Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[C:7]([NH2:9])[N:6]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[N:5]=1)([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[C:31]([O:33][C:34]([CH3:36])=[CH2:35])=[O:32]>>[CH:1]([C:4]1[CH:8]=[C:7]([NH:9][C:31](=[O:32])[O:33][C:34]([CH3:36])=[CH2:35])[N:6]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(N)n(-c2ccc3ncccc3c2)n1
Reactant: C=C(C)OC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: C=C(C)OC(=O)Nc1cc(C(C)C)nn1-c1ccc2ncccc2c1
Yield: 63.2 %

Procedure:
Using the procedure of Example B26, 3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-amine from Example B9 (1.00 g, 4.0 mmol), lithium bis(trimethylsilyl)amide (1.0 M in THF, 7.9 mL, 7.9 mmol) and isopropenyl chloroformate (0.48 mL, 4.4 mmol) were combined to provide prop-1-en-2-yl 3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-ylcarbamate (0.85 g, 65% yield). MS (ESI) m/z: 337.2 (M+H+).
Reaction SMILES: [CH2:1]([NH:6][C:7]([C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=1)=[O:8])[CH2:2][CH2:3][CH:4]=[CH2:5].[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>C(#N)C>[CH2:1]([NH:6][C:7]([C:9]1[N:10]=[N:11][C:12]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:13][CH:14]=1)=[O:8])[CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: C=CCCCNC(=O)c1ccc(Cl)nn1
Reactant: C1CNCCN1
Solvent: CC#N
Product: C=CCCCNC(=O)c1ccc(N2CCNCC2)nn1
Yield: 88.6 %

Procedure:
To a solution of 6-chloropyridazine-3-carboxylic acid pent-4-enylamide synthesized above (1.08 g, 4.79 mmol) in acetonitrile (39 mL) was added piperazine (1.25 g, 14.5 mmol). The reaction mixture was heated to reflux overnight (TLC inindicated the reaction was complete). The mixture was evaporated and the solid residue was dissolved in a mixture of ethyl acetate (100 mL) and water (100 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined ethyl acetate layer were dried over Na2SO4 and concentrated to yield the title compound as a yellow solid (1.169 g, 88.6% yield).
Reaction SMILES: [C:1]([CH:4]([CH:10]([CH3:19])[C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)[CH3:2].C([O-])(=O)C.[NH4+:24]>>[CH3:2][C:1]1[NH:24][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([CH3:19])[C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(C(C)=O)C(C)C(=O)c1ccccc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Product: CCOC(=O)c1c(C)[nH]c(-c2ccccc2)c1C
Yield: 90.8 %

Procedure:
Using ethyl 2-acetyl-3-methyl-4-oxo-4-phenylbutanoate (20.3 g) and ammonium acetate (6.61 g), a procedure as in Reference Example 14 was performed to give the title compound as a brown oil (yield 17.1 g, 91%).
Reaction SMILES: Cl.[CH3:2][N:3]([C@H:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]([OH:13])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[N:45]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[C@@H:47](O)[CH2:46]2>O1CCOCC1>[N:45]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[C@@H:47]([O:12][C:11](=[O:13])[CH:10]([N:3]([CH3:2])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:46]2
Reactant: CN(c1ccccc1)[C@@H](C(=O)O)c1ccccc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Product: CN(c1ccccc1)C(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 37.5 %

