Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][N:4]=1.[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4].O1CCCC1>[CH:10](=[N:9][C:6]1[CH:5]=[N:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CSc1ccc(N)cn1
Reactant: O=Cc1ccccc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CSc1ccc(N=Cc2ccccc2)cn1

Procedure:
2-(methylthio)-5-aminopyridine (1 g, 7 mmol), benzaldehyde (0.76 g, 7 mmol), tetraisopropyl titanate (3 mL) and tetrahydrofuran (25 mL) were mixed and stirred to react at 70° C. for 24 hours. Saturated sodium carbonate solution was added into the reaction mixture, and the mixture was extracted with ethyl acetate for three times. The combined organic phase was dried with anhydrous sodium sulfate, filtered and concentrated to yield the residual (1.72 g), which was directly used in the next reaction step without purification.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[F:8][C:9]1[CH:18]=[CH:17][C:16]2[NH:15][CH:14]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH:20]=3)[C:13]([CH3:32])([CH3:31])[CH2:12][C:11]=2[C:10]=1[C:33](O)=[O:34].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[F:8][C:9]1[CH:18]=[CH:17][C:16]2[NH:15][CH:14]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)[CH:20]=3)[C:13]([CH3:31])([CH3:32])[CH2:12][C:11]=2[C:10]=1[C:33]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:34]
Reactant: CC1(C)Cc2c(ccc(F)c2C(=O)O)NC1c1cccc(N2CCOCC2)c1
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2c(ccc(F)c2C(=O)NS(C)(=O)=O)NC1c1cccc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a suspension of 60% sodium hydride (102 mg, 2.5 mmol) in N,N-dimethylformamide (2.5 mL) was added methanesulfonamide (247 mg, 2.6 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 6-fluoro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid (100 mg, 0.26 mmol) and 1,1′-carbonyldiimidazole (106 mg, 0.65 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of methanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-[6-fluoro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carbonyl]-methanesulfonamide (36 mg, 30%) as a white solid: LC/MS m/e calcd for C23H28FN3O4S (M+H)+: 462.56, observed: 462.1.
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[F:27])[CH:22]=O>ClCCl.CC1C=CC(S(O)(=O)=O)=CC=1>[F:18][C:19]1[CH:20]=[C:21]([C@H:22]2[O:15][CH2:14][C@H:13]([CH2:12][CH2:11][C@H:8]3[CH2:7][CH2:6][C@H:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:10][CH2:9]3)[CH2:16][O:17]2)[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: CCCC[C@H]1CC[C@H](CCC(CO)CO)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CCCC[C@H]1CC[C@H](CC[C@H]2CO[C@H](c3ccc(F)c(F)c3)OC2)CC1

Procedure:
A solution of 2.4 g (0.01 mol) of 2-[2'-(trans-4"-butylcyclohexyl)-ethyl]propane-1,3-diol, 2.8 g (0.01 mol) of 3,4-difluorobenzaldehyde (manufactured by Aldrich) and 0.1 g of TsOH in 50 cm3 of dichloromethane was refluxed for 3 hours over a hot water bath with a Dean-Stark trap. The reaction solution was washed with water and the dichloromethane was distilled off. The residue was recrystallized from a solvent mixture of acetone and methanol to yield 3.0 g (0.008 mol) of trans-2-(3',4'-difluorophenyl)-5-[2'-(trans-4"-butylcyclohexyl)-ethyl]-1,3-dioxane. The phase transition points of this compound, measured by DSC, were: ##STR45## wherein C is the crystal phase, N is the nematic phase, and I is the isotropic liquid phase.
Reaction SMILES: [CH:1]([C:4]1[C:5]([S:14][C:15]#[N:16])=[CH:6][C:7]([N+:11]([O-])=O)=[C:8]([NH2:10])[CH:9]=1)([CH3:3])[CH3:2].[H][H]>[Ni].C1COCC1>[CH:1]([C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH2:11])=[CH:6][C:5]=1[S:14][C:15]#[N:16])([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(N)c([N+](=O)[O-])cc1SC#N
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: CC(C)c1cc(N)c(N)cc1SC#N

