mmol) in CH2Cl2 (50 mL) is added trimethylsilyldiazomethane (2.0 M in hexanes, 40 mmol). The mixture is stirred for 2 hours at room temp, then cooled to 0° C. and a solution of HBr/HOAc (6.33 mL, 33% of HBr in HOAc, 35 mmol) is added dropwise (N2 evolution). After addition the mixture is stirred at 0° C. for 5 minutes, concentrated and purified by silica gel chromatography (CH2Cl2) to give the title compound (2.42 g, 93% yield) as a light yellow solid: Rf 0.61 (CH2Cl2)
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:29]=[C:28]([C:30]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([OH:40])[CH:35]=2)=[O:31])[CH:27]=[C:26]([Cl:41])[C:5]=1[C:6]([NH:8][C@H:9]([C:22]([O:24]C)=[O:23])[CH2:10][NH:11][C:12](=[O:21])[C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=1)=[O:7]>CO>[Cl:3][C:4]1[CH:29]=[C:28]([C:30]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([OH:40])[CH:35]=2)=[O:31])[CH:27]=[C:26]([Cl:41])[C:5]=1[C:6]([NH:8][C@H:9]([C:22]([OH:24])=[O:23])[CH2:10][NH:11][C:12](=[O:21])[C:13]1[CH:14]=[C:15]([F:20])[CH:16]=[C:17]([F:19])[CH:18]=1)=[O:7]
Reactant: COC(=O)[C@H](CNC(=O)c1cc(F)cc(F)c1)NC(=O)c1c(Cl)cc(C(=O)NCc2cccc(O)c2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(NCc1cccc(O)c1)c1cc(Cl)c(C(=O)N[C@@H](CNC(=O)c2cc(F)cc(F)c2)C(=O)O)c(Cl)c1
Reaction time: 8 h
Yield: 39.3 %

Procedure:
An aqueous solution of sodium hydroxide (1 M; 0.386 mL, 0.386 mmol) was added to a solution of N-[2,6-dichloro-4-[[[(3-hydroxyphenyl]methyl]amino]-carbonyl]benzoyl]-3-[(3,5-difluorobenzoyl)amino]-L-alanine, methyl ester (112 mg, 0.193 mmol) in methanol (2 mL). The solution was allowed to stir overnight and then concentrated. The residue was purified by HPLC and lyophilized to give N-[2,6-dichloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-[(3,5-difluorobenzoyl)amino]-L-alanine (43 mg, 39%) as a white solid.
Reaction SMILES: Br[C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].[NH:8]1[CH:12]=[CH:11][CH:10]=[N:9]1>C(N(CC)CC)C>[CH3:10][CH:11]1[CH2:12][CH2:2][CH2:3][O:4]1.[CH3:6][C:2]([N:8]1[CH:12]=[CH:11][CH:10]=[N:9]1)([CH3:7])[C:3]([OH:5])=[O:4]
Reactant: c1cn[nH]c1
Reactant: CC(C)(Br)C(=O)O
Solvent: CCN(CC)CC
Product: CC(C)(C(=O)O)n1cccn1
Product: CC1CCCO1

