Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[NH2:17][C:18]1[C:32]([Cl:33])=[CH:31][C:21]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=O)=[CH:20][C:19]=1[Cl:34]>COCCOC>[NH2:17][C:18]1[C:19]([Cl:34])=[CH:20][C:21]([C:22]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:31][C:32]=1[Cl:33]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: Nc1c(Cl)cc(C(=O)c2ccc(Cl)cc2)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C=C(c1ccc(Cl)cc1)c1cc(Cl)c(N)c(Cl)c1

Procedure:
A solution of 108 g (0.55 mol) of ethyl diethylphosphonoacetate in 150 ml of dry 1,2-dimethoxyethane was slowly added dropwise, while stirring and cooling with ice to a suspension of 13.2 g (0.55 mol) of sodium hydride (26.4 g of 50% oil suspension) in 50 ml of dry 1,2-dimethoxyethane, whereupon the mixture foamed vigorously. After all the solution had been added the mixture was stirred for another 30 minutes. It was then combined with a suspension of 150 g (0.5 mol) of 4-amino-3,4',5-trichloro-benzophenone in 800 ml of dry 1,2-dimethoxyethane and heated for one hour at reflux temperature, whereby a clear solution was formed. The solution was evaporated to dryness in vacuo, and the residue was distributed between chloroform and water. The organic phase was dried and evaporated to dryness in vacuo. After mixing with 150 ml of ethanol, crystallization set in. The crystals were suction-filtered off and washed with ethanol and petroleum ether.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.OS(O)(=O)=O.[O:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23]3[C:24]4[CH2:38][O:37][C:36](=[O:39])[C:25]=4[CH:26]=[C:27]4[C:35]=3[C:31]3[O:32][CH2:33][O:34][C:30]=3[CH:29]=[CH:28]4)=[CH:22][C:17]=2[O:16][CH2:15]1>C(#N)C>[O:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23]3[C:24]4[CH2:38][O:37][C:36](=[O:39])[C:25]=4[CH:26]=[C:27]4[C:35]=3[C:31]3[O:32][CH2:33][O:34][C:30]=3[CH:29]=[C:28]4[I:1])=[CH:22][C:17]=2[O:16][CH2:15]1
Reactant: O=C1CCC(=O)N1I
Reactant: O=C1OCc2c1cc1ccc3c(c1c2-c1ccc2c(c1)OCO2)OCO3
Agent: O=S(=O)(O)O
Solvent: CC#N
Product: O=C1OCc2c1cc1c(I)cc3c(c1c2-c1ccc2c(c1)OCO2)OCO3
Temperature: 25 °C
Reaction time: 36 h
Yield: 55.4 %

Procedure:
N-iodosuccinimide (13.6 mg, 0.06 mmol) and concentrated H2SO4 (5 μL) was added to a solution of 2 (14 mg, 0.04 mmol) in acetonitrile (1 mL). The mixture was stirred at room temperature for 36 h, concentrated at reduced pressure, and then diluted with ether (30 mL). The same workup and purification procedure as described for the isolation of 37 afforded 39 (10.5 mg, 55%) as a yellow powder. mp 255° C. (decomp.); 1H NMR (CDCl3) δ 8.78 (s, 1H, H4), 7.93 (s, 1H, H6), 6.75-6.90 (m, 3H, H2′+H5′+H6′), 6.08 (AB, 2H, 3′,4′-OCH2O—, Δδ=8.7 Hz, J=1.5 Hz), 5.97 (AB, 2H, 7,8-OCH2O—, Δδ=7.8 Hz, J=1.5 Hz), 5.23 (q, 2H, lactone-CH2—, J=8.7 Hz); MS (EI) m/z 474 [M]+.
Reaction SMILES: [CH2:1]1[CH:3]([C@H:4]([NH2:8])[C:5]([OH:7])=[O:6])[CH2:2]1.O.[F:10][C:11]([F:29])([F:28])[C:12]([O:15][C:16](=O)[O:17]C1C=CC([N+]([O-])=O)=CC=1)([CH3:14])[CH3:13].CCN(C(C)C)C(C)C>CC#N.CO>[CH:3]1([CH:4]([NH:8][C:16]([O:15][C:12]([CH3:14])([CH3:13])[C:11]([F:29])([F:28])[F:10])=[O:17])[C:5]([OH:7])=[O:6])[CH2:2][CH2:1]1
Reactant: CC(C)(OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reactant: N[C@H](C(=O)O)C1CC1
Solvent: CO
Solvent: CC#N
Solvent: O
Product: CC(C)(OC(=O)NC(C(=O)O)C1CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h
Yield: 68.1 %