Procedure:
5-Isopropyl-2-nitro-4-thiocyanato-phenylamine (prepared in Example QQ-1; 7.83 g, 33 mmol) was hydrogenated using Raney nickel (2 g) and THF (100 mL) in the presence of hydrogen (50 psi) as described in General Method 3. MS(APCI): 208(M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([CH:14]([CH3:16])[CH3:15])[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2-].[Na+].[Cl:19][CH2:20][CH2:21][CH2:22]I.O>C1(C)C=CC=CC=1>[Cl:19][CH2:20][CH2:21][CH2:22][C:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)([CH:14]([CH3:16])[CH3:15])[C:12]#[N:13]
Reactant: COc1ccc(C(C#N)C(C)C)cc1OC
Reactant: ClCCCI
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C(C#N)(CCCCl)C(C)C)cc1OC
Temperature: 25 °C
Yield: 85.7 %

Procedure:
2-(3,4-dimethoxyphenyl)-3-methylbutanenitrile (1.21 g, 5.52 mmol) was added to a suspension of sodium amide (0.59 g, 14.4 mmol) in toluene (12 ml). The mixture was then heated to reflux for 2 hours before the addition of 1-chloro-3-iodopropane (0.9 ml, 8.3 mmol). The mixture was cooled to room temperature over 80 minutes, and worked up by addition of water. The product was extracted with methyl-t-butyl ether (MTBE). After usual work-up, including drying the organic extract using MgSO4 and concentrating under reduced pressure the product was purified on column chromatography eluting with (ethyl acetate: light petroleum (b.p. 40 -60° C.) =1:2), to give 1.4g (82% yield) of the required product.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.C(OCC)(=O)C.O1C=CCCC1.Cl.CNC>C(N(CC)CC)C>[N:3]1[CH:4]=[C:5]2[C:9]([N:8]=[CH:7][NH:6]2)=[N:10][CH:2]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: C1=COCCC1
Agent: CNC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: c1ncc2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 140 %

Procedure:
In a 100 ml three-mouth bottle, 2,6-dichloropurine (10 g), ethyl acetate (50 ml), pyridinium salt of paratoluenesulfonic acid (0.2 g) are mixed. The above mixture is stirred and heated to a temperature of 35° C., 2,3-dihydropyrane (12 ml) is added thereto within 5 min. The above mixture is reacted at 50˜60° C. for 3 h. The completion of reaction is checked with TCL analysis. Dimethylamine hydrochloride (7.3 g) is added to the bottle, and triethylamine (22 ml) is added thereto at the temperature within 30 min, the above mixture is further reacted at the temperature for 0.5 h. The completion of reaction is checked with TCL analysis. The reaction mixture is cooled to room temperature. After filtration, a filter cake is completely washed with ethyl acetate, and a filtrate is washed with water for 3 times and delaminated. Organic layer is concentrated till large amount of solid is separated out. After filtration, a filter cake is washed with ethyl acetate for 3 times and then dried in vacuum at 50° C. for 5 h to obtain solid purin (8.9 g). The yield is about 59.8%.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Cl:13])=[N:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.[F:15][C:16]1[CH:17]=[C:18]([CH2:28][NH2:29])[CH:19]=[N:20][C:21]=1[O:22][CH2:23][C:24]([F:27])([F:26])[F:25]>>[Cl:13][C:12]1[C:3]2[CH2:2][N:29]([CH2:28][C:18]3[CH:19]=[N:20][C:21]([O:22][CH2:23][C:24]([F:26])([F:27])[F:25])=[C:16]([F:15])[CH:17]=3)[C:5](=[O:7])[C:4]=2[CH:9]=[CH:10][N:11]=1
Reactant: NCc1cnc(OCC(F)(F)F)c(F)c1
Reactant: COC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: O=C1c2ccnc(Cl)c2CN1Cc1cnc(OCC(F)(F)F)c(F)c1
Yield: 46 %

Procedure:
The title compound is prepared in 46% yield (98 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and (5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine hydrochloride (148 mg, 0.57 mmol, Amine-22) in a similar manner to Intermediate-2.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH3:11])=[O:9])[C:4]([CH:12]([CH3:14])[CH3:13])=[CH:3]1.[H][H]>CO.[Pd]>[O:1]=[C:2]1[CH2:7][CH2:6][C@@H:5]([C:8]([O:10][CH3:11])=[O:9])[C@@H:4]([CH:12]([CH3:14])[CH3:13])[CH2:3]1
Reactant: COC(=O)C1CCC(=O)C=C1C(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H]1CCC(=O)C[C@@H]1C(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 51 %

