Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][CH2:9][CH2:10][CH2:11][NH2:12])=[CH:3][CH:2]=1.[N+:13]([CH:16]=[C:17](SC)SC)([O-:15])=[O:14]>CO>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH2:9][CH2:10][CH2:11][NH:12][C:17]2=[CH:16][N+:13]([O-:15])=[O:14])=[CH:3][CH:2]=1
Reactant: NCCCNCc1ccncc1
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CO
Product: O=[N+]([O-])C=C1NCCCN1Cc1ccncc1
Temperature: 25 °C
Yield: 68.4 %

Procedure:
A mixture of N-(4-pyridylmethyl)trimethylenediamine (16.5 g), 1-nitro-2,2-bis(methylthio)ethylene (16.5 g) and methanol (100 ml) was refluxed for 2 hours with stirring. The generated gas was collected by an alkali trap. The reaction mixture was cooled to room temperature, and the resulting crystals were filtered to give 1-(4-pyridylmethyl)-2-(nitromethylene)tetrahydropyrimidine (16 g) of the following formula as pale yellow crystals. Concentrating the filtrate further gave 3 g of this compound.mp. 226°-228° C. ##STR14##
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[N:5][N:6]=1.[CH2:7]([C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].O>N1C=CC=CC=1>[CH2:7]([C:15]1[CH:16]=[CH:17][C:18]([S:21]([NH:1][C:2]2[S:3][CH:4]=[N:5][N:6]=2)(=[O:23])=[O:22])=[CH:19][CH:20]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nncs1
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCc1ccc(S(=O)(=O)Nc2nncs2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.8 %

Procedure:
To a stirred solution of 2-amino-1,3,4-thiadiazole (2.0 g, 19.7 mmol) in pyridine (30 mL) under argon at −20° C. was added p-octylbenzenesulfonyl chloride (6.06 g, 21 mmol) over 10 min. The reaction mixture was stirred at room temperature for 16 hours. Water (300 mL) was added to quench the reaction. The mixture was extracted with CH2Cl2 and the organic extracts washed with 2N HCl (2×150 mL), brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluted with methanol:DCM 1:33 to give the product (3.83 g, 10.8 mmol, 55% yield) as a solid, mp 123-124° C.; 1H NMR (300 MHz, CDCl3) δ 0.87 (t, 3H, J=7 Hz), 1.36 (m, 10H), 1.59 (m, 2H), 2.63 (t, 2H, J=7 Hz), 7.27 (d, 2H, J=8 Hz), 7.82 (d, 2H, J=8 Hz), 8.23 (s, 1H); 13C NMR (75 MHz, CDCl3) 14.1, 22.6, 29.2, 29.3, 29.4, 31.1, 31.8, 35.9, 126.5, 129.0, 138.1, 142.6, 148.7, 167.3; MS (Q-TOF) Calcd for C16H24N3O2S2 354.1310, found 354.1211 (M+H)+; Calcd for C16H23N3N3O2S2 376.1129, found 376.1154 (M+Na)+.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]#[N:13])(=O)OCC)C.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([C:31](=O)[CH3:32])[CH:29]=3)[C:24]([CH3:35])([CH3:34])[CH2:23][CH:22]=2)=[CH:17][CH:16]=1>C1COCC1.CCOCC>[CH3:34][C:24]1([CH3:35])[CH2:23][CH:22]=[C:21]([C:18]2[CH:17]=[CH:16][C:15]([CH3:14])=[CH:20][CH:19]=2)[C:30]2[CH:29]=[C:28](/[C:31](/[CH3:32])=[CH:11]/[C:12]#[N:13])[CH:27]=[CH:26][C:25]1=2
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CC(=O)c1ccc2c(c1)C(c1ccc(C)cc1)=CCC2(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C/C(=C\C#N)c1ccc2c(c1)C(c1ccc(C)cc1)=CCC2(C)C
Reaction time: 0.67 h