Procedure:
2-Bromo-2-methylpropanoic acid 15 and pyrazole were reacted in triethylamine and 2-methyltetrahydrofuran to give 16.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[S:22]1[C:30]2[CH:29]=[C:28]([CH:31]=O)[N:27]=[CH:26][C:25]=2[O:24][CH2:23]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(Cl)(Cl)[Cl:48]>CO>[ClH:48].[ClH:48].[F:20][C:17]1[CH:18]=[C:19]2[C:14]([CH:13]=[CH:12][C:11](=[O:21])[N:10]2[CH2:9][CH2:8][N:5]2[CH2:6][CH2:7][CH:2]([NH:1][CH2:31][C:28]3[N:27]=[CH:26][C:25]4[O:24][CH2:23][S:22][C:30]=4[CH:29]=3)[CH2:3][CH2:4]2)=[CH:15][CH:16]=1
Reactant: ClC(Cl)Cl
Reactant: NC1CCN(CCn2c(=O)ccc3ccc(F)cc32)CC1
Reactant: O=Cc1cc2c(cn1)OCS2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: Cl
Product: O=c1ccc2ccc(F)cc2n1CCN1CCC(NCc2cc3c(cn2)OCS3)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-[2-(4-amino-1-piperidinyl)ethyl]-7-fluoro-2(1H)-quinolinone (100 mg; 0.364 mmol) and [1,3]oxathiolo[5,4-c]pyridine-6-carbaldehyde (for a synthesis see WO2004058144, Example 61) (57 mg; 0.364 mmol) were dissolved in a 5:1 mixture of chloroform and methanol (5 ml: 1 ml) and stirred at rt under argon for 1 h. The mixture was then treated with NaBH(OAc)3 (231 mg; 1.092 mmol) and stirred for a further 1 h. The solvents were then removed and the crude residues purified by chromatography on silica gel using a 0-15% MeOH/DCM gradient to provide the title compound as free base (140 mg; 92%)
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:34][C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=1[F:43])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18]([C:30]([F:33])([F:32])[F:31])=[N:19][C:20]([C:21]([N:23]3[CH2:27][CH2:26][CH2:25][C@H:24]3[CH2:28][OH:29])=[O:22])=[C:14]2[CH2:13]1)=[O:11])(C)(C)C.[Cl:45]CCl.Cl>CO>[ClH:45].[NH2:7][C@H:8]([CH2:34][C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=1[F:43])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18]([C:30]([F:33])([F:32])[F:31])=[N:19][C:20]([C:21]([N:23]3[CH2:27][CH2:26][CH2:25][C@H:24]3[CH2:28][OH:29])=[O:22])=[C:14]2[CH2:13]1)=[O:11]
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCC[C@H]3CO)c2C1)Cc1cc(F)c(F)cc1F
Agent: Cl
Solvent: CO
Product: N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCC[C@H]3CO)c2C1)Cc1cc(F)c(F)cc1F
Yield: 84 %

Procedure:
(R)-[3-[1-((S)-2-Hydroxymethyl-pyrrolidine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluorobenzyl)-propyl]-carbamic acid tert-butyl ester 30a (0.16 g, 0.25 mmol) and 2 mL of dichloromethane were added into the reaction flask. A solution of 2.7 N hydrochloric acid in 5 mL of methanol was then added to the flask. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-3-amino-1-[1-((S)-2-hydroxymethyl-pyrrolidine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-4-(2,4,5-trifluoro-phenyl)-butan-1-one hydrochloride 30 (120 mg, yield 84%) as a white solid.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[N-:6]([C:9]#[N:10])[C:7]#[N:8].[Na+].CN(C)C(=O)N(C)C>CC(O)CC>[NH2:8][C:7]([NH:6][C:9]#[N:10])=[C:2]([C:1]#[N:5])[C:3]#[N:4]
Reactant: N#C[N-]C#N
Reactant: N#CCC#N
Agent: [Na+]
Solvent: CCC(C)O
Solvent: CN(C)C(=O)N(C)C
Product: N#CNC(N)=C(C#N)C#N
Temperature: 145 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
To a 500 ml flask is charged 13.2 gm (0.2 mole) of malononitrile, 18.2 gm (0.2 mole) of sodium dicyanamide and 80 ml of tetramethylurea. The stirred mixture is heated at 145° C. for 2.5 hours; then cooled to about room temperature. The slurry is diluted with 300 ml 2-butanol and stirred in an ice bath for one hour. The solids are filtered, washed with 50 ml of 2-butanol. The product is dried overnight at 70° C. in a vacuum oven to yield 25.0 gm of 1-amino-1-cyanamido-2,2-dicyanoethylene, sodium salt, 80.7% pure or a 65.0% yield.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[OH:16])[C:11]#[N:12].I[CH2:18][CH3:19].O>CC(C)=O>[Br:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH2:18][CH3:19])[C:11]#[N:12]
Reactant: CCI
Reactant: N#Cc1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOc1ccc(C#N)cc1Br
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Add potassium carbonate (5.2 g, 37.9 mmol) to 3-bromo-4-hydroxy-benzonitrile (5.0 g, 25.2 mmol) in acetone with stirring at room temperature. After 15 minutes, add iodoethane (2.4 mL, 130.3 mmol) and continue stirring at room temperature. After 18 hours, pour the reaction mixture into water and extract with EtOAc. Combine the organic extracts, wash with water and brine, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify the residue by flash chromatography eluting with ethyl acetate:hexanes to provide the title compound.
Reaction SMILES: [OH-].[Na+].[CH2:3]([OH:21])[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][OH:20].[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O.[Cl-].[Na+].O>[CH2:22]([O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][OH:21])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: ClCc1ccccc1
Reactant: OCCOCCOCCOCCOCCOCCO
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCCOCCOCCOCCOCCOCCOCc1ccccc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 70.6 %

