Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][C@H:5]1[NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[N+]=[N-].[BH4-].[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.CO.O.O.[Ni](Cl)Cl>[NH2:1][C@@H:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][C@H:5]1[NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N=[N+]=[N-])[C@H](NC(=O)OCc2ccccc2)C1
Agent: Cl[Ni]Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl trans(±)-4-azido-3-{[(benzyloxy)carbonyl]amino}piperidine-1-carboxylate obtained in Example (79b) (265.6 mg, 0.71 mmol) was dissolved in THF (6 mL) and methanol (3 mL). Nickel chloride dihydrate (345 mg, 1.42 mmol) and sodium borohydride (117 mg, 2.85 mmol) were added under ice-cooling, and the mixture was heated to room temperature and stirred for 30 minutes. Saturated aqueous sodium bicarbonate solution was added to the reaction solution, followed by filtration through celite and extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting compound was used for the next reaction without purification.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([O:11][C:12]1[N:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH:27]([NH2:29])[CH3:28])=[CH:21][CH:20]=2)=[CH:14][CH:13]=1)([CH3:10])[CH3:9].Cl[C:31]([O:33][CH3:34])=[O:32]>>[CH:8]([O:11][C:12]1[N:17]=[CH:16][C:15]([O:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][CH:27]([NH:29][C:31](=[O:32])[O:33][CH3:34])[CH3:28])=[CH:23][CH:24]=2)=[CH:14][CH:13]=1)([CH3:10])[CH3:9]
Reactant: CC(N)CCc1ccc(Oc2ccc(OC(C)C)nc2)cc1
Reactant: COC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)NC(C)CCc1ccc(Oc2ccc(OC(C)C)nc2)cc1

Procedure:
3-[4-(6-Isopropoxypyridin-3-yloxy)phenyl]-1-methylpropylamine trifluoroacetate (115 mg, 0.28 mmol) was reacted with methyl chloroformate in analogy to example 44. Yield: 48 mg (48%), M+H+: 359.13.
Reaction SMILES: Br[CH2:2][C:3]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:4]=1[C:5]([O:7]CC)=O.[CH:15]([C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)([CH3:17])[CH3:16].[O-]CC.[Na+]>C(O)C>[Cl:14][C:11]1[CH:10]=[C:4]2[C:3]([CH2:2][N:22]([C:21]3[CH:23]=[CH:24][C:18]([CH:15]([CH3:17])[CH3:16])=[CH:19][CH:20]=3)[C:5]2=[O:7])=[CH:13][CH:12]=1
Reactant: CC(C)c1ccc(N)cc1
Reactant: CCOC(=O)c1cc(Cl)ccc1CBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)c1ccc(N2Cc3ccc(Cl)cc3C2=O)cc1
Temperature: 25 °C
Yield: 53.1 %

Procedure:
A mixture of ethyl 2-(bromomethyl)-5-chlorobenzoate (0.553 g, 1.99 mmol), 4-isopropylaniline (0.269 g, 1.99 mmol) and sodium ethoxide (0.406 g, 5.97 mmol) in ethanol (40 mL) was heated at reflux overnight. After this time, the mixture was cooled to room temperature and concentrated under vacuum. The mixture was partitioned between 1 N HCl and ethyl acetate. The organic layer was separated, washed with 1 N HCl, then with 1:1 water/brine solution, dried over sodium sulfate and filtered. Concentration under vacuum and recrystallization from ethyl acetate afforded 6-chloro-2-(4-isopropylphenyl)isoindolin-1-one (0.302 g, 53%) as an off-white solid: m.p. 206-209° C.; 1H NMR (500 MHz, CDCl3) δ 7.89 (d, J=1.9 Hz, 1H), 7.73 (dt, J=8.6, 2.7 Hz, 2H), 7.55 (dd, J=8.1, 1.9 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.30 (dt, J=8.5, 2.5 Hz, 2H), 4.83 (s, 2H), 2.96-2.90 (m, 1H), 1.26 (d, 6H); ESI MS m/z 286 [M+H]+.
Reaction SMILES: [CH2:1]([CH:3]1[N:7]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([O:16][CH3:17])[CH:9]=2)[C:6](=[O:18])[C:5]([CH3:20])([CH3:19])[C:4]1=[O:21])[CH3:2].C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].C1COCC1>>[CH2:1]([C@H:3]1[N:7]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([O:16][CH3:17])[CH:9]=2)[C:6](=[O:18])[C:5]([CH3:20])([CH3:19])[C@H:4]1[OH:21])[CH3:2]
Reactant: CCC1C(=O)C(C)(C)C(=O)N1c1ccc(C#N)c(OC)c1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@@H]1[C@H](O)C(C)(C)C(=O)N1c1ccc(C#N)c(OC)c1