Procedure:
Commercially available L-cyclopropyl glycine (500.8 mg, 4.35 mmol) was dissolved in CH3CN (30 mL), H2O (4 mL), and MeOH (4 mL). Carbonic acid 4-nitro-phenyl ester 2,2,2-trifluoro-1,1-dimethyl-ethyl ester (1.91 g, 6.52 mmol) was added followed by DIPEA (1.89 mL, 10.9 mmol). The reaction was allowed to stir at room temperature for three days. The reaction was acidified and extracted with EtOAc (3×50 mL). The organic layer was mixed with saturated NaHCO3 solution (100 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (30 mL) and the organic was discarded. The aqueous layer was acidified with HCl (1N) and extracted with EtOAc (3×50 mL). The organic layer was washed with brine (30 mL), dried over Na2SO4, and concentrated to produce cyclopropyl-(2,2,2-trifluoro-1,1-dimethyl-ethoxycarbonylamino)-acetic acid (797.6 mg, 68%). LCMS found 267.7 [M−H]−.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10]([N:12]([CH2:16][CH3:17])[CH2:13][CH2:14]Cl)[CH3:11].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:10]([N:12]([CH2:16][CH2:17][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:13][CH3:14])[CH3:11]
Reactant: CCN(CC)CCCl
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN(CC)CCOc1ccc(C=O)cc1
Yield: 60.3 %

Procedure:
To the solution of 18.4 g (0.15 mol) of 4-hydroxybenzaldehyde in 100 ml acetone, 27.5 g (0.16 mol) of N,N-diethyl-N-(2-chlorethyl)-amine IX and 22.1 g (0.16 mol) potassium carbonate was added at the room temperature under stirring. The mixture was then intensively stirred at the boiling temperature for 12 hours. The mixture was cooled, potassium chloride was separated, washed with acetone. The solvent was distilled off from the solution on the vacuum rotatory evaporator. Afforded 20 g (60.6%) of 4-diethylaminoethoxybenzaldehyde X. Colourless fluid boiling point 120-123° C./0.5 torr, n20D=1.536. Lit. [5] reports boiling point 123-125° C./0.8 torr, n20D=1.530.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[S:9][C:10]3[CH:15]=[CH:14][C:13]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:12][C:11]=3[C:7]=2[C:6]([S:20](Cl)(=[O:22])=[O:21])=[CH:5][CH:4]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1.N1C=CC=CC=1>CC(C)=O.O>[CH3:1][O:2][C:3]1[C:8]2[S:9][C:10]3[CH:15]=[CH:14][C:13]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:12][C:11]=3[C:7]=2[C:6]([S:20](=[O:22])(=[O:21])[NH:32][C:29]2[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)Cl)c2c1sc1ccc(S(=O)(=O)Cl)cc12
Reactant: COc1ccc(N)cc1
Solvent: c1ccncc1
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(NS(=O)(=O)c2ccc(OC)c3sc4ccc(S(=O)(=O)Cl)cc4c23)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-methoxy-dibenzo[b,d]thiophene-1,8-disulfonylchloride (0.2 g, 0.49 mmols) from step 1 in dry acetone (10 ml) was added p-anisidine (0.6 g, 0.49 mmols) and pyridine (0.06 g, 0.73 mmols). The reaction mixture was stirred at room temperature for 18 hrs. Acetone was evaporated and reaction mixture was diluted with water and extracted in ethyl acetate. Ethyl acetate layer on concentration gave crude product which was purified by silica gel column chromatography to get the pure product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:14]O)=[C:9]([CH:11]3[CH2:13][CH2:12]3)[N:10]=2)[N:7]=1.[F:16][C:17]([F:25])=[CH:18][CH:19]1[CH2:23][NH:22][C:21](=[O:24])[CH2:20]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:14][N:22]3[CH2:23][CH:19]([CH:18]=[C:17]([F:25])[F:16])[CH2:20][C:21]3=[O:24])=[C:9]([CH:11]3[CH2:12][CH2:13]3)[N:10]=2)[N:7]=1
Reactant: OCc1c(C2CC2)nc2ccc(Cl)nn12
Reactant: O=C1CC(C=C(F)F)CN1
Solvent: Cc1ccccc1
Product: O=C1CC(C=C(F)F)CN1Cc1c(C2CC2)nc2ccc(Cl)nn12
Yield: 28 %