Procedure:
The product of Step 1 (5.11 g, 26.0 mmol) was dissolved in MeOH (80 ml). Palladium on carbon (0.416 g, 0.391 mmol) was added, and the flask was fitted with a hydrogen balloon. The flask was evacuated and backfilled with hydrogen (3×) and stirred 15 h at room temperature. The reaction was then filtered through Celite and the celite was washed with EtOAc. The filtrate was concentrated in vacuo. Purification via silica gel flash chromatography (0-15% EtOAc:Hexanes) gave methyl(cis)-4-oxo-2-(propan-2-yl)cyclohexanecarboxylate (2.63 g, 51%) as a colorless oil.
Reaction SMILES: FC(F)(F)C(O)=[O:4].[Cl:8][C:9]1[CH:10]=[C:11]([CH:43]=[CH:44][CH:45]=1)[C:12]([NH:14][C@H:15]1[CH2:19][CH2:18][N:17]([C@H:20]2[CH2:25][CH2:24][C@@H:23]([N:26]([CH:28]([CH3:30])[CH3:29])[CH3:27])[CH2:22][C@H:21]2[CH2:31][S:32]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[C:16]1=[O:42])=[O:13].ClC1C=C(C=CC=1)C(OO)=O>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[C:11]([CH:43]=[CH:44][CH:45]=1)[C:12]([NH+:14]([O-:4])[C@H:15]1[CH2:19][CH2:18][N:17]([C@H:20]2[CH2:25][CH2:24][C@@H:23]([N:26]([CH:28]([CH3:30])[CH3:29])[CH3:27])[CH2:22][C@H:21]2[CH2:31][S:32]([C:35]2[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=2)(=[O:33])=[O:34])[C:16]1=[O:42])=[O:13]
Reactant: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H](NC(=O)c3cccc(Cl)c3)C2=O)[C@H](CS(=O)(=O)c2ccc(Cl)cc2)C1
Reactant: O=C(O)C(F)(F)F
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H]([NH+]([O-])C(=O)c3cccc(Cl)c3)C2=O)[C@H](CS(=O)(=O)c2ccc(Cl)cc2)C1
Reaction time: 1.25 h
Yield: 58.2 %

Procedure:
A solution of Example 86 (13.6 mg) in CH2Cl2 (1.5 mL) was cooled to 0° C., then 3-chloroperoxybenzoic acid (77%, 10 mg) was added portion-wise. The mixture was stirred for 1.25 h, then diluted with CH2Cl2 (400 mL), washed with satd NaHCO3 (3×100 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by semi-preparative HPLC to give the title compound (6.8 mg, 57%) as a white solid after lyophilization from MeCN/aqueous TFA. ESI MS m/z 596 [C28H35Cl2N3O5S+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)([CH2:13][CH2:14]S(C)(=O)=O)[CH2:9]1)=[O:7].[NH:36]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[N:38]=[C:37]1[C:45]([CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)=[O:46].C(N(C(C)C)CC)(C)C.C(#N)C>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:50]2[CH2:51][CH2:52][CH:47]([C:45]([C:37]3[NH:36][C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=4[N:38]=3)=[O:46])[CH2:48][CH2:49]2)([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[CH2:9]1)=[O:7]
Reactant: COc1ccc(C2(CCS(C)(=O)=O)CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)C2)cc1OC
Reactant: O=C(c1nc2ccccc2[nH]1)C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ccc(C2(CCN3CCC(C(=O)c4nc5ccccc5[nH]4)CC3)CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)C2)cc1OC

