Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5](Br)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2
Reactant: OB(O)c1ccccc1
Reactant: Nc1ccc(Br)c2c1C(=O)NC2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1ccc(-c2ccccc2)c2c1C(=O)NC2
Yield: 88.8 %

Procedure:
In a similar manner to Step 2 of Example 1, 7-amino-4-bromoisoindolinone (250 mg, 1.10 mmol) was dissolved in acetonitrile (15 mL), and the solution was treated with phenylboronic acid (402 mg, 3.30 mmol), palladium acetate (20 mg, 0.088 mmol), tri(o-tolyl)phosphine (53.6 mg, 0.176 mmol) and triethylamine (1.53 mL, 11.0 mmol), followed by purification by preparative thin-layer chromatography (chloroform/methanol=15/1, chloroform/acetonitrile=6/1) to obtain 7-amino-4-phenylisoindolinone (219 mg, yield 89%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.C(Cl)(=O)C(Cl)=O.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl.CN(C=O)C>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[C:23]([C:9](=[O:11])[CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH:24]=1
Reactant: O=C(O)Cc1ccccc1F
Reactant: COc1ccc(Br)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cc1ccccc1F)c1cc(Br)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
2-Fluorophenylacetic acid (2.96 g, 19.24 mmoles) was dissolved in 50 ml dichloromethane. To this mixture, oxalylchloride (2.1 ml, 24.05 mmoles) and DMF (3 drops) were added at 0° C. and stirred for 30 min. The solvent was evaporated and dissolved in 30 ml dichloromethane. To this mixture, 4-bromoanisole (3.0 g, 16.03 mmoles) was added and cooled to 0° C. At 0° C. AlCl3 (3.21 g, 24.05 mmoles) was added and the reaction mixture was warmed to RT and stirred for 12 h. The reaction mixture was quenched by the addition of 2N HCl and extracted with ethyl acetate, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as off-white solid (4.0 g, 81% yield. 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 11.97(s,1H), 8.01(d, J=1.7 Hz, 1H), 7.58(dd, J=8.8,2.3.1 Hz, 1H), 7.35(m,1H), 7.23(d, J=7.3 Hz, 1H), 7.17(m, 2H), 6.92(d, J=8.9 Hz, 1H),4.33(s, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].[C:12](=O)([O-])[O-].[K+].[K+].CO>CC(C)=O>[CH3:12][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11]
Reactant: O=C1CCc2c(O)cccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CO
Product: COc1cccc2c1CCC2=O
Reaction time: 10 h
Yield: 79.4 %

Procedure:
To a mixture of 4-hydroxy-indan-1-one (14.5 g, 0.0979 mol) and 27.08 g (0.195 mol) of potassium carbonate was added 500 ml of acetone and 48.7 ml (0.78 mol) of methanol with stirring and the resulting mixture was heated to reflux for 4 h, cooled, and allowed to stand at room temperature for 10 h. The above mixture was filtered concentrated under vacuo, the solid residue was dissolved in methanol, heated and filtered. The filtrate was concentrated to a volume of 100 ml, cooled and filtered to afford 12.6 g (79%) of 4-methoxy-indan-1-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:27](O)=[O:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)[CH:5]=[CH:6][C:7]=1[CH:27]=[O:28]
Reactant: Cc1ccc(-c2cccc(Cl)c2)cc1
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: Cc1ccc(-c2ccc(C=O)c(Cl)c2)cc1
Reaction time: 0.25 h