Procedure:
A solution of (6-chloro-2-cyclopropylimidazo[1,2-b]pyridazin-3-yl)methanol x115 (889 mg, 3.97 mmol), 4-(2,2-difluorovinyl)pyrrolidin-2-one (643 mg, 4.37 mmol, 1.1 eq) and paratoluenesulfonic acid (76 mg, 0.40 mmol, 0.1 eq) in toluene (20 ml) is heated under reflux for 16 h. After cooling, the solvent is removed under reduced pressure, the crude product is dissolved in dichloromethane (100 ml). The organic layer is washed by water (150 ml). The aqueous layer is extracted by dichloromethane (100 ml). The cumulated organic layers are dried over MgSO4, filtered and evaporated under reduced pressure. The residue is purified by preparative chromatography over silicagel (benzine/AcOEt:60/40) to afford 1-[(6-chloro-2-cyclopropylimidazo[1,2-b]pyridazin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one 62 after recristallization in diisopropylether.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C:8]3([C:16]4[N:17]=[CH:18][NH:19][CH:20]=4)[CH:13]([C:14]=2[CH:15]=1)[CH2:12][CH2:11][CH2:10][CH2:9]3.Br.N>O>[NH:19]1[CH:20]=[C:16]([C:8]23[CH2:7][C:6]4[CH:5]=[CH:4][C:3]([OH:2])=[CH:15][C:14]=4[CH:13]2[CH2:12][CH2:11][CH2:10][CH2:9]3)[N:17]=[CH:18]1
Reactant: COc1ccc2c(c1)C1CCCCC1(c1c[nH]cn1)C2
Agent: Br
Agent: N
Solvent: O
Product: Oc1ccc2c(c1)C1CCCCC1(c1c[nH]cn1)C2

Procedure:
4-(3-Methoxy-4b,5,6,7,8,9-hexahydrofluoren-8a-yl)-1H-imidazole (0.042 g) was mixed with 48% HBr (2 ml) and refluxed for 2 hours. After cooling to the ambient temperature, water (2 ml) was added and the pH was adjusted to 10 with 25% NH3-solution. The precipitated crude product was filtered and washed with water (10 ml). Recrystallisation from methylene chloride/methanol (95:5) gave the pure product. The yield was 0.030 g.
Reaction SMILES: [Cl:1][C:2](Cl)=[CH:3][C:4]1[O:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1.CC(C)([O-])C.[K+]>C(O)(C)(C)C>[Cl:1][C:2]#[C:3][C:4]1[O:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(C=C(Cl)Cl)o1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=[N+]([O-])c1ccc(C#CCl)o1
Reaction time: 1 h