Procedure:
(R)-(Methyl-phenyl-amino)-phenyl-acetic acid hydrochloride (I74) (97 mg, 0.35 mmol), HOBT (107 mg, 0.70 mmol), DCC (144 mg, 0.70 mmol) and (R)-quinuclidin-3-ol (89 mg, 0.70 mmol) are dissolved in dioxane (5 mL) and the mixture is stirred at RT for 15 hours. The white precipitate is filtered and discarded whereas the clear solution is evaporated to dryness. The residue is dissolved in EtOAc and washed with sat. Na2CO3 and then brine. The organic phase is dried over sodium sulphate, filtered and evaporated to dryness. The resulting crude is purified by flash chromatography on silica gel (DCM/MeOH=97/3 to 95/5) to obtain the title compound as a pale yellow oil (46 mg, 38% yield, mixture of diastereoisomers).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[C:16]#[N:17])[NH:12][CH:11]=[CH:10]2.O.[OH-].[Na+].CN([CH:24]=[O:25])C>>[Br:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[C:16]#[N:17])[NH:12][CH:11]=[C:10]2[CH:24]=[O:25]
Reactant: N#Cc1cc2[nH]ccc2cc1Br
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cc2[nH]cc(C=O)c2cc1Br
Temperature: 80 °C
Yield: 92 %

Procedure:
Phosphorus oxychloride (1.39 mL, 14.9 mmol) was added dropwise over 5 minutes to DMF (10 mL) with stirring. The clear mixture was stirred at room temperature for 10 minutes. A solution of 5-bromo-1H-indole-6-carbonitrile (1.10 g, 4.97 mmol) in DMF (1.5 with 0.5 mL wash) was added to the clear red solution, and the reaction mixture was stirred at room temperature for 5 min. The resulting grey suspension was heated to 80° C. under nitrogen for 25 min, and then allowed to cool to room temperature. The reaction mixture was treated slowly with water (30 mL) and aqueous 1 N NaOH (30 mL) at room temperature. The resulting thick suspension was then heated to 85° C. for five minutes with vigorous stirring. The reaction mixture was allowed to cool to room temperature over 5 minutes, and the solids were collected by filtration. The solids were dried in vacuo for 16 hours at 55° C. to afford the title compound (1.15 g, 92%) as a cream-colored solid. MS (ES−) 247.1 (M−H)−. 1H NMR (500 MHz, DMSO-d6) δ 12.76 (br. s., 1H), 9.99 (s, 1H), 8.60 (s, 1H), 8.43 (s, 1H), 8.18 (s, 1H).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:50]1[C:54]2[CH:55]=[CH:56][C:57]([C:59]3[CH:60]=[C:61]([NH2:65])[CH:62]=[CH:63][CH:64]=3)=[CH:58][C:53]=2[O:52][CH2:51]1>CN(C=O)C>[O:50]1[C:54]2[CH:55]=[CH:56][C:57]([C:59]3[CH:60]=[C:61]([NH:65][C:23]([C:18]4[C:19](=[O:22])[O:20][C:21]5[C:16]([CH:17]=4)=[CH:15][CH:14]=[CH:13][C:12]=5[O:11][CH3:10])=[O:25])[CH:62]=[CH:63][CH:64]=3)=[CH:58][C:53]=2[O:52][CH2:51]1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: Nc1cccc(-c2ccc3c(c2)OCO3)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccc5c(c4)OCO5)c3)c(=O)oc12
Temperature: 25 °C
Yield: 79.1 %

Procedure:
DIEA (0.014 mL, 0.077 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.016 g, 0.070 mmol) and HATU (0.029 g, 0.077 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Benzo[1,3]dioxol-5-yl-phenylamine (0.015 g, 0.070 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.023 g of product in 77% yield: LCMS (ESI) m/z 416 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[C:10]([O:13][CH2:14][CH2:15]Br)(=[O:12])[CH3:11]>>[CH2:14]([O:13][C:10](=[O:12])[CH2:11][NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][C:4]=1[F:9])[CH3:15]
Reactant: CC(=O)OCCBr
Reactant: Nc1ccc(Cl)cc1F
Product: CCOC(=O)CNc1ccc(Cl)cc1F