Procedure:
An aqueous sodium hydroxide solution prepared by dissolving 3.99 g (100 mmol) NaOH in 4 ml water was added slowly to monodispersed hexaethylene glycol (28.175 g, 25 ml, 100 mmol). Benzyl chloride (3.9 g, 30.8 mmol, 3.54 ml) was added and the reaction mixture was heated with stirring to 100° C. for 18 hours. The reaction mixture was then cooled, diluted with brine (250 ml) and extracted with methylene chloride (200 ml×2). The combined organic layers were washed with brine once, dried over Na2SO4, filtered and concentrated in vacuo to a dark brown oil. The crude product mixture was purified via flash chromatography (silica gel, gradient elution: ethyl acetate to 9/1 ethyl acetate/methanol) to yield 8.099 g (70%) of monodispersed compound 1 as a yellow oil.
Reaction SMILES: COC[O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([CH:17]=[O:18])[C:11]([CH3:16])([CH3:15])[O:12]2)=[CH:7][CH:6]=1.[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CCO>[OH:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([CH:17]=[O:18])[C:11]([CH3:15])([CH3:16])[O:12]2)=[CH:7][CH:6]=1
Reactant: COCOc1ccc2c(c1)OC(C)(C)C(C=O)=C2
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Product: CC1(C)Oc2cc(O)ccc2C=C1C=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
7-(Methoxymethoxy)-2,2-dimethyl-2H-chromene-3-carbaldehyde (300 mg) was dissolved in EtOH (10 mL), and (1S)-(+)-10-camphor sulfonic acid (421 mg) was added thereto, followed by stirring at 80° C. overnight. To the reaction liquid was added silica gel, followed by concentration. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=90:10 to 70:30) to obtain 7-hydroxy-2,2-dimethyl-2H-chromene-3-carbaldehyde (175 mg) as a red powder.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH2:5]([C:7]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[C:10]([CH2:17][CH3:18])[C:8]=1[NH2:9])[CH3:6]>C1(C)C=CC=CC=1>[CH2:17]([C:10]1[CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=[C:7]([CH2:5][CH3:6])[C:8]=1[N:9]=[C:1]=[O:2])[CH3:18]
Reactant: CCc1cc([N+](=O)[O-])cc(CC)c1N
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: CCc1cc([N+](=O)[O-])cc(CC)c1N=C=O

Procedure:
Excess phosgene is bubbled into a warm solution of 21.5 g (0.11 moles) of 2,6-diethyl-4-nitroaniline in toluene (250 ml). After the addition, the mixture is heated to reflux and approximately 200 ml of toluene are distilled. The remainder of the toluene is removed under vacuum and the remaining brown semi-solid is distilled under vacuum to give 2,6-diethyl-4-nitrophenylisocyanate, b.p. 135°-144° C./1 mm, as a yellow liquid which crystallized on standing.
Reaction SMILES: CCCCCON=O.[Br:9][C:10]1[CH:16]=[CH:15][C:13](N)=[C:12]([O:17][CH3:18])[CH:11]=1.[CH:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[Br:9][C:10]1[CH:16]=[CH:15][C:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:12]([O:17][CH3:18])[CH:11]=1
Reactant: c1ccccc1
Reactant: COc1cc(Br)ccc1N
Agent: CCCCCON=O
Product: COc1cc(Br)ccc1-c1ccccc1
Temperature: 25 °C