Procedure:
To a stirred solution of 20.8 g of 1 in 100 ml of dry tert-butanol was added dropwise at 5°-10° over a 30-minute period a solution of 11.2 g of potassium tert-butoxide in 100 ml of tert-butanol. The mixture then was stirred at 5°-10° for 1 hour longer. Concentration of the mixture under reduced pressure gave a dark residue which was extracted with ether and water. The ether phase was separated, dried over magnesium sulfate and Claisen distilled to give 4 as a liquid, b.p.: 73°-76° at 0.2 torr which solidified on standing, the solid having a melting point of 38°-41°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[F:31][C:32]1[CH:33]=[C:34]([NH2:38])[CH:35]=[CH:36][CH:37]=1>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:38][C:34]1[CH:35]=[CH:36][CH:37]=[C:32]([F:31])[CH:33]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccccc1
Reactant: Nc1cccc(F)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Nc1cccc(F)c1)c1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Solid 5-bromo-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 5, method C; 200 mg, 0.65 mmol) was added to a stirred suspension of CDI (106 mg, 0.65 mmol) in THF (6 ml) under nitrogen at 20° C. The reaction mixture was stirred at room temperature for 10 min and 3-fluorobenzenamine (72.4 mg, 0.65 mmol) was added dropwise. After refluxing for 14 h, the reaction mixture was concentrated to obtain crude product. The crude product was purified by silica gel chromatography eluting with hexane:ethyl acetate (10:1). The product was then purified by preparative HPLC (A: 0.05% trifluoroacetic acid/water B: dichloromethane) to yield the title compound. 73 mg.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([C:12]2[NH:16][N:15]=[CH:14][CH:13]=2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])([O-:3])=[O:2].O[CH2:18][CH2:19][NH:20]C(=O)OC(C)(C)C>>[NH2:20][CH2:19][CH2:18][N:15]1[CH:14]=[CH:13][C:12]([C:10]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N+:1]([O-:3])=[O:2])[CH:11]=2)=[N:16]1
Reactant: N#Cc1ccc(-c2ccn[nH]2)cc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)NCCO
Product: N#Cc1ccc(-c2ccn(CCN)n2)cc1[N+](=O)[O-]
Yield: 63.6 %

Procedure:
The title compound was prepared from 2-nitro-4-(1H-pyrazol-5-yl)benzonitrile (0.828 g, 3.87 mmol) and tert-butyl 2-hydroxyethylcarbamate (0.748 g, 4.64 mmol) using the method of Example 34(c) affording 0.633 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 3.21-3.29 (m, 2H), 4.02-4.04 (m, 2H), 7.02 (d, 1H), 7.88 (d, 1H), 8.13 (d, 1H), 8.29 (m, 1H), 8.50 (d, 1H).
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:10]=[C:11]([C:12]#[N:13])[C:6]2=[N:5][CH:4]=1)#[CH:2].[NH2:24][C:25]1[CH:30]=[CH:29][C:28](I)=[CH:27][N:26]=1>>[NH2:24][C:25]1[N:26]=[CH:27][C:28]([C:2]#[C:1][C:3]2[N:7]3[CH:8]=[C:9]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][CH:15]=4)[CH:10]=[C:11]([C:12]#[N:13])[C:6]3=[N:5][CH:4]=2)=[CH:29][CH:30]=1
Reactant: Nc1ccc(I)cn1
Reactant: C#Cc1cnc2c(C#N)cc(-c3ccc(C(F)(F)F)cc3)cn12
Product: N#Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(C#Cc3ccc(N)nc3)cnc12

Procedure:
The title compound was prepared from 3-ethynyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine-8-carbonitrile (example C.23) (150 mg, 0.5 mmol) and commercially available 2-amino-5-iodopyridine (106 mg, 0.5 mmol) according to general procedure II. Obtained as a light brown solid (15 mg, 7%). MS (ISP) 404.3 [(M+H)+].
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:20]I.[H-].[Na+]>CN(C=O)C>[CH3:20][O:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CI
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2ccccc2)cc1OC
Temperature: 0 °C
Yield: 90 %