Procedure:
A mixture of 4.76 g of 3-chloro-4'-methylbiphenyl, 2.94 g of hexamethylenetetramine and 30 ml of trifluoroacetic acid is heated to boiling under reflux for 5 days. The reaction mixture is then concentrated and treated with ice-water, whereupon it is stirred for 15 minutes, made basic with sodium carbonate and extracted with ether. After evaporation of the ethereal extracts and chromatography of the residue on silica gel with methylene chloride/methanol 9:1 as the eluent, there is obtained 2-chloro-4-(4'-methylphenyl)benzaldehyde, b.p. 210°-215° C./25 Pa.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]1[C:10]2=[CH:11][CH:12]=[CH:13][N:9]2[CH2:8][C:7]2[CH:14]=[CH:15][CH:16]=[CH:17][C:6]=2[NH:5]1.[C:18]([O:22][CH3:23])(=[O:21])[CH:19]=[CH2:20]>>[CH3:1][N:2]([CH2:3][CH:4]1[C:10]2=[CH:11][CH:12]=[CH:13][N:9]2[CH2:8][C:7]2[CH:14]=[CH:15][CH:16]=[CH:17][C:6]=2[NH:5]1)[CH2:20][CH2:19][C:18]([O:22][CH3:23])=[O:21]
Reactant: C=CC(=O)OC
Reactant: CNCC1Nc2ccccc2Cn2cccc21
Product: COC(=O)CCN(C)CC1Nc2ccccc2Cn2cccc21

Procedure:
The starting material is prepared as follows: The solution of 1.5 g of 11-(N-methylaminomethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (Example 1) in 7.5 ml of methyl acrylate is stirred at room temperature for 24 hours and the excess reagent is evaporated to yield the 11-(N-methyl-N-methoxycarbonylethylamino-methyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine as an oil, which is chromatographed on silica gel and eluted with 2% methanol-methylene chloride.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH:9]([CH2:18][C:19]2[O:23][N:22]=[C:21]([CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[N:20]=2)[CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>ClCCl>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[C:1]1([S:7][CH2:8][CH:9]([CH2:18][C:19]2[O:23][N:22]=[C:21]([CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[N:20]=2)[CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)CC(CSc1ccccc1)Cc1nc(CCCCNc2ccccn2)no1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CC(CSc1ccccc1)Cc1nc(CCCCNc2ccccn2)no1
Yield: 99 %

Procedure:
The product from step 3 (50.4 mg, 0.10 mmoles) was stirred at RT in 1:1 mix of TFA and dichloromethane (2 mL) for 30 min. The solvent was removed under reduced pressure to give the product 56.2 mg (99%). 1H NMR (CD3OD) δ 7.84-7.79 (m, 2H), 7.39-7.35 (m, 2H), 7.32-7.26 (m, 2H), 7.22-7.17 (t, 1H), 6.95 (d, 1H), 6.82 (t, 1H), 3.37 (t, 2H), 3.22-3.02 (series of m, 4H), 2.81 (t, 2H), 2.65-2.57 (series of m, 2H), 2.49 (t, 1H), 1.92-1.82 (series of m, 2H), 1.80-1.72 (series of m, 2H); MS (ESI+) for C22H26N4O3S m/z 427 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH2:15]([SH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>O>[CH2:15]([S:22][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(SCc2ccccc2)c([N+](=O)[O-])c1
Yield: 92.1 %