Procedure:
In a manner similar to that employed in Referential Example 267, the title compound was prepared from 4-chloro-2-fluoroaniline and bromoethyl acetate.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:49][OH:50])[C@@H:21]([OH:48])[C@@H:22]([OH:47])[C@H:23]([OH:46])[C:24]([NH:26][C@H:27]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:28][C:29]([O:31][CH2:32][O:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])=[O:30])=[O:25])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])=O)C1C=CC=CC=1>CO.[Pd]>[OH:46][C@@H:23]([C@H:22]([OH:47])[C@H:21]([OH:48])[C@@H:20]([NH:19][C:17](=[O:18])[C@H:12]([CH2:13][CH:14]([CH3:15])[CH3:16])[NH2:11])[CH2:49][OH:50])[C:24]([NH:26][C@H:27]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:28][C:29]([O:31][CH2:32][O:33][C:34](=[O:39])[C:35]([CH3:36])([CH3:37])[CH3:38])=[O:30])=[O:25]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)OCOC(=O)C(C)(C)C)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@H](N)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)OCOC(=O)C(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83.2 %

Procedure:
To a solution of pivaloyloxymethyl (S)-3-[(2S,3R,4R,5S)-5-(N-benzyloxycarbonyl-L-leucyl)amino-2,3,4,6-tetrahydroxyhexanoyl]amino-3-phenylpropionate (150 mg) in methanol (5 ml) was added 10% palladium on activated carbon (30 mg) and the mixture was stirred under hydrogen atmosphere at room temperature for 1.5 hours. After removal of the catalyst by filtration, the filtrate was concentrated under reduced pressure. Recrystallization from ethyl acetate-hexane provided the title compound (101 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:14][CH2:15][C:16]([C:18]2[S:25][C:24]([CH3:26])=[C:23]3[C:19]=2[CH2:20][C@H:21]2[C:27]([CH3:29])([CH3:28])[C@H:22]23)=[O:17])[CH:5]=[C:6]([CH3:13])[C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][O:11]1.[CH3:30][O-:31].[Na+]>CO>[OH:11][CH:10]([CH2:12][O:31][CH3:30])[CH2:9][O:8][C:7]1[C:6]([CH3:13])=[CH:5][C:4]([CH2:14][CH2:15][C:16]([C:18]2[S:25][C:24]([CH3:26])=[C:23]3[C:19]=2[CH2:20][C@H:21]2[C:27]([CH3:28])([CH3:29])[C@H:22]23)=[O:17])=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1OCC1CO1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCC(O)COc1c(C)cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc1C

Procedure:
3-[4-(2-Hydroxy-3-methoxy-propoxy)-3,5-dimethyl-phenyl]-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one is prepared by treating 3-(3,5-dimethyl-4-oxiranylmethoxy-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one with sodium methylate in methanol at 65° C. for 16 h in analogy to the procedure given in Example 99; LC-MS: tR=1.10 min, [M+1]+=443.18.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[CH:27]=[CH:28][C:29]([O:41][CH3:42])=[C:30]([S:32]([NH:35][C:36]([CH3:40])([CH3:39])[CH2:37][OH:38])(=[O:34])=[O:33])[CH:31]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[CH:27]=[CH:28][C:29]([O:41][CH3:42])=[C:30]([S:32]([NH:35][C:36]([CH3:39])([CH3:40])[CH2:37][OH:38])(=[O:34])=[O:33])[CH:31]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: COc1ccc(Br)cc1S(=O)(=O)NC(C)(C)CO
Product: COc1ccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1S(=O)(=O)NC(C)(C)CO

Procedure:
The title compound was prepared from 7-Difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2)(337 mg, 1.0 mmol) and 5-Bromo-N-(2-hydroxy-1,1-dimethyl-ethyl)-2-methoxy-benzenesulfonamide (example B.7) (440 mg, 1.3 mmol) according to general procedure II. Obtained as a yellow solid (135 mg, 23%). MS (ISP) 595.3[(M+H)+]; mp 178-180° C.
Reaction SMILES: [CH:1]1[C:17]2[CH2:16][C@H:15]3[N:18]([CH2:20][CH2:21][C@@:7]45[C@H:14]3[CH:13]=[CH:12][C@H:10]([OH:11])[C@@H:8]4[O:9][C:5]([C:6]=25)=[C:3]([OH:4])[CH:2]=1)[CH3:19].[OH-].[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CO.O>[CH2:24]([C:3]1([OH:4])[C:5]2[O:9][C@@H:8]3[C@@:7]45[CH2:21][CH2:20][N:18]([CH3:19])[C@@H:15]([C@@H:14]4[CH:13]=[CH:12][C@@H:10]3[OH:11])[CH2:16][C:17]([C:6]5=2)=[CH:1][CH2:2]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN1CC[C@]23C4=C5O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1CC4=CCC5(O)Cc1ccccc1
Reaction time: 3.5 h
Yield: 70.1 %