Procedure:
Combine 1-(3,4,5-trimethoxy-benzoyl)-3-(3,4-dimethoxy-phenyl)-3-(2-methanesulfonyl-ethyl)-pyrrolidine (1.19 g, 2.27 mmol), 4-[1H-benzoimidazole-2-carbonyl]-piperidine (1.65 g, 3.41 mmol) and diisopropylethylamine (1.47 g, 11.35 mmol) and acetonitrile (11 mL). Reflux the reaction mixture overnight, dilute with ethyl acetate and extract successively with a saturated aqueous NH4Cl solution, 5% aqueous NaHCO3 solution, water and saturated aqueous NaCl solution. Separate the organic layer, dry over anhydrous Na2So4, filter and remove the solvent in vacuo. Chromatograph the residue on silica gel eluting with ethyl acetate/methanol (5/1), evaporate the solvent and dry overnight at 82° C. at 0.20 torr to yield title compound: mp; 113.0-116.0° .C, Rf=0.23 (silica gel, 5/1 ethyl acetate/methanol). Elemental Analysis calculated for C37H44N4O7: C 67.66; H 6.75; N 8.53; Found: C 67.00; H 6.77; N 8.39.
Reaction SMILES: [F:1][C:2]1([CH2:8][OH:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[H-].[Na+].[Cl:12][C:13]1[CH:14]=[C:15]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:16]=[CH:17][C:18]=1F.Cl>O1CCCC1.ClCCl.CN(C)C=O>[Cl:12][C:13]1[CH:14]=[C:15]([S:20]([NH2:23])(=[O:21])=[O:22])[CH:16]=[CH:17][C:18]=1[O:9][CH2:8][C:2]1([F:1])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: NS(=O)(=O)c1ccc(F)c(Cl)c1
Reactant: OCC1(F)CCOCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(OCC2(F)CCOCC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of EXAMPLE 296C (0.175 g) in tetrahydrofuran (5 ml) was added sodium hydride (0.209 g) and the reaction stirred at room temperature for 15 minutes. 3-Chloro-4-fluorobenzenesulfonamide (0.273 g) was added and the reaction stirred for 3 hours. To the thick suspension was added tetrahydrofuran (2 ml) and N,N-dimethylformamide (3 ml). The reaction was stirred for 3 hours at 60° C. then poured into dichloromethane (50 ml) and 1N aqueous HCl (50 ml). The organic layer was washed with brine (35 ml) dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography (Reveleris 40 g) eluting with a gradient of 10-100% ethyl acetate/hexanes over 30 minutes (flow=40 ml/minute) gave the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1N.C(=O)(O)[O-]>>[NH:18]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[C:17]1[C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[C:7]2[C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1
Reactant: N#Cc1ccc2nccc(-c3ccncc3)c2c1
Reactant: Nc1ccccc1N
Agent: O=C([O-])O
Product: c1ccc2[nH]c(-c3ccc4nccc(-c5ccncc5)c4c3)nc2c1
Temperature: 250 °C

Procedure:
A mixture of 4-(4-pyridinyl)-6-quinolinecarbonitrile, (231 mg, 1 mmol) 1,2-diaminobenzene (108 mg, 1 mmol) and polyphosphoric acid (1.4 g) was heated in the microwave at 250° C. for 1.5 hours. The reaction was poured onto water which was neutralized with bicarbonate. The product was filtered, washed with water, and dried. The product was further purified by dissolving in hot methanol, filtering and cooling to obtain crystals. The yield was 47.7 mg, 30%. MS (ES)+ m/e 323 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3=[N:20][CH:21]=[C:22]([C:24]4[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=4)[CH:23]=[C:18]3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH:30]C(=O)C)[CH:10]=1.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3=[N:20][CH:21]=[C:22]([C:24]4[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=4)[CH:23]=[C:18]3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH2:30])[CH:10]=1
Reactant: CC(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cnn(C)c4)cnc32)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1cc(-c2cnc3c(c2)ncn3-c2cc(N)cc(-c3ccc(F)cc3F)c2)cn1
Temperature: 85 °C
Yield: 79 %