Procedure:
n-Amyl nitrite (8.1 ml, 60 mmol) was slowly added to a stirred mixture of 4-bromo-2-methoxyaniline (J.Med.Chem., 1989, 32, 1936; 8.1 g, 60 mmol) and benzene (175 ml), under nitrogen, at about 50° C. When the addition was complete, the reaction mixture was heated under reflux for about 3 hours, then allowed to cool to room temperature and evaporated under reduced pressure. The residue was azeotroped with tetrahydrofuran, then with ethyl acetate, and purified by flash chromatography, using an elution gradient of hexane:ethyl acetate (100:0 to 95:5) to give the title compound (1.66 g) as a colourless solid, m.p. 50-52° C. δ(CDCl3): 3.77 (s,3H), 7.08 (s,1H), 7.14 (s,2H), 7.30 (m,1H), 7.36-7.41 (m,2H), 7.41-7.49 (m,2H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.C(N(CC)CC)C.[CH:29]1([CH2:35][CH2:36][CH2:37][C@@H:38]([C:47]([NH:49][CH:50]([C:54]([O:56][CH3:57])=[O:55])[C:51](=[O:53])[CH3:52])=O)[CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>O1CCCC1.O>[C:43]([O:42][C:40](=[O:41])[CH2:39][C@H:38]([C:47]1[O:53][C:51]([CH3:52])=[C:50]([C:54]([O:56][CH3:57])=[O:55])[N:49]=1)[CH2:37][CH2:36][CH2:35][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)([CH3:44])([CH3:46])[CH3:45]
Reactant: COC(=O)C(NC(=O)[C@H](CCCC1CCCCC1)CC(=O)OC(C)(C)C)C(C)=O
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1nc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)oc1C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 62.9 %

Procedure:
A suspension of triphenylphosphine (9.49 g, 36.18 mmol), iodine (7.98 g, 31.44 mmol) and triethylamine (8.49 ml, 60.75 mmol) in tetrahydrofuran was cooled to −78° C. then treated with tert-butyl (3R)-6-cyclohexyl-3-({[1-(methoxycarbonyl)-2-oxopropyl]amino}carbonyl)hexanoate (Preparation 172) (4.86 g, 11.80 mmol) over 15 minutes. The mixture was stirred at −78° C. for 30 minutes then at 0-5° C. for 2 hours. The mixture was diluted with water and extracted with dichloromethane. The combined organic layers were dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of ethyl acetate:pentane (0:100 to 10:90) to afford the title compound as a colourless oil (2.92 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([N:15](CC)[CH2:16][C:17]3C=CC(OC)=CC=3)[C:12]3=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:11]3[N:10]=2)=[CH:6][C:5]([C:32]#[N:33])=[CH:4][C:3]=1[N:34]1[CH2:43][CH2:42][C@@H:41]2[C@H:36]([O:37][CH2:38][CH2:39][N:40]2C(OC(C)(C)C)=O)[CH2:35]1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>ClCCCl>[Cl:1][C:2]1[C:3]([N:34]2[CH2:43][CH2:42][C@@H:41]3[C@H:36]([O:37][CH2:38][CH2:39][NH:40]3)[CH2:35]2)=[CH:4][C:5]([C:32]#[N:33])=[CH:6][C:7]=1[NH:8][C:9]1[N:14]=[C:13]([NH:15][CH2:16][CH3:17])[C:12]2=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:11]2[N:10]=1
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(Nc2cc(C#N)cc(N3CC[C@@H]4[C@@H](C3)OCCN4C(=O)OC(C)(C)C)c2Cl)nn2c(C#N)cnc12
Solvent: COc1ccccc1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@H]4NCCO[C@@H]4C3)c2Cl)nn2c(C#N)cnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
(+/−)-(4aR,8aR)-tert-butyl 6-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)octahydro-1H-pyrido[3,4-b][1,4]oxazine-1-carboxylate (75 mg, 0.104 mmol) was taken up in DCE (2 mL), anisole (0.05 mL, 0.458 mmol) and TFA (0.5 mL, 6.49 mmol). The mixture stirred 2 h at 25° C. and solvents removed. 50 ml 2N NH3/MeOH was added and stirred for 30 min. The white precipitate was collected by filtration and washed with 20 ml cold MeOH, then ether and dried under air-suction for 2 hrs to give (+/−)-2-((2-chloro-5-cyano-3-((4aR,8aR)-hexahydro-1H-pyrido[3,4-b][1,4]oxazin-6(7H)-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (38 mg).
Reaction SMILES: [CH3:1][N:2]1[CH:15]([CH3:16])[CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:28])=[CH2:27])=[CH:22][N:21]=1.O>CN1C(=O)CCC1>[CH3:1][N:2]1[CH:15]([CH3:16])[CH2:14][C:5]2[N:6]([CH2:27][CH:26]([C:23]3[CH:22]=[N:21][C:20]([CH3:19])=[CH:25][CH:24]=3)[CH3:28])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)C(C)C3
Reactant: C=C(C)c1ccc(C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)c2ccc(C)nc2)CC(C)N(C)C1
Temperature: 140 °C