Procedure:
A solution of morphine (14.27 g, 50.0 mmol), NaOH (2.04 g, 51.0 mmol), and benzylbromide (8.47 g, 49.5 mmol) in MeOH (150 ml) and water (50 ml) was stirred at rt. for 3.5 hr., evaporated in vacuo to remove MeOH. The residue was extracted with CH2Cl2 (120 ml). The extract was dried over anhydrous Na2SO4 and evaporated in vacuo to dryness to give a crude residue, which was chromatographed on silica gel (column: d=6.5 cm, I=10.5 cm; eluting solvent: 15% MeOH in CH2Cl2) to obtain 3-benzylmorphine (13.1 g, 70% yield). The Rf value in TLC and the IR spectrum of the product were comparable to those obtained from an authentic sample.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:13])[C:5](=[O:12])[NH:6]2.S(=O)(=O)(O)[OH:15].OO>C(O)(=O)C>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[NH:6][C:5](=[O:15])[O:12][C:4](=[O:13])[C:3]=12
Reactant: O=S(=O)(O)O
Reactant: O=C1Nc2ccc(F)c(Cl)c2C1=O
Agent: OO
Solvent: CC(=O)O
Product: O=c1[nH]c2ccc(F)c(Cl)c2c(=O)o1

Procedure:
7.8 g (0.039 mol) of 4-chloro-5-fluoro-isatin are suspended in 50 ml of 100 percent acetic acid, treated with 0.25 ml of concentrated sulphuric acid and then 4.4 ml (0.043 mol) of 30 percent hydrogen peroxide are added dropwise thereto. The mixture is subsequently heated to 70° for 2.5 hours, then cooled to 10° and filtered. The crude product is recrystallized from acetone/hexane, there being obtained 6-chloro-5-fluoro-isatoic acid anhydride of melting point 275°-278° (decomposition).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=2)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=3)[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C)c(C)c23)cc1Cl
Reactant: c1cn[nH]c1
Product: COc1ccc(CNc2nc(-n3cccn3)nc3sc(C)c(C)c23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-5,6-dimethyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5,6-dimethyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]1[C:26]([OH:27])=[CH:25][CH:24]=[C:23]([F:28])[C:3]=1[CH2:4][O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@H:9]1[CH2:21][CH3:22])=[O:7].[CH3:29][O:30][CH2:31][CH2:32][CH2:33]OS(C1C=CC(C)=CC=1)(=O)=O>>[F:1][C:2]1[C:26]([O:27][CH2:33][CH2:32][CH2:31][O:30][CH3:29])=[CH:25][CH:24]=[C:23]([F:28])[C:3]=1[CH2:4][O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:10][C@H:9]1[CH2:21][CH3:22])=[O:7]
Reactant: COCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1c(F)ccc(O)c1F
Product: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1c(F)ccc(OCCCOC)c1F
Yield: 97 %