Procedure:
To a solution of methyl 2-hydroxy-4-benzyloxybenzoate (50 g, 194 mmol) in dry DMF (500 mL) was added methyl iodide (30 mL, 2.5 eq) and the solution was cooled to 0° C. under argon. The solution was stirred at 0° C. and sodium hydride (60% dispersion in mineral oil, 12 g, 1.5 eq) was added in several portions over 15 minutes. The reaction was allowed to warm to ambient temperature with stirring over 18 hours. The reacton was quenched with 12 mL of acetic acid and the solvent was removed under reduced pressure. The residue was partitioned between methylene chloride (700 mL) and saturated sodium bicarbonate (700 mL) and the organic layer was washed with water (2×700 mL), brine, dried over MgSO4, and filtered. The solvent was removed under reduced pressure to give methyl 2-methoxy-4-benzyloxybenzoate as a crystalline solid in 90% yield.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>C(OCC)(=O)C>[O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:20])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C1CC2(CCN1)OCCO2
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Oc1ccccc1)N1CCC2(CC1)OCCO2
Temperature: 25 °C
Yield: 95.1 %

Procedure:
To a stirred solution of 1,4-dioxa-8-azaspiro[4.5]decane (2.00 g, 13.9 mmol) and triethylamine (2.90 mL, 20.9 mmol) in ethyl acetate (50 mL) at 0° C. was added phenyl chloroformate (2.10 mL, 13.9 mmol). The mixture was allowed to warm to room temperature overnight. Then, the mixture was filtered to remove triethylamine hydrochloride salts. The filtrate was concentrated, and the obtained residue was chromatographed (silica gel, hexanes to 50:50 hexanes/ethyl acetate) to give the title compound (3.48 g, 95%) as a white solid:
Reaction SMILES: C(NC1C=C(OC)C=CC=1C1CCC2C(=CC=C(OC)C=2)C1)C.Cl.C(Cl)(=O)C1C=CN=CC=1.[CH2:34]([N:36]([C:45]1[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[CH:47][C:46]=1[CH:53]1[CH2:62][CH2:61][C:60]2[C:55](=[CH:56][CH:57]=[C:58]([O:63][CH3:64])[CH:59]=2)[CH2:54]1)[C:37]([C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1)=O)[CH3:35]>>[CH2:34]([N:36]([C:45]1[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[CH:47][C:46]=1[CH:53]1[CH2:62][CH2:61][C:60]2[C:55](=[CH:56][CH:57]=[C:58]([O:63][CH3:64])[CH:59]=2)[CH2:54]1)[CH2:37][C:39]1[CH:40]=[CH:41][N:42]=[CH:43][CH:44]=1)[CH3:35]
Reactant: CCN(C(=O)c1ccncc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Agent: CCNc1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Agent: Cl
Agent: O=C(Cl)c1ccncc1
Product: CCN(Cc1ccncc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Yield: 27.3 %

Procedure:
Synthesized from ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine and isonicotinoyl chloride hydrochloride according to an analogous synthetic method to Preparation Example 86, pyridine-4-carboxylic acid ethyl [5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amide (163 mg) was used according to an analogous synthetic method to Example 337 described below to provide ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]pyridin-4-ylmethylamine (43 mg). The total amount of this compound was used according to an analogous synthetic method to Example 111 described below to provide the title compound (42 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[F:19])[C:15](=[O:20])[NH:14][CH:13]=[CH:12]2)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[NH2:22][C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][N:24]=1.OC1C=CC=C2C=1N=CC=C2.C(=O)([O-])[O-].[K+].[K+]>[Cu]I.CS(C)=O>[C:1]([O:5][C:6](=[O:21])[N:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[F:19])[C:15](=[O:20])[N:14]([C:26]1[CH:25]=[N:24][C:23]([NH2:22])=[CH:28][CH:27]=1)[CH:13]=[CH:12]2)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)c1cc2cc[nH]c(=O)c2cc1F
Reactant: Nc1ccc(I)cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: CN(C(=O)OC(C)(C)C)c1cc2ccn(-c3ccc(N)nc3)c(=O)c2cc1F
Temperature: 115 °C
Reaction time: 50 h
Yield: 49.8 %