Procedure:
A flask was charged with 2,3,8-trimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (117 mg, 0.5 mmol) and KOH (392 mg, 7 mmol) in NMP (2 mL) and heated at 140° C. for 10 min. The mixture was cooled to 0° C. and to it was added 2-methyl-5-(prop-1-en-2-yl)pyridine (199 mg, 1.5 mmol) dropwise. The mixture was heated at 140° C. for 2 h. The progress of the reaction was monitored by LCMS (5% conversion). The mixture was cooled to RT, water was added and the mixture filtered and evaporated. The solid obtained was purified by HPLC. 1HNMR (CD3OD, TFA salt) d (ppm): 8.10 (m, 2H), 7.60 (m, 1H), 7.22 (s, 1H), 7.10 (d, 1H), 6.96 (d, 1H), 4.62 (m, 1H), 4.38 (m, 2H), 4.22 (m, 2H), 3.50 (m, 2H), 3.0 (s, 3H), 2.80 (s, 3H), 2.40 (s, 3H), 1.60-1.30 (m, 7H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8]([C:11]([OH:13])=O)=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=[N:29][C:24]2[CH:25]=[CH:26][CH:27]=[N:28][C:23]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:38](N(CC)C(C)C)(C)[CH3:39].CN(C=O)C>CO>[N:28]12[CH2:27][CH2:26][CH:25]([CH2:38][CH2:39]1)[C@@H:24]([NH:29][C:11]([C:8]1[O:9][C:10]3[C:2]([Br:1])=[CH:3][CH:4]=[CH:5][C:6]=3[CH:7]=1)=[O:13])[CH2:23]2
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1cc2cccc(Br)c2o1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(Br)c2o1
Reaction time: 0.5 h

Procedure:
300 mg (1.25 mmol) of 7-bromobenzofuran-2-carboxylic acid, 248 mg (1.25 mmol) of R-3-aminoquinuclidine dihydrochloride, 568 mg (1.494 mmol) of HATU, 579 mg (4.48 mmol) of N,N-diisopropylethylamine and 5 ml of DMF are reacted according to the general procedure (variant B). The product is taken up in methanol and, together with acidic ion exchange resin (Dowex WX2-200), shaken for about 30 min. The loaded ion exchanger is washed with DMF, water, methanol, dichloromethane, water, DMF and once again with methanol. The product is eluted with methanol/triethylamine 90:10. The solvent is removed under reduced pressure using a rotary evaporator. The pre-purified product is purified by preparative HPLC. 320 mg (74% of theory) of the title compound are isolated.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH2:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[C:20]([C:28]3[CH:33]=[CH:32][C:31]([CH:34](O)[CH2:35][CH3:36])=[CH:30][CH:29]=3)[N:19]=2)[CH2:14][CH2:13]1)[CH3:11].C(=O)(O)[O-].[Na+].C(OCC)(=O)C.C(Cl)[Cl:50]>>[ClH:50].[CH2:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[C:20]([C:28]3[CH:33]=[CH:32][C:31]([CH:34]([F:7])[CH2:35][CH3:36])=[CH:30][CH:29]=3)[N:19]=2)[CH2:14][CH2:13]1)[CH3:11]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCC(O)c1ccc(-c2cc3ccccc3c(N3CCN(CC)CC3)n2)cc1
Reactant: ClCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCC(F)c1ccc(-c2cc3ccccc3c(N3CCN(CC)CC3)n2)cc1
Product: Cl
Reaction time: 1 h