Procedure:
In a similar fashion using route 38 general procedure 92, 1-chloro-4-methanesulfonyl-2-nitrobenzene (750 mg, 3.19 mmol), benzylmercaptan (450 ml, 3.82 mmol), Na2CO3 (439 mg, 4.14 mmol) and EtOH:water (25 ml: 18 ml) at 90° C. for 4 h gave the title compound (950 mg, 92%) which was used in the next step without further purification. The structure was confirmed by 1H NMR.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:11]3[CH2:15][CH2:16][CH2:17][C@H:18](O)[C:10]=3[CH:9]=[CH:8][C:7]=2[CH2:6]1)=[O:4].C1C=CC(P([N:36]=[N+:37]=[N-:38])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1.Cl>C1(C)C=CC=CC=1>[N:36]([C@H:18]1[C:10]2[CH:9]=[CH:8][C:7]3[CH2:6][N:5]([C:3](=[O:4])[C:2]([F:21])([F:20])[F:1])[CH2:14][CH2:13][C:12]=3[C:11]=2[CH2:15][CH2:16][CH2:17]1)=[N+:37]=[N-:38]
Reactant: O=C(N1CCc2c(ccc3c2CCC[C@@H]3O)C1)C(F)(F)F
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: [N-]=[N+]=N[C@@H]1CCCc2c1ccc1c2CCN(C(=O)C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-2,2,2-trifluoro-1-(7-hydroxy-1,2,7,8,9,10-hexahydrobenzo[f]isoquinolin-3(4H)-yl)ethanone (299 mg, 1 mmol) in 3 mL of toluene at −10° C. was added DPPA (0.26 mL, 1.2 mmol). To this stirred solution was then added DBU (0.18 mL, 1.2 mmol) dropwise while keeping the temperature below 0° C. After stirring at room temperature for 3 h, 0.5 mL of 10% HCl was added and the resulting solution was evaporated to dryness and directly submitted to flash chomatography (SiO2, hexane/EtOAc=100:10 to 100:15 to 100:18) to afford (R)-1-(7-azido-1,2,7,8,9,10-hexahydrobenzo[f]-isoquinolin-3(4H)-yl)-2,2,2-trifluoroethanone as a colorless oil which was directly used in the next step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[N:7]([CH:9]([C:11](=[O:42])[NH:12][C:13]1[CH:18]=[C:17]([C:19]2[C:20]3[N:27]([CH3:28])[N:26]=[C:25]([CH3:29])[C:21]=3[N:22]=[CH:23][N:24]=2)[CH:16]=[C:15]([C:30]#[C:31][Si](C(C)C)(C(C)C)C(C)C)[N:14]=1)[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:43])[N:7]([CH:9]([C:11](=[O:42])[NH:12][C:13]1[CH:18]=[C:17]([C:19]2[C:20]3[N:27]([CH3:28])[N:26]=[C:25]([CH3:29])[C:21]=3[N:22]=[CH:23][N:24]=2)[CH:16]=[C:15]([C:30]#[CH:31])[N:14]=1)[CH3:10])[CH3:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1nn(C)c2c(-c3cc(C#C[Si](C(C)C)(C(C)C)C(C)C)nc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)c3)ncnc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C#Cc1cc(-c2ncnc3c(C)nn(C)c23)cc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl-N-{1-[(4-{1,3-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl}-6-{2-[tris(propan-2-yl)silyl]ethynyl}pyridin-2-yl)carbamoyl]ethyl}-N-methylcarbamate D1 (0.52 g, 0.86 mmol), THF (10 ml) and tetrabutylammonium fluoride (1 mol/l solution in THF, 0.95 ml, 0.95 mmol) is stirred at RT for 1 h. The mixture is diluted with DCM and extracted with a saturated aqueous solution of sodium hydrogencarbonate and brine. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The crude product is used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:20]=[CH:19][C:6]([CH2:7][NH:8][C:9](=[O:18])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:11]=2[NH2:17])=[CH:5][CH:4]=1.Cl[CH2:24][C:25](Cl)=[O:26].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:1][C:2]([F:21])([F:22])[C:3]1[CH:20]=[CH:19][C:6]([CH2:7][NH:8][C:9]([C:10]2[C:11]3[NH:17][C:25](=[O:26])[CH2:24][O:16][C:12]=3[CH:13]=[CH:14][CH:15]=2)=[O:18])=[CH:5][CH:4]=1
Reactant: Nc1c(O)cccc1C(=O)NCc1ccc(C(F)(F)F)cc1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1COc2cccc(C(=O)NCc3ccc(C(F)(F)F)cc3)c2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
N-(4-(trifluoromethyl)benzyl)-2-amino-3-hydroxybenzamide 22a (1 g, 3.2 mmol) was dissolved in 20 ml of DMF and at 0° C. TEA (0.9 ml, 2 equiv.) and chloroacetyl chloride (0.3 ml, 1.2 equiv.) were added. The mixture was stirred at rt for 2 hours. K2CO3 (885 mg, 2 equiv.) was added and the reaction was stirred at rt for 20 hours. The solvent was evaporated and the crude was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by chromatographic column using AcOEt 1/petroleum ether 1 as eluant gave 500 mg of a white solid. Yield=44% 1HNMR (DMSO, 200 MHz) δ 4.56 (2H, d, J=5.4 Hz), 4.65 (2H, s), 7.04 (2H, t), 7.17 (1H, d, J=7.8 Hz), 7.55 (2H, d, J=8 Hz), 7.71 (2H, d, J=8.2 Hz), 9.52 (1H, bs), 10.96 (1H, bs); [M+1] 351.1 (C17H13F3N2O3 requires 350.3).
Reaction SMILES: C(OC([N:8]1[CH:12]([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][S:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:18][C:16]([F:17])([F:19])[C:15]([NH:14][CH2:13][CH:12]1[CH2:11][S:10][CH2:9][NH:8]1)=[O:20]
Reactant: CC(C)(C)OC(=O)N1CSCC1CNC(=O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCC1CSCN1)C(F)(F)F
Reaction time: 20 h