Procedure:
To a solution of the compound of Example 131 (0.5 g, 1.1 mmol) in ethanol (10 ml) was added aqueous solution of NaOH (392 mg, 9.79 mmol, 8.9 eq.) and the mixture was heated at 85° C. for 2 h. The mixture was quenched and extracted as in Example 1(d). The solvent was distilled off to afford the product in 79% yield (0.35 g).
Reaction SMILES: [C:1]1([C:7]2[N:11]3[CH:12]=[CH:13][N:14]=[C:15]([NH2:16])[C:10]3=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([N:21]=[C:22]=[O:23])[CH2:18][CH2:19][CH3:20]>C(Cl)Cl.CN(C=O)C.C1COCC1.CCOC(C)=O>[CH2:17]([NH:21][C:22]([NH:16][C:15]1[C:10]2[N:11]([C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][N:9]=2)[CH:12]=[CH:13][N:14]=1)=[O:23])[CH2:18][CH2:19][CH3:20]
Reactant: Nc1nccn2c(-c3ccccc3)cnc12
Reactant: CCCCN=C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCNC(=O)Nc1nccn2c(-c3ccccc3)cnc12
Temperature: 60 °C
Yield: 36 %

Procedure:
To a mixture of 3-phenyl-imidazo[1,2-a]pyrazin-8-ylamine (Example 11) (28 mg, 0.133 mmol) in DCM (0.5 ml), DMF (1 ml) and THF (0.5 ml) was added butyl isocyanate (0.03 ml, 2 eq.). The mixture was heated at 60° C. for 8 hr. After cooling to rt, the mixture was diluted with EtOAc. The organic layer was washed with brine, dried and concentrated. The residue was purified on a silica gel column to give 15 mg (yield 36%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][C:8](=[CH:13]N(C)C)[C:7](=O)[C:6]=2[CH:18]=1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH2:28][C:29]([NH2:31])=[NH:30])=[CH:20]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][C:8]3[CH:13]=[N:30][C:29]([CH2:28][C:21]4[C:22]5[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=5)[NH:19][CH:20]=4)=[N:31][C:7]=3[C:6]=2[CH:18]=1
Reactant: N=C(N)Cc1c[nH]c2ccccc12
Reactant: CN(C)C=C1CC(=O)Nc2ccc(Cl)cc2C1=O
Product: O=C1Cc2cnc(Cc3c[nH]c4ccccc34)nc2-c2cc(Cl)ccc2N1
Yield: 46 %

Procedure:
Analogous to Scheme 1, from 7-chloro-4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepine-2,5-dione and 2-(1H-indol-3-yl)-acetamidine. Yield: 46%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:16])[N:5]=[C:4]([NH:17][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[N:3]=1.CO[CH:28](OC)[N:29]([CH3:31])[CH3:30]>>[Cl:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([Cl:15])[C:9]=1[CH2:8][C:6]1[N:7]=[C:2]([N:1]=[CH:28][N:29]([CH3:31])[CH3:30])[N:3]=[C:4]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([C:22]#[N:23])=[CH:24][CH:25]=2)[N:5]=1
Reactant: COC(OC)N(C)C
Reactant: N#Cc1ccc(Nc2nc(N)nc(Cc3c(Cl)cccc3Cl)n2)cc1
Product: CN(C)C=Nc1nc(Cc2c(Cl)cccc2Cl)nc(Nc2ccc(C#N)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound (1) (0.0016 mol) and 1,1-dimethoxy-N,N-dimethylmethanamine (21 ml) were combined and stirred vigorously at ambient temperature for 8 hours. The reaction mixture was filtered and the collected solid was washed with ether (Fraction A). Additional compound was obtained by concentration of the filtrate (Fraction B). Fractions A and B were combined and recrystallized from ethanol, yielding 0.15 g of 4-[[4-[(2,6-dichlorophenyl)methyl]-6-[[(dimethylamino)methylene]amino]-1,3,5-triazin-2-yl]amino]benzonitrile (compound 62).
Reaction SMILES: [Br:1][CH:2]1[N:6](C(C)C)[C:5]([C:10]([OH:12])=O)=[CH:4][S:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[Br:1][C:2]1[S:3][CH:4]=[C:5]([C:10]([NH:28][CH:25]([CH3:27])[CH3:26])=[O:12])[N:6]=1
Reactant: CC(C)N1C(C(=O)O)=CSC1Br
Reactant: CC(C)N
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC(C)NC(=O)c1csc(Br)n1