Procedure:
Using 4-(5-ethyl-3,3-dimethyl-2,4-dioxopyrrolidin-1-yl)-2-methoxybenzonitrile (120 mg) and lithium tri(sec-butyl)borohydride-THF solution (0.629 mL, 1 mol/L), and in the same manner as in Example 5, the title compound was obtained as a colorless solid (yield: 93 mg, 77%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[Li+].CC([N-]C(C)C)C.I[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1.[Cl-].[NH4+].[Cl-].[Cl-].[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Brc1ccncc1
Reactant: Ic1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Solvent: C1CCOC1
Product: Brc1ccncc1-c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 153.7 %

Procedure:
4-bromopyridine hydrochloride (1-BA-2, 1 g, 5.14 mmol) was dissolved in 5.1 mL of THF and the resulting solution was cooled to −78° C. LDA (10.28 mL of a 1 M solution in THF) was added over 10 minutes and the reaction mixture became brown. After stirring for 30 minutes, ZnCl2 (10.3 mL of a 0.5 M solution in THF) was added over 10 minutes and the resulting mixture was stirred for 10 minutes and then allowed to warm to rt. Iodobenzene (0.229 mL, 2.06 mmol) and Pd(PPh3)4 (593 mg, 0.514 mmol) were added and the resulting mixture was stirred under reflux for 2 h. The reaction mixture was diluted with aqueous saturated ammonium chloride and extracted with ethyl acetate. The organic phase was dried over Na2SO4 and evaporated. The residue was purified by silica column (hexane:EtOAc) to give 4-bromo-3-phenylpyridine (2-BA-2, 741 mg, 62%); LCMS: 234.0 m/z (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]=[C:14]=[O:15])([CH3:3])[CH3:2].[NH2:16][C@H:17]([C:19]([NH:21][C@H:22]1[N:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:26]2[CH:35]=[CH:36][CH:37]=[CH:38][C:25]=2[N:24]([CH3:39])[C:23]1=[O:40])=[O:20])[CH3:18]>>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:11])[CH3:12])[C:5]=1[NH:13][C:14]([NH:16][C@H:17]([C:19]([NH:21][CH:22]1[N:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:26]2[CH:35]=[CH:36][CH:37]=[CH:38][C:25]=2[N:24]([CH3:39])[C:23]1=[O:40])=[O:20])[CH3:18])=[O:15])([CH3:2])[CH3:3]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: C[C@H](N)C(=O)N[C@H]1N=C(c2ccccc2)c2ccccc2N(C)C1=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)N[C@@H](C)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O

Procedure:
Following General Procedure (5-A1) using 2,6-diisopropylphenyl isocyanate and (S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one, as described in Example 8-B above, the title compound was prepared. The molecular weight as determined by mass spectrometry (FD) was: 539 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[N+:21]([O-])=O.[C:24]1([CH2:30][CH:31]=O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:30]([C:31]1[NH:1][C:2]2=[N:7][C:6]([N:8]3[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([N:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)=[O:15])[CH2:9]3)=[CH:5][CH:4]=[C:3]2[N:21]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ccc1[N+](=O)[O-]
Reactant: O=CCc1ccccc1
Product: O=C([C@@H]1CCCN(c2ccc3nc(Cc4ccccc4)[nH]c3n2)C1)N1CCCC1

Procedure:
(R)-(1-(2-Benzyl-3H-imidazo[4,5-b]pyridin-5-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone was prepared by a method analogous to the one used for Example 163, Step 1 at a temperature of 120° C. using (R)-(1-(6-amino-5-nitropyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone and 2-phenylacetaldehyde. MS (ES+APCI) (M+H) 390.1; LCMS retention time 3.859 min (Method I).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:15])[CH2:12][CH2:13]Cl)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]>S(=O)(=O)(O)O>[CH2:1]([C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][CH:6]=1)[C:11](=[O:15])[CH2:12][CH2:13]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C(=O)CCCl)cc1
Agent: O=S(=O)(O)O
Product: CCCCc1ccc2c(c1)CCC2=O
Temperature: 25 °C