Procedure:
In a dry flask was combined (7-Fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-methyl-carbamic acid tert-butyl ester (Example 45, compound 10, Scheme B) (102 mg, 0.35 mmol), 2-amino-5-iodopyridine (84 mg, 0.38 mmol, 1.1 eq), copper (I) iodide (7 mg, 0.037 mmol, 0.11 eq), 8-hydroxyquinoline (6 mg, 0.041 mmol, 0.12 eq) and powdered potassium carbonate (58 mg, 0.42 mmol, 1.2 eq). Under Ar atmosphere, dry dimethylsulfoxide (DMSO, 1.5 mL) was added, and the mixture was stirred at 115° C. for 50 hr. The reaction was cooled, concentrated and purified by chromatography (silica, 2-15% isopropyl alcohol/dichloromethane) to give 67 mg (50%) of [2-(6-Amino-pyridin-3-yl)-7-fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester as a grey solid. ES-MS (M+H)+=385. 1H-NMR (DMSO-d) δ (ppm): 1.33 (s, 9), 3.19 (s, 3), 6.25 (br m, NH2), 6.53 (m, 1), 6.64-6.65 (d, 1), 7.37-7.39 (d, 1), 7.44-7.46 (d, 1), 7.77-7.79 (d, 1), 7.87-7.90 (d, 1), 7.95 (m, 1H).
Reaction SMILES: [C:1]12([OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3]([OH:11])([CH2:4]3)[CH2:2]1)[CH2:8]2.N1C=CC=CC=1.[CH3:19][O:20][C:21](Cl)=[O:22]>CN(C=O)C>[CH3:19][O:20][C:21]([O:12][C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3]([OH:11])([CH2:4]3)[CH2:2]1)[CH2:8]2)=[O:22]
Reactant: COC(=O)Cl
Reactant: OC12CC3CC(C1)CC(O)(C3)C2
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)OC12CC3CC(CC(O)(C3)C1)C2
Temperature: 25 °C
Yield: 85 %

Procedure:
In an atmosphere of nitrogen, 10 mmole of 1,3-adamantanediol and 12 mmole of pyridine was dissolved in 10 ml of DMF. To the mixture, 11 mmole of methoxycarbonyl chloride was added dropwise with stirring at room temperature. Cooling of the resultant mixture with ice was started at about the time exothermic reaction began. When the exothermic reaction is completed, the mixture was heated to 60° C. and then stirred for one hour. As a result, the conversion of 1,3-adamantanediol was 99% and 1-methoxycarbonyloxy-3-adamantanol (yield 85%) was formed.
Reaction SMILES: [CH3:1][C:2]1([C:5](=O)[CH2:6][C:7]#[N:8])[CH2:4][CH2:3]1.Cl.[CH3:11][NH:12][NH2:13]>CCO.O1CCOCC1>[CH3:11][N:12]1[C:5]([C:2]2([CH3:1])[CH2:4][CH2:3]2)=[CH:6][C:7]([NH2:8])=[N:13]1
Reactant: CC1(C(=O)CC#N)CC1
Reactant: CNN
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: Cn1nc(N)cc1C1(C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(1-methyl-cyclopropyl)-3-oxo-propionitrile (1.0 g, 8.1 mmol) in EtOH (10 mL) is added 4N HCl in Dioxane (10 mL). The mixture is stirred at room temperature for 16 hour. Concentrated under reduced pressure, the residue is dissolved in MeOH (40 mL) and treated with methylhydrazine (0.56 g, 12.2 mmol). The mixture is heated at 80° C. for 16 h. The solution is then concentrated in vacuo and the residue is purified by HPLC give product. MS (ESI) m/z 152.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:11]=2[O:18][CH3:19])=[O:9])=[CH:6][N:5]=[C:4](S(CC)(=O)=O)[N:3]=1.[CH3:25][S:26]([N:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1)(=[O:28])=[O:27]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:11]=2[O:18][CH3:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:35][CH:32]2[CH2:33][CH2:34][N:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:30][CH2:31]2)[N:3]=1
Reactant: CCS(=O)(=O)c1ncc(C(=O)c2cc(F)c(F)cc2OC)c(N)n1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Product: COc1cc(F)c(F)cc1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N