Procedure:
To a cold (0° C.) solution of 4-[(2,2,2-trifluoro-acetylamino)-methyl]-thiazolidine-3-carboxylic acid tert-butyl ester (19 mmol) in dry DCM (10 mL) was added dropwise TFA (133 mmol, 7 eq). The reaction mixture was stirred for 20 h and concentrated in vacuo to give the title compound. LC-MS: tR=0.24 min; [m+H]+=214.99.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]=[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]=1[C:7]#[N:8].[C:13](O)(=[O:15])[CH3:14].C(OC(=O)C)(=O)C>>[C:13]([NH:1][C:2]1[O:3][CH:4]=[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]=1[C:7]#[N:8])(=[O:15])[CH3:14]
Reactant: CC(=O)O
Reactant: CC(C)(C)c1coc(N)c1C#N
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1occ(C(C)(C)C)c1C#N
Yield: 83.4 %

Procedure:
16.4 g (0.1 mole) of 2-amino-3-cyano-4-tert.-butylfuran were heated to 100° C. with 24 ml (0.4 mole) of acetic acid and 10.4 ml (0.11 mole) of acetic anhydride for one hour. Thereafter, the reaction mixture was evaporated under reduced pressure and the residue was recrystallized from a mixture of toluene/cyclohexane (1:2). 17.2 g of 2-acetylamino-3-cyano-4-tert.-butyl-furan of melting point 135° C. were obtained in this manner.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20][NH2:21])[CH:17]=[CH:18][CH:19]=1>ClCCl>[Cl:1][C:2]1[C:7]([C:8]([NH:21][CH2:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[CH:15]=2)=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1
Reactant: COc1cccc(CN)c1
Reactant: O=C(Cl)c1c(Cl)ncnc1Cl
Solvent: ClCCl
Product: COc1cccc(CNC(=O)c2c(Cl)ncnc2Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
4,6-Dichloropyrimidine-5-carbonyl chloride (587 mg, 2.78 mmol, prepared according to E. V. Tarasov et al. Synlett 2000, 5, 625-626) was dissolved in dichloromethane (2.5 ml) and TEA (400 μl, 2.87 mmol) was added. To this solution, (3-methoxyphenyl)methanamine (379 mg, 2.76 mmol) in 3 ml DCM was added dropwise and the mixture was stirred for 30 min at room temperature. The reaction mixture was then diluted with dichloromethane, washed with 4% sodium bicarbonate solution, dried over magnesium sulphate, filtered and evaporated. After evaporation of the solvent, the residue was purified by flash chromatography using SP1® Purification System (10% to 30%, hexane-ethyl acetate) to obtain 534 mg (61% yield) of the title compound.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:20]3[C:21]([Cl:37])=[CH:22][C:23]([F:36])=[C:24]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:28])[CH:25]=3)[C:13](=[O:19])[N:14]2[CH2:17][CH3:18])=[CH:9][N:8]=1.[CH3:38][O:39][C:40](Cl)=[O:41]>N1C=CC=CC=1>[Cl:37][C:21]1[CH:22]=[C:23]([F:36])[C:24]([NH:26][C:27]([NH:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:28])=[CH:25][C:20]=1[C:12]1[C:13](=[O:19])[N:14]([CH2:17][CH3:18])[C:15]2[C:10]([CH:11]=1)=[CH:9][N:8]=[C:7]([NH:6][C:40](=[O:41])[O:39][CH3:38])[CH:16]=2
Reactant: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2Cl)cc2cnc(N)cc21
Reactant: COC(=O)Cl
Agent: CS(=O)(=O)O
Solvent: c1ccncc1
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2Cl)cc2cnc(NC(=O)OC)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.6 %