Procedure:
To a slurry of NaH (48.0 mg, 2.00 mmol) in THF (6 ml), was added diethylcyanomethylphosphonate (450.0 mg, 2.50 mmol). After 40 mins, a solution of 3,4-dihydro-1-(4-methylphenyl)-4,4-dimethyl-7-acetylnaphthalene (Compound V) 95.0 mg, (0.33 mmol) in THF (4 ml) was added. The mixture was stirred for 16 hours, diluted with ether (100 ml), and washed with water, and saturated aqueous NaCl before being dried over MgSO4. Removal of the solvents under reduced pressure, and column chromatography (3% EtOAc/hexanes) afforded the title compound as a solid. 1H NMR (CDCl3): δ 7.39 (1H, d, J=1H), 7.32 (1H, dd, J=2.0, 8.1 Hz), 7.20-7.25 (4H, brs), 7.15 (1H, d, J=2.0 Hz), 6.03 (1H, t, J=6.0 Hz), 5.44 (1H, s), 2.42 (3H, s), 2.36 (2H, d, J=6.0 Hz), 2.35 (3H, s), 1.35 (6H, s).
Reaction SMILES: [N:1]1([C:6]2[CH:16]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:9]([OH:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][CH:20]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:31][CH3:32])[N:22]=[CH:21][CH:20]=[C:19]2[O:17][C:9]1[CH:8]=[CH:7][C:6]([N:1]2[CH:5]=[CH:4][CH:3]=[CH:2]2)=[CH:16][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1cc(-n2cccc2)ccc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)c1cc(-n2cccc2)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 22.1 %

Procedure:
Ethyl 5-(pyrrol-1-yl)salicylate (170 mg), 4-chloro-6,7-dimethoxyquinoline (87 mg), and 4-dimethylaminopyridine (143 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. overnight. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (36 mg, yield 15%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([NH:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:20].Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([N:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])[C:25]([Cl:41])=[CH:24][N:23]=1>>[Cl:41][C:25]1[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([N:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])=[N:27][C:22]([NH:20][C:4]2[CH:5]=[CH:6][C:7]3[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]([F:18])([F:17])[F:19])[CH2:10][CH2:9][C:8]=3[C:3]=2[O:2][CH3:1])=[N:23][CH:24]=1
Reactant: COc1c(N)ccc2c1CCC(NCC(F)(F)F)CC2
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: COc1c(Nc2ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n2)ccc2c1CCC(NCC(F)(F)F)CC2
Yield: 34.9 %

Procedure:
In an analogous procedure to Example 651, part c, 1-Methoxy-N*7*-(2,2,2-trifluoro-ethyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine was combined with 2-(2,5-dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide to yield 2-{5-Chloro-2-[1-methoxy-7-(2,2,2-trifluoro-ethylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino]-pyrimidin-4-ylamino}-N,N-dimethyl-benzenesulfonamide (36.29, 34.9% yield) as a beige foam. 9.40 (s, 1H), 8.56 (d, J=8.4 Hz, 1H), 8.14 (s, 1H), 7.99 (d, J=8.4 Hz, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.61 (m, 1H), 7.47 (s, 1H), 6.82 (d, J=8.2 Hz, 1H), 3.73 (s, 3H), 3.25 (m, 3H), 2.87 (m, 2H), 2.75 (s, 6H), 2.66 (m, 1H), 2.50 (m, 1H), 2.10 (m, 2H), 1.54 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][C:5]=1[Cl:11])=[O:3].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19]>>[Cl:11][C:5]1[CH:6]=[C:7]([O:19][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[Cl:12])[CH:8]=[CH:9][C:4]=1[C:2](=[O:3])[CH3:1]
Reactant: Oc1ccccc1Cl
Reactant: CC(=O)c1ccc(F)cc1Cl
Product: CC(=O)c1ccc(Oc2ccccc2Cl)cc1Cl

Procedure:
Obtained analogously to Example 74a) starting from 2-chloro-4-fluoracetophenone and 2-chlorophenol.
Reaction SMILES: [CH:1]1([NH:10][C@H:11]([C:13]([OH:15])=[O:14])[CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:16]([S:19][CH2:20][CH:21]([CH3:25])[C:22](Cl)=[O:23])(=[O:18])[CH3:17].O>CC(N(C)C)=O>[C:16]([S:19][CH2:20][CH:21]([CH3:25])[C:22]([N:10]([CH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)[C@H:11]([C:13]([OH:15])=[O:14])[CH3:12])=[O:23])(=[O:18])[CH3:17]
Reactant: CC(=O)SCC(C)C(=O)Cl
Reactant: C[C@H](NC1CCc2ccccc21)C(=O)O
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(=O)SCC(C)C(=O)N(C1CCc2ccccc21)[C@@H](C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
N-(1-Indanyl)alanine (3.0 g) is suspended in 30 ml of dimethylacetamide, then 3.3 g of 3-acetylthio-2-methylpropionyl chloride is added dropwise with stirring at room temperature, and thereafter stirring is continued at room temperature for 2 hours. The reaction mixture is poured into 200 ml of water, and extracted with 200 ml of ethyl acetate. The extract is washed with 10 ml of 10% hydrochloric acid and with water, and dried. The ethyl acetate is distilled off under reduced pressure, and the residue is crystallized from an ethyl ether-petroleum ether mixture, to give 2.3 g of N-(3-acetylthio-2-methylpropionyl)-N-(1-indanyl)alanine, colorless needles having a melting point of 133°-137° C.
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:5])[CH3:4].Br[CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28].O>CN(C)C=O>[C:3]([N:6]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:5])[CH3:4]
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: CC(=O)Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N(CCCCN1C(=O)c2ccccc2C1=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 52.9 %