Procedure:
The same procedure as described in Example 90 was used, starting with (4-amino-2-ethanesulfonyl-pyrimidin-5-yl)-(4,5-difluoro-2-methoxy-phenyl)-methanone, Example 99, and 1-methanesulfonyl-piperidin-4-ylamine (compound with trifluoro-acetic acid), Example 162, to give [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(4,5-difluoro-2-methoxy-phenyl)-methanone as a white solid. MS (M+H)+: 442.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[C:12]2=[C:13]3[CH:19]=[CH:18][NH:17][C:14]3=[N:15][CH:16]=[C:11]2[NH:10][C:9]1=[O:20].[CH3:21][N+:22]([CH3:24])=[CH2:23].[I-]>CN(C)C=O.CCOC(C)=O>[CH3:21][N:22]([CH2:24][C:19]1[C:13]2[C:14](=[N:15][CH:16]=[C:11]3[NH:10][C:9](=[O:20])[N:8]([C@H:3]4[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]4[CH3:1])[C:12]3=2)[NH:17][CH:18]=1)[CH3:23]
Reactant: C=[N+](C)C
Reactant: C[C@@H]1CCCC[C@@H]1n1c(=O)[nH]c2cnc3[nH]ccc3c21
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H]1CCCC[C@@H]1n1c(=O)[nH]c2cnc3[nH]cc(CN(C)C)c3c21
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 53.3 %

Procedure:
To a solution of 1-[(1S,2R)-2-methylcyclohexyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (30 mg, 0.111 mmol) in N,N-dimethylformamide (0.6 mL) was added N,N-dimethylmethyleneiminium iodide (26.7 mg), and stirred at 85° C. for 1.5 hours. To the mixture was added Eschenmoser's salt (12.3 mg), and stirred at 80° C. for 30 minutes. The mixture was diluted with EtOAc, washed with saturated aqueous sodium hydrogencarbonate, 10% NaCl solution (×5), and brine, dried over MgSO4, evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform:methanol=15:1 to 10:1) to give 8-[(dimethylamino)methyl]-1-[(1S,2R)-2-methylcyclohexyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (11.6 mg) as a pale yellow amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]#[N:21])[CH:14]=2)[NH:9]1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:23]=1>N1C=CC=CC=1.O>[C:20]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][S:28]([C:24]1[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=1)(=[O:30])=[O:29])[CH2:17][C:16]2([CH3:18])[CH3:19])#[N:21]
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CC1(C)CC(c2ccccc2N)Nc2ccc(C#N)cc21
Solvent: c1ccncc1
Solvent: O
Product: CC1(C)CC(c2ccccc2NS(=O)(=O)c2cccnc2)Nc2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(2-aminophenyl)-4,4-dimethyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile (500 mg, 1.8 mmol) in pyridine (3 mL) was added pyridine-3-sulfonyl chloride (385 mg) at ice-bath under nitrogen. After addition, the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Sodium sulfate, and then concentrated. The residue was purified by HPLC to give pyridine-3-sulfonic acid [2-(6-cyano-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-amide LC/MS m/e obsd. (ESI+) [(M+H)+] 419.3.