Procedure:
A solution of 1-(4-n-butylphenyl)-3-chloropropan-1-one (17.88 g, 79.8 mmol) in concentrated sulphuric acid (69 ml) is heated at 90° C. for 4 hours. After cooling to ambient temperature, the reaction mixture is poured on to ice and extracted with toluene. The combined organic phases are washed with saturated NaHCO3, brine, dried (MgSO4) and evaporated to afford the title compound. NMR δH 0.85 (t J 7.3 3H), 1.28 (sextet J 7.3 2H), 1.56 (quintet J 7.3 2H), 2.6 (m 4H), 3.02 (t J 5 2H), 7.10 (d J 8.3 1H), 7.20 (s 11H), 7.60 (d J 8.3 2H)
Reaction SMILES: [F:1][C:2]1[N:9]=[C:8](F)[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].C(N(CC)CC)C.[CH3:19][C:20]1[NH:24][N:23]=[C:22]([NH2:25])[CH:21]=1>C(#N)C>[F:1][C:2]1[N:9]=[C:8]([NH:25][C:22]2[CH:21]=[C:20]([CH3:19])[NH:24][N:23]=2)[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1cc(N)n[nH]1
Reactant: N#Cc1cc(F)c(F)nc1F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(Nc2nc(F)c(C#N)cc2F)n[nH]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 29.7 %

Procedure:
To a solution of 2,5,6-trifluoronicotinonitrile (1.0 g, 6.3 mmol) and triethylamine (0.83 g, 8.2 mmol) in ACN (30 ml) at 0° C. was added 5-methyl-1H-pyrazol-3-amine (0.67 g, 6.9 mmol). The reaction was stirred at 0° C. for 1 hour, at which point the reaction was filtered. The resulting solid was washed with cold ACN, dried and collected to give the title compound (0.44 g, 29%). MS: Calcd.: 235. Found: [M+H]+ 236.
Reaction SMILES: CN(C)S([N:6]1[C:10]([C:11](=[O:13])[CH3:12])=[CH:9][C:8]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:7]1)(=O)=O.C([O-])(O)=O.[Na+]>Cl.CO>[O:15]([CH2:14][C:8]1[CH:9]=[C:10]([C:11](=[O:13])[CH3:12])[NH:6][N:7]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)c1cc(COc2ccccc2)nn1S(=O)(=O)N(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(=O)c1cc(COc2ccccc2)n[nH]1
Temperature: 65 °C
Reaction time: 24 h
Yield: 79.5 %

Procedure:
5-Acetyl-3-phenoxymethyl-pyrazole-1-sulfonic acid dimethylamide (0.1 g, 0.32 mmol) was dissolved in a 1.25M solution of HCl in methanol (3.79 mL) in a sealed tube and under nitrogen. The mixture was stirred at 65° C. for 24 hours, then basified with a saturated solution of NaHCO3 and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 40/60). The desired fractions were collected and the solvents evaporated in vacuo to yield 1-(5-phenoxymethyl-2H-pyrazol-3-yl)-ethanone (55 mg, 81% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([O:16]C)=[O:15])=[C:10]([CH2:18][N:19]2[C:23](=[O:24])[N:22]([CH2:25][CH:26]([OH:31])[C:27]([F:30])([F:29])[F:28])[C:21]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)=[N:20]2)[CH:9]=1.[OH-].[Li+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[C:10]([CH2:18][N:19]2[C:23](=[O:24])[N:22]([CH2:25][CH:26]([OH:31])[C:27]([F:28])([F:29])[F:30])[C:21]([C:32]3[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=3)=[N:20]2)[CH:9]=1
Reactant: COC(=O)c1ccc(-c2ccccc2Cl)cc1Cn1nc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccccc2Cl)cc1Cn1nc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
204 mg (0.36 mmol) of the compound from Example 129 were dissolved in 3 ml of THF, and 0.4 ml of a 1 N aqueous lithium hydroxide solution was added. The mixture was stirred at RT for 20 h. For work-up, the solvent was removed under reduced pressure, the residue was taken up in about 5 ml of water and 0.07 ml of 6 N hydrochloric acid was added. The precipitated solid was filtered off with suction and dried. Further purification of the crude product was carried out by chromatography on silica gel (mobile phase: first cyclohexane/ethyl acetate 1:3, then pure ethyl acetate, finally dichloromethane/methanol 1:1). This gave 97 mg (47% of theory) of the target compound.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:7]=2[CH:8]=1)([OH:3])=[O:2].OS(O)(=O)=O.[CH3:21]O>>[CH3:21][O:2][C:1]([C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:7]=2[CH:8]=1)=[O:3]
Reactant: CO
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2o1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc2cc([N+](=O)[O-])ccc2o1
Temperature: 60 °C