Procedure:
A mixture of Example 21 (100 mg, 0.221 mmol) in pyridine (3 mL) was treated drop-wise with methylchloroformate (23 mg, 0.243 mmol) and stirred at RT for 4 h. Additional methylchloroformate (50 mL) was added and the mixture stirred overnight. The mixture was treated with additional methylchloroformate (100 mL) and stirred for another 2 days. The mixture was concentrated to dryness, treated with EtOAc and water and the resulting solid collected via filtration. The material was purified via reverse-phase chromatography (MeCN/H2O with 0.1% TFA); the organics were removed under reduced pressure and the aqueous mixture was neutralized with satd. NaHCO3. The resulting solid was collected via filtration, washed with water and dried to afford methyl (3-(2-chloro-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)carbamate (101 mg, 87% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.56 (br s, 1H), 9.31-8.78 (m, 2H), 8.67 (s, 1H), 8.20 (d, J=8.6 Hz, 1H), 7.96 (s, 2H), 7.56 (d, J=11.0 Hz, 1H), 7.42 (d, J=8.0 Hz, 2H), 7.26 (t, J=7.8 Hz, 2H), 6.96 (t, J=7.4 Hz, 1H), 4.20 (q, J=7.2 Hz, 2H), 3.71 (s, 3H), 1.25 (t, J=7.1 Hz, 3H); MS (ESI) m/z: 510.1 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:10]O>>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1
Reactant: CO
Product: Cc1ccccc1C(C)C

Procedure:
Isopropylbenzene could not be selectively alkylated with methanol to form isopropyltoluene. At 200° C. disproportionation of the isopropylbenzene was the predominate reaction. The product was 41% diisopropylbenzene, 24% benzene and 20% isopropyltoluene. Part of the benzene was alkylated as shown by the presence of 6% toluene.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([O:12]C)=[CH:7]2.B(Br)(Br)Br.ClCCl>ClCCCl>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([OH:12])=[CH:7]2
Reactant: COc1cnc2c(Cl)nccc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: ClCCCl
Product: Oc1cnc2c(Cl)nccc2c1
Temperature: 25 °C

Procedure:
To a 75 mL pressure vessel were charged with 8-chloro-3-methoxy-1,7-naphthyridine (0.8 g, 4.11 mmol) and DCE (10 ml). To this was added boron tribromide, 1.0M in dichloromethane (20.55 ml, 20.55 mmol) slowly. The brown heterogeneous mixture was stirred at RT and then was heated to 60° C. in oil bath and stirred for 3 h. It was cooled to 0° C. by ice bath and quenched with sat. Na2CO3 very slowly. Organic solvents were reduced, and 100 ml EtOH was added to the resulting residue. The white precipitate was filtered out. The filtrate was concentrated to yield 8-chloro-1,7-naphthyridin-3-ol as crude product which was used for next step directly. MS m/z: 181.2 [M+H].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4](O)[C:3]=1[CH3:9].[CH3:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:16][C:15]2[CH:17]=[CH:18][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)[C:3]=1[CH3:9]
Reactant: COc1ccc(N)cc1
Reactant: Cc1c(O)ncnc1Cl
Product: COc1ccc(Nc2ncnc(Cl)c2C)cc1