Procedure:
This compound was prepared from (R)-2-ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester 1-(2,6-difluoro-3-hydroxy-benzyl) ester and toluene-4-sulfonic acid 3-methoxy-propyl ester according to the procedure described in Example 207 to give the product as a colorless oil (117 mg; 97%); MS (ISP): 490.4 (M+NH4)+.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]#[C:22][C:23]3[CH:46]=[CH:45][C:26]([O:27][CH2:28][CH2:29][N:30]([CH3:44])[CH:31]4[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]4)=[CH:25][CH:24]=3)=[N:19][CH:20]=2)=[CH:11][CH:10]=1>C(Cl)Cl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]#[C:22][C:23]3[CH:24]=[CH:25][C:26]([O:27][CH2:28][CH2:29][N:30]([CH3:44])[CH:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)=[CH:45][CH:46]=3)=[N:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: CN(CCOc1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(CCOc1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
60 μL (0.8 mmol) trifluoroacetic acid are added to a solution of 22 mg (0.04 mmol) tert-butyl 4-[(2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-ethyl)-methyl-amino]-piperidin-1-carboxylate in 5 mL DCM and the reaction mixture is stirred for 24 h at RT. The mixture is evaporated down i. vac. and the residue is stirred with diethyl ether. The precipitate is suction filtered, washed with diethyl ether and dried.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:10]=[C:9]1[SH:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[NH4+].I[CH3:26]>C(O)C>[CH2:1]([N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:10]=[C:9]1[S:21][CH3:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: Sc1nc2cnc3ccccc3c2n1Cc1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CSc1nc2cnc3ccccc3c2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Benzyl-1H-imidazo[4,5-c]quinoline-2-thiol (4.15 g, 14.2 mmol), deionized water (35 mL), ethanol (35 mL), and aqueous ammonium hydroxide (3.2 mL) were combined, and iodomethane (1.06 mL, 17.0 mmol) was added. The reaction was stirred at room temperature for one hour, and a precipitate formed. The precipitate was collected by filtration, washed with diethyl ether (5×100 mL), and dried under vacuum to provide 1-benzyl-2-(methylthio)-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[C:9]([C:11]1[CH:12]=[C:13]([C:17]2[CH:26]=[C:25]3[C:20]([CH:21]=[CH:22][NH:23][C:24]3=[O:27])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1)#[N:10]>CC(N(C)C)=O>[Cl:1][C:21]1[C:20]2[C:25](=[CH:26][C:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([C:9]#[N:10])[CH:12]=3)=[CH:18][CH:19]=2)[C:24](=[O:27])[NH:23][CH:22]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: N#Cc1cccc(-c2ccc3cc[nH]c(=O)c3c2)c1
Solvent: CC(=O)N(C)C
Product: N#Cc1cccc(-c2ccc3c(Cl)c[nH]c(=O)c3c2)c1
Temperature: 25 °C
Yield: 80.9 %

Procedure:
A solution of N-chlorosuccinimide (307 g, 2.3 mol) in DMA (1.2 L) was added to a stirred suspension of 7-(3-cyanophenyl)isoquinolinone (0.54 kg, 2.2 mol) in boiling DMA (3.9 L) over a period of 1 hour under N2. The mixture was heated at reflux overnight and cooled to room temperature. The solid was collected by filtration, washed with MeCN (1.0 L) and dried in vacuo at 50° C. to give 4-chloro-7-(3-cyanophenyl)isoquinolinone (0.5 kg, 1.78 mol, 81%) as an off white solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:12]3[CH2:17][CH2:16][CH2:15][C@@H:14]4[C:18]5[CH:19]=[C:20]([C:25]([OH:27])=O)[CH:21]=[CH:22][C:23]=5[CH2:24][C@H:13]34)=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH3:28]>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:12]3[CH2:17][CH2:16][CH2:15][C@@H:14]4[C:18]5[CH:19]=[C:20]([C:25]([NH2:28])=[O:27])[CH:21]=[CH:22][C:23]=5[CH2:24][C@H:13]34)=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: N
Reactant: O=C(O)c1ccc2c(c1)[C@H]1CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1C2
Product: NC(=O)c1ccc2c(c1)[C@H]1CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1C2
Yield: 64 %