Procedure:
Oily sodium hydride (60%, 2.45 g) was added to a solution of acetanilide (7.0 g) in N,N-diemthylformamide (50 ml), and the mixture was stirred at 0° C. for 15 minutes. Then a solution of N-(4-bromobutyl)phthalimide (15.3 g) in N,N-dimethylformamide (80 ml) was added dropwise. The mixture was stirred at room temperature for 4 hours, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), and then the solvent was distilled off. The residue was subjected to column chromatography on silica gel and eluted with ethyl acetate-chloroform (1:9, v/v) to obtain N-[4-(N-acetyl-N-phenylamino)butyl]phthalimide (9.21 g, 52.9%), which was then recrystallized from isopropyl ether. Colorless prism, mp: 83°-84° C.
Reaction SMILES: [Na].Cl[C:3]1[N:8]=[C:7]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:6]=[C:5]([NH:15][S:16]([CH:19]=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:18])=[O:17])[C:4]=1[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35].Cl>C(O)CO>[OH:27][CH2:28][CH2:29][O:34][C:3]1[N:8]=[C:7]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:6]=[C:5]([NH:15][S:16]([CH:19]=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:18])=[O:17])[C:4]=1[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1NS(=O)(=O)C=Cc1ccccc1
Agent: Cl
Agent: [Na]
Solvent: OCCO
Product: COc1ccccc1Oc1c(NS(=O)(=O)C=Cc2ccccc2)nc(-c2ncccn2)nc1OCCO
Yield: 192.1 %

Procedure:
Sodium (230 mg) was dissolved in 5.6 ml of ethylene glycol and 495 mg of N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide was added thereto under ice cooling with stirring. The reaction mixture was stirred at 80° C. for three hours and poured into a mixture of 1N hydrochloric acid and ice. The crystals separated out therefrom were collected by filtration and the resulting crystals were purified by a silica gel column chromatography (chloroform-methanol=20:1) to give 500 mg of N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][NH:8][S:9]([CH2:12][CH:13]1[CH2:18][CH2:17][C:16]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])[CH2:15][CH2:14]1)(=[O:11])=[O:10])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([S:27]([C:16]2([C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[F:26])[CH2:15][CH2:14][CH:13]([CH2:12][S:9]([NH:8][CH2:7][C:6]([OH:37])=[O:5])(=[O:10])=[O:11])[CH2:18][CH2:17]2)(=[O:29])=[O:28])=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)CNS(=O)(=O)CC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CNS(=O)(=O)CC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Reaction time: 3 h

Procedure:
To a stirred solution of [4-(4-chloro-benzenesulfonyl)-4-(2,5-difluoro-phenyl) -cyclohexylmethanesulfonylamino]-acetic acid tert-butyl ester (Example 20) (80 mg) in dichloromethane (10 mL) was added trifluoroacetic acid (2 mL) and the reaction stirred for 3 hours then evaporated. Purification by column chromatography on silica, eluting with ethyl acetate:dichloromethane:acetic acid (75:25:1), afforded the desired product. MS (ES+) 522 ([MH]+).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:6]=1[C:7]([OH:9])=O.[CH3:20][CH:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22]1.C(N(CCCC)CCCC)CCC.[I-].ClC1C=CC=C[N+]=1C>ClCCl>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:6]=1[C:7]([N:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:29][CH2:30][CH:21]1[CH3:20])=[O:9]
Reactant: O=C(O)c1cc(F)ccc1Oc1cc(Cl)ccc1Cl
Reactant: CC1CCc2ccccc2N1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCCCN(CCCC)CCCC
Solvent: ClCCl
Product: CC1CCc2ccccc2N1C(=O)c1cc(F)ccc1Oc1cc(Cl)ccc1Cl
Temperature: 40 °C
Yield: 15.1 %