Procedure:
A mixture of 2-carboxy-5-nitrobenzofuran (2.0 g), MeOH (10 mL) and Concentrated H2SO4 (2.1 mL) was heated in a sealed tube at 60° C. for 3 h. Upon cooling to the room temperature it was quenched with ice-water and carefully basified with addition of NaHCO3. The solid obtained was filtered, washed with water, dried and analyzed to give 2-methoxycarbonyl-5-nitrobenzofuran. 1H NMR (CDCl3): δ 8.66 (d, 1H, J=2.4 Hz), 8.36 (dd, 1H, J=2.4 and 9.6 Hz), 7.71 (d, 1H, J=9.3 Hz), 7.65 (s, 1H), 4.01 (s, 3H); LCMS: purity: 97%; MS (m/e): 222 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:15])[C:12]([OH:14])=[O:13].[C:21](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:15])[C:12]([O:14][CH3:21])=[O:13]
Reactant: O=C(O)C(=O)c1ccccc1Nc1c(Cl)cccc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)C(=O)c1ccccc1Nc1c(Cl)cccc1Cl
Yield: 94.9 %

Procedure:
To a solution of 12.4 g of 2-(2,6-dichloroanilino)-phenylglyoxylic acid in 80 ml of anhydrous acetone were added 6.05 g of anhydrous potassium carbonate and then 7.5 ml of dimethyl sulfate at room temperature, and the mixture was stirred for 1 hour. The reaction mixture was filtered and washed with anhydrous acetone. The filtrate was concentrated under 10 mmHg without heating. The residue was recrystallized from ethanol to give 12.3 g of methyl 2-(2,6-dichloroanilino)phenylglyoxylate as yellow prisms. m.p. 124.5-125.5° C. Yield: 95% of theoretical amount
Reaction SMILES: Br[C:2]1[C:3]2[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=2[S:5][C:6]=1[CH2:7][CH2:8][N:9]([CH3:11])[CH3:10].CN(CCN(C)C)C.[Li]CCCC.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH:35]=[O:36]>C1(C)C=CC=CC=1>[CH3:10][N:9]([CH3:11])[CH2:8][CH2:7][C:6]1[S:5][C:4]2[CH:12]=[CH:13][CH:14]=[CH:15][C:3]=2[C:2]=1[CH:35]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=1)[OH:36]
Reactant: CN(C)CCc1sc2ccccc2c1Br
Reactant: O=Cc1ccccn1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CN(C)CCc1sc2ccccc2c1C(O)c1ccccn1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 82.4 %

Procedure:
To a cooled (−78° C.) solution of [2-(3-bromo-benzo[b]thiophen-2-yl)-ethyl]-dimethyl-amine (800 mg, 2.8 mmol) in anhydrous toluene (30 mL), TMEDA (420 uL, 2.8 mmol) was added followed by nBuLi (2.1 mL, 2.6 mmol, 1.6M in hexanes). The mixture was stirred for 40 min at −78° C. and pyridine-2-carbaldehyde (800 uL, 8.4 mmol) was added. The mixture was stirred for 6 hrs during which the temperature reached 0° C., quenched with sat NH4Cl/NaHCO3 and extracted with EtOAc (3×). The combined organic layers were dried (Na2SO4), concentrated and purified by silical gel column chromatography (gradient of DCM/MeOH=98/2 up to 94/6) to afford [2-(2-dimethylamino-ethyl)-benzo[b]thiophen-3-yl]-pyridin-2-yl-methanol (Compound 13-1) (721 mg) in 82% yield. MH+=313.0, tR=2.49 min (Method 2).
Reaction SMILES: [C:1]([C:4]1[NH:5][C:6](=[O:9])[S:7][CH:8]=1)(O)=[O:2].S(Cl)([Cl:12])=O>>[Cl:12][C:1]([C:4]1[NH:5][C:6](=[O:9])[S:7][CH:8]=1)=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1csc(=O)[nH]1
Product: O=C(Cl)c1csc(=O)[nH]1

Procedure:
A mixture of 29 g of 4-carboxy-4-thiazoline-2-one [Enlenmeyer et al, Helv., Chim. Acta., Vol. 27 (1944), p.1432-6] and 200 ml of thionyl chloride was refluxed for 24 hours and was then cooled. The mixture was vacuum filtered to obtain 21 g of 4-chloroformyl-4-thiazoline-2-one melting at 184°C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:28])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]1([CH2:37][CH2:38][CH2:39]Br)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:39][CH2:38][CH2:37][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:18]1=[O:28])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCCc1ccccc1
Reactant: CC(C)(CC(=O)NC1CCc2ccccc2NC1