Procedure:
The title compound is prepared from cis-1-(1H-benzoimidazole-5-carbonyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carboxylic acid and ammonia (0.5 mol/L in 1,4-dioxane) following a procedure analogous to that described in Example 1. Yield: 64% of theory; LC (method 1): tR=1.64 min; Mass spectrum (ESI+): m/z=361 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1C(O)(S(O)(=O)=O)[CH2:6][CH2:5][O:4][CH2:3]1.[Na].CO[CH:16]([O:19][CH3:20])[O:17][CH3:18]>CO>[CH3:20][O:19][C:16]1([O:17][CH3:18])[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[OH:1]
Reactant: O=S(=O)(O)C1(O)CCOCC1O
Reactant: COC(OC)OC
Agent: [Na]
Solvent: CO
Product: COC1(OC)CCOCC1O

Procedure:
reacting said 3,4-dihydroxytetrahydro-2H-pyran-4-sulfonic acid, sodium salt with methanol and trimethylorthoformate in the presence of an acid to form 4,4-dimethoxytetrahydro-2H-pyran-3-ol; and
Reaction SMILES: [CH3:1][NH2:2].[NH2:3][C:4]1[C:5]([F:27])=[CH:6][C:7]([F:26])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([CH3:21])=[C:17](F)[CH:18]=3)[C:13](=[O:22])[C:12]([C:23]([OH:25])=[O:24])=[CH:11]2)[CH:9]=1>CS(C)=O>[NH2:3][C:4]1[C:5]([F:27])=[CH:6][C:7]([F:26])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([CH3:21])=[C:17]([NH:2][CH3:1])[CH:18]=3)[C:13](=[O:22])[C:12]([C:23]([OH:25])=[O:24])=[CH:11]2)[CH:9]=1
Reactant: CN
Reactant: Cc1cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2cc1F
Solvent: CS(C)=O
Product: CNc1cc2c(cc1C)c(=O)c(C(=O)O)cn2-c1cc(N)c(F)cc1F
Temperature: 40 °C
Reaction time: 72 h

Procedure:
Dimethyl sulfoxide (100 mg) and a 40% aqueous solution (50 mg) of methylamine were added to 1-(5-amino-2,4-difluorophenyl)-7-fluoro-6-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (30 mg), and the mixture was heated and stirred at 40° C. for 3 days. The solvent and the like were distilled off under reduced pressure, and ethanol (0.5 ml) was added to the residue. The mixture was left to stand for 3 days, and solids deposited were collected by filtration and washed with (ethanol and diethyl ether to obtain the title compound (11 mg) as a pale gray powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1.[Li]CCCC.[Br:15][C:16]1[C:17](=[O:21])[CH2:18][CH2:19][CH:20]=1.C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O>C1COCC1.O>[Br:15][C:16]1[C:17](=[O:21])[CH2:18][CH2:19][C:20]=1[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1
Reactant: O=C1CCC=C1Br
Reactant: CSc1ccc(Br)cc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Li]CCCC
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: C1CCOC1
Product: CSc1ccc(C2=C(Br)C(=O)CC2)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a -78° C. solution of 4-bromothioanisole (35.1 g, 173 mmol) in THF (500 mL) was added nBuLi (1.6M in hexanes, 107.5 mL, 172 mmol). The solution was stirred for 45 min, then a solution of 2-bromo-2-cyclopenten-1-one (25.4 g, 158 mmol) in THF (150 mL) was added and the mixture was allowed to warm to 0° C. and was quenched with saturated aqueous NH4Cl. The majority of the solvent was removed in vacuo and the residue was suspended in water and extracted with two portions of EtOAc. The organic layers were washed with brine, dried over MgSO4, faltered and concentrated. This material was dissolved in DMF (300 mL), cooled to 0° C. and treated with PDC (72.4 g, 192 mmol). The resulting mixture was warmed to r.t. and stirred for 2 h, then poured into H2O (1.2 L) and extracted with two 500 mL portions of EtOAc. The organic layers were washed with brine, dried over MgSO4, filtered and concentrated to give the title compound as a light brown solid which was used directly in the next step.