Procedure:
To a solution of 2-(2,5-dichloro-phenoxy)-5-fluoro-benzoic acid (36.1 mg, 0.12 mmol, 1.0 equiv; Example 113, Step 1) in dichloromethane (1 mL) was added 2-methyl-1,2,3,4-tetrahydro-quinoline (21.2 mg, 0.14 mmol, 1.2 equiv; [CAS RN 1780-19-4]), tri-n-butylamine (111.2 mg, 143 μL, 0.60 mmol, 5.0 equiv; [CAS RN 102-82-9]) and 2-chloro-1-methylpyridinium iodide (36.8 mg, 0.14 mmol, 1.2 equiv; [CAS RN 14338-32-0]). The reaction mixture was heated to 40° C. over night. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μM, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 7.8 mg (15%) of the title compound. MS (ISP): 430.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[CH:8]=[C:9]3[C:14](=[C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=24)[N:13]=[CH:12][N:11]([C@H:21]2[CH2:26][CH2:25][O:24][CH2:23][C@@H:22]2[OH:27])[C:10]3=[O:28])=[CH:4][CH:3]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[OH:27][C@@H:22]1[C@@H:21]([N:11]2[C:10](=[O:28])[C:9]3[C:14](=[C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]4=[C:7]([CH2:6][C:5]4[CH:4]=[CH:3][C:2]([N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[CH:30][CH:29]=4)[CH:8]=3)[N:13]=[CH:12]2)[CH2:26][CH2:25][O:24][CH2:23]1
Reactant: C1COCCN1
Reactant: O=c1c2cc(Cc3ccc(Cl)cc3)c3ccccc3c2ncn1[C@H]1CCOC[C@@H]1O
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2cc(Cc3ccc(N4CCOCC4)cc3)c3ccccc3c2ncn1[C@H]1CCOC[C@@H]1O
Temperature: 65 °C

Procedure:
To a solution of 6-(4-chlorobenzyl)-3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]benzo[h]quinazolin-4(3H)-one (0.100 g, 0.238 mmol) in 2 mL of DMF under an atmosphere of nitrogen was added morpholine (0.083 g, 0.95 mmol), bis(tri-tert-butylphosphine)palladium(0) (0.012 g, 0.024 mmol), cesium carbonate (0.232 g, 0.713 mmol), and 0.2 mL of water. The mixture was warmed to 65° C. for 5 min, flushed with nitrogen, and irradiated in a microwave reactor at 130° C. for 25 min. The reaction was cooled to rt and diluted with water and dichloromethane. The aqueous layer was reextracted with dichloromethane and the combined organic fractions were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-4% methanol in dichloromethane to provide the title compound that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 471.9 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 9.01 (s, 1H), 8.30 (s, 1H), 8.01-7.98 (m, 2H), 7.65-7.59 (m, 2H), 7.07 (d, J=8.7 Hz, 2H), 7.77 (d, J=8.7 Hz, 2H), 4.89-4.82 (m, 1H), 4.35 (s, 2H), 4.22-4.18 (m, 1H), 4.13-4.08 (m, 2H), 3.79 (t, J=4.8 Hz, 4H), 3.59-3.52 (m, 1H), 3.34-3.28 (m, 1H), 3.06 (t, J=4.8 Hz, 4H), 2.66 (br 5, 1H), 2.32-2.22 (m, 1H), 2.03-1.99 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:11]([OH:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[N:3]=1.Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][CH:15]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH3:27])[N:17]=[CH:16][CH:15]=[C:14]2[O:12][C:11]1[C:2]([CH3:1])=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][N:7]=[CH:6][CH:5]=2
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1nc2ccncc2cc1O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc4cnccc4nc3C)c2cc1OC
Temperature: 140 °C
Reaction time: 3 h
Yield: 53 %