Procedure:
The product was prepared from 2-bromo-N-(1-methylethyl)-1,3-thiazole-4-carboxylic acid (WO 9848799) (0.77 g), carbonyldiimidazole (0.66 g) and isopropylamine (0.24 g) using the method of example 115 step (i). Yield 0.82 g.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:17])[NH:5][C:6](=[O:16])[NH:7][C:8]=1[S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:2].[Si:18]([O:25][CH2:26][CH:27]1[CH2:31][C:30]([CH2:32]Br)=[CH:29][CH2:28]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C(=O)(O)[O-].[Na+]>CN(C)C=O>[Si:18]([O:25][CH2:26][CH:27]1[CH2:31][C:30]([CH2:32][N:7]2[C:8]([S:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:17])[NH:5][C:6]2=[O:16])=[CH:29][CH2:28]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CCc1c(Sc2ccccc2)[nH]c(=O)[nH]c1=O
Reactant: CC(C)(C)[Si](C)(C)OCC1CC=C(CBr)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1c(Sc2ccccc2)n(CC2=CCC(CO[Si](C)(C)C(C)(C)C)C2)c(=O)[nH]c1=O

Procedure:
A mixture of 5-ethyl-6-phenylthio-2,4-pyrimidinedione (0.16 g, 0.66 mmol) and (4-t-butyldimethylsilyloxymethylcyclopent-1-en-1-yl)methyl bromide (0.20 g, 0.66 mmol) in dimethylformamide (10 mmol) were heated at 50° C. for overnight in the presence of sodium bicarbonate (66 mg, 0.79 mmol). After the concentration of dimethylformamide, [(4-t-butyldimethylsilyloxymethyl cyclopent-1-en-1-yl)methyl]-5-ethyl-6-phenylthio-2,4-pyrimidinedione was obtained by the separation of the column chromatography. And then, this compound in THF (10 ml) was reacted with n-tetrabutylammoniumfluoride at room temperature for 1 hr. After the concentration of THF, the residue was separated by column chromatography to give a desirable product (35 mg).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:19]([CH3:21])=[C:18]([CH3:22])[N:17]=[C:16]([NH2:23])[C:15]=2[N:14]=[C:13]1[CH3:24].[N:25]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C(Cl)(Cl)Cl>[NH2:23][C:16]1[C:15]2[N:14]=[C:13]([CH3:24])[N:12]([CH2:11][CH2:10][CH2:9][NH:8][C:31]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:32])[C:20]=2[C:19]([CH3:21])=[C:18]([CH3:22])[N:17]=1
Reactant: Cc1nc(N)c2nc(C)n(CCCN)c2c1C
Reactant: O=C(Cl)N1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1nc(N)c2nc(C)n(CCCNC(=O)N3CCOCC3)c2c1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 40.9 %

Procedure:
Triethylamine (0.78 mL, 5.6 mmol) was added to a solution of 1-(3-aminopropyl)-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine (1.00 g, 4.3 mmol) in chloroform (50 mL). The solution was cooled in an ice bath and then 4-morpholinecarbonyl chloride (0.55 mL, 4.7 mmol) was added. After 15 minutes the reaction mixture was removed from the ice bath and allowed to stir at ambient temperature for 2 days. The reaction mixture was diluted with water (30 mL) and the pH was adjusted to 11 with potassium carbonate. The resulting precipitate was isolated by filtration and then recrystallized from isopropanol/water to provide 0.61 g of N-[3-(4-amino-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-1-yl)propyl]morpholine-4-carboxamide as a white solid, m.p. 128.9-129.7° C.
Reaction SMILES: O[CH:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[O:23]=[C:21]1[C:20]2[C:19](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:18](=[O:28])[N:22]1[CH:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)NCC(O)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(c1ccccc1)N1C(=O)c2ccccc2C1=O
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
To a solution of 1,1-dimethylethyl (2-hydroxy-2-phenylethyl)carbamate (2 g, 8.44 mmol), phthalimide (1 g, 7.03 mmol) and triphenylphosphine (2.76 g, 10.5 mmol) in THF (35 mL) at 25° C. was added DEAD (1.7 mL, 10.5 mmol) dropwise. After 0.5 h, the solution was concentrated and purified via column chromatography (silica, 15% EtOAc in hexanes) affording the title compound (2 g, 80%) as a white foam: LC-MS (ES) m/z=367 (M+H)+.