Procedure:
Diethylaminosulfur trifluoride (0.27 g) was added to a solution of 1-(4-ethylpiperazin-1-yl)-3-[4-(1-hydroxypropyl)phenyl]isoquinoline (0.53 g) obtained in Example 19 in methylene chloride (30 ml) at −78° C. After stirring the resulting mixture for 1 hr, it was returned to room temperature. An aqueous solution of saturated sodium bicarbonate and ethyl acetate were added to the resulting reaction solution, for partitioning. The resulting organic layer was washed with water and brine, dried and concentrated. The resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system) (0.38 g), and was then converted into a hydrochloride in a conventional manner, to give 0.36 g of the title compound as a yellow powder.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Cl:24])(Cl)(Cl)Cl.[CH2:25]([S:27]([C:30]1[CH:50]=[CH:49][C:33]([CH2:34][C:35]2[C:44]3[C:39](=[CH:40][CH:41]=[C:42]([F:45])[CH:43]=3)[CH:38]=[C:37](CO)[C:36]=2[CH3:48])=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH3:26]>O1CCCC1.C(OCC)(=O)C>[CH2:25]([S:27]([C:30]1[CH:50]=[CH:49][C:33]([CH2:34][C:35]2[C:44]3[C:39](=[CH:40][CH:41]=[C:42]([F:45])[CH:43]=3)[CH:38]=[C:37]([CH2:20][Cl:24])[C:36]=2[CH3:48])=[CH:32][CH:31]=1)(=[O:28])=[O:29])[CH3:26]
Reactant: CCS(=O)(=O)c1ccc(Cc2c(C)c(CO)cc3ccc(F)cc23)cc1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)c1ccc(Cc2c(C)c(CCl)cc3ccc(F)cc23)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.1 %

Procedure:
A mixture of triphenylphosphine (1.10 g, 4.19 mmol), carbon tetrachloride (1.62 mL, 16.8 mmol) and tetrahydrofuran (5 mL) was stirred at room temperature for 10 minutes. A mixture of [4-(4-ethanesulfonyl-benzyl)-6-fluoro-3-methyl-naphthalen-2-yl]-methanol (780 mg, 2.09 mmol) in tetrahydrofuran (2.5 mL) was added, and the reaction mixture was stirred at 75° C. for 4 hours. The reaction mixture was cooled to room temperature, and then diluted with ethyl acetate. The resulting mixture was washed with water. The organic phase was dried over MgSO4, filtered, and concentrated. A solution of the crude product in dichloromethane was evaporated over silica gel, and the silica gel supported crude product was loaded onto an Analogix SuperFlash™ column. Flash chromatography (10%-30% ethyl acetate in hexanes) afforded 450 mg (55%) of 1-(4-ethanesulfonyl-benzyl)-3-chloromethyl-7-fluoro-2-methyl-naphthalene as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.04 (s, 1 H), 7.96-8.04 (m, 1 H), 7.76 (d, J=8.2 Hz, 2 H), 7.68-7.75 (m, 1 H), 7.41 (td, J=8.6, 2.1 Hz, 1 H), 7.30 (d, J=8.2 Hz, 2 H), 5.01 (s, 2 H), 4.63 (s, 2 H), 3.22 (q, J=7.2 Hz, 2 H), 2.47 (s, 3 H), 1.06 (t, J=7.2 Hz, 3 H). MS (ES+) cald. for C21H20CIFO2S [(M−Cl)+] 355, obsd. 355.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29](C(O)=O)=[CH:28][CH:27]=1.[CH3:35][NH2:36]>>[CH3:15][O:14][N:13]=[C:11]1[CH2:12][N:8]([C:6]([C:29]2[CH:30]=[CH:31][C:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH3:19])=[CH:27][CH:28]=2)=[O:7])[C@H:9]([C:16]([NH:36][CH3:35])=[O:18])[CH2:10]1
Reactant: CN
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1
Product: CNC(=O)[C@@H]1CC(=NOC)CN1C(=O)c1ccc(-c2ccccc2C)cc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and methylamine (2M in methanol), the title compound was obtained in 96% purity by HPLC. MS(ESI+): m/z=366.