Procedure:
2-Methyl-[1,6]naphthyridin-3-ol (20 mg), 4-chloro-6,7-dimethoxyquinoline (84 mg), and 4-dimethylaminopyridine (46 mg) were suspended in o-dichlorobenzene (2 ml), and the suspension was stirred at 140° C. for 3 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (23 mg, yield 55%).
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].O.[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[C:22]3[N:23]([CH2:35][C@H:36]4[CH2:41][CH2:40][C@H:39]([CH3:42])[CH2:38][CH2:37]4)[C:24]([N:26]4[CH2:30][CH2:29][CH2:28][C@H:27]4[C:31]([F:34])([F:33])[F:32])=[N:25][C:21]=3[CH:20]=[C:19]([C:43]#[N:44])[N:18]=2)[CH:14]=[N:15][CH:16]=1>C(O)C>[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[C:22]3[N:23]([CH2:35][C@H:36]4[CH2:37][CH2:38][C@H:39]([CH3:42])[CH2:40][CH2:41]4)[C:24]([N:26]4[CH2:30][CH2:29][CH2:28][C@H:27]4[C:31]([F:33])([F:32])[F:34])=[N:25][C:21]=3[CH:20]=[C:19]([C:43](=[N:2][OH:3])[NH2:44])[N:18]=2)[CH:14]=[N:15][CH:16]=1
Reactant: NO
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCC[C@H]3C(F)(F)F)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C[C@H]1CC[C@H](Cn2c(N3CCC[C@H]3C(F)(F)F)nc3cc(C(N)=NO)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
Hydroxylamine hydrochloride (44.5 mg, 0.64 mmol), sodium bicarbonate (81 mg, 0.96 mmol), and water (0.64 mL) were combined in a vial and stirred for 15 minutes. This solution was added to a vial containing 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(25)-2-(trifluoromethyl)pyrrolidin-1-yl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (161 mg, 0.32 mmol) dissolved in ethanol (1.5 mL). The mixture was sealed and heated at 100° C. for 1 hour. The reaction was cooled to room temperature, quenched with water, and extracted with ethyl acetate (2×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to afford 4-(5-chloropyridin-3-yl)-N′-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide. MS ESI calc'd. for C25H29ClF3N7O [M+H]+ 536. found 536.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:18]([CH3:19])[C:6]2=[N:7][C:8]([S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:9][CH:10]=[C:5]2[N:4]=1.O[C:21]1[CH:53]=[CH:52][C:24]([CH2:25][CH:26]2[S:30][C:29](=[O:31])[N:28]([C:32]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]2=[O:51])=[CH:23][CH:22]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH3:19][N:18]1[C:6]2=[N:7][C:8]([S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1[CH2:2][O:1][C:21]1[CH:53]=[CH:52][C:24]([CH2:25][CH:26]2[S:30][C:29](=[O:31])[N:28]([C:32]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]2=[O:51])=[CH:23][CH:22]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1c(CO)nc2ccc(Sc3ccccc3)nc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2ccc(Sc3ccccc3)nc21

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 0.70.g of 2-hydroxymethyl-3-methyl-5-phenylthio-3H-imidazo[4,5-b]pyridine (prepared as described in Preparation 90), 1.20 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 0.64 ml of tributylphosphine, 0.65 g of 1,1'-(azodicarbonyl)dipiperidine and 25 ml of toluene were used, and that the product was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.61 g of the title compound, melting at 90°-95° C. (softening).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]2[CH2:9][CH2:10][CH2:11][C:4]=2[N:3]=1.[CH2:12]([NH:19][CH2:20][CH3:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C>C(O)C>[CH2:12]([N:19]([C:6]1[C:5]2[CH2:9][CH2:10][CH2:11][C:4]=2[N:3]=[C:2]([Cl:1])[N:7]=1)[CH2:20][CH3:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Clc1nc(Cl)c2c(n1)CCC2
Reactant: CCNCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCN(Cc1ccccc1)c1nc(Cl)nc2c1CCC2
Temperature: 27.5 °C
Yield: 99.3 %

Procedure:
A mixture of 2,4-dichloro-6,7-dihydro-5H-cyclopentapyrimidine (0.4 g, 2.1 mmol), N-benzyl-ethylamine (0.35 mL, 2.3 mmol) and diisopropylethylamine (0.4 mL, 2.1 mmol) in anhydrous ethanol (5 mL) was heated at a temperature in the range of 20° C. to 90° C. for 18 hours. After cooling to about 20 to 35° C., the reaction mixture was concentrated under reduced pressure. The crude residue was diluted with ethyl acetate, washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford a light pink liquid (0.60 g, 98% yield).