Procedure:
Synthesized according to the method of reagent preparation 49 using 6-chloro-5-methylpyrimidin-4-ol and 4-methoxyaniline in step 1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[N:34]1([CH2:40][CH2:41][CH2:42][C:43]2[CH:44]=[C:45]([NH2:49])[CH:46]=[CH:47][CH:48]=2)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[C:24]([NH:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:49][C:45]4[CH:46]=[CH:47][CH:48]=[C:43]([CH2:42][CH2:41][CH2:40][N:34]5[CH2:35][CH2:36][O:37][CH2:38][CH2:39]5)[CH:44]=4)[N:7]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH:18]=1)=[O:33]
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: Nc1cccc(CCCN2CCOCC2)c1
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(CCCN4CCOCC4)c3)n2)c1)c1c(F)cccc1F

Procedure:
N-{3-[3-(2-Chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and {3-[3-(4-morpholinyl)propyl]phenyl}amine were reacted in a manner analogous to Example 27, Step D, to give the title compound. MS (ESI): M+H=646.27.
Reaction SMILES: [CH2:1]([N:4]([CH2:10][CH2:11][CH3:12])[CH2:5][CH2:6][CH2:7][CH2:8][NH2:9])[CH2:2][CH3:3].C(OC)(OC)OC.[C:20]([O:24][C:25](=[O:36])[NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]=O)=[CH:30][CH:29]=1)([CH3:23])([CH3:22])[CH3:21].[BH4-].[Na+]>CO>[C:20]([O:24][C:25](=[O:36])[NH:26][CH2:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][NH:9][CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH2:10][CH2:11][CH3:12])=[CH:32][CH:33]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CCCN(CCC)CCCCN
Reactant: CC(C)(C)OC(=O)NCc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: CCCN(CCC)CCCCNCc1ccc(CNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
The compound (9.25 g) obtained in Example 1-2 was dissolved in anhydrous methanol (200 ml) and then added with trimethyl orthoformate (8.81 ml) and the compound (12.6 g) obtained in Example 23-3. The whole was stirred at room temperature for 1.5 hours under a nitrogen atmosphere. Then, sodium borohydride (2.03 g) was added thereto in an ice bath and the whole was stirred at room temperature for 2 hours. After completion of the reaction, distilled water was added thereto and the whole was stirred for a while. The solution was subjected to extraction with chloroform and washed with a saturated saline solution. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off, thereby obtaining the subject compound (19.3 g) as a colorless oily substance.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].Cl[CH2:7][C:8]([CH3:10])=[CH2:9].[OH-].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([N:3]([CH2:4][CH3:5])[CH2:7][C:8]([CH3:10])=[CH2:9])[CH3:2]
Reactant: C=C(C)CCl
Reactant: CCNCC
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: C=C(C)CN(CC)CC

Procedure:
54.86 g (0.75 mol) of diethylamine and 45.28 g (0.50 mol) of 1-chloro-2-methyl-2-propene were dissolved in chloroform (100.14 g), 20.0 g of sodium hydroxide was added, and the system was allowed to react for 15 hours at 70° C. Upon completion of the reaction, the chloroform solution was washed with a sodium carbonate aqueous solution to remove the unreacted diethylamine, diethylamine hydrochloride, and sodium hydroxide, which yielded a chloroform solution of N,N-diethyl-2-methyl-2-propene-1-amine. 150 g of a 4 N hydrochloric acid aqueous solution was added to the chloroform solution, the N,N-diethyl-2-methyl-2-propene-1-amine was converted into a hydrochloride and extracted from the aqueous phase, and the water was removed by freeze drying, which yielded 60.57 g (0.37 mol; 74% yield) of 2-propene-1-aminium, N,N-diethyl-2-methyl, hydrochloride in the form of a white powder. The structure of the 2-propene-1-aminium, N,N-diethyl-2-methyl, hydrochloride thus obtained was confirmed by 1H-NMR (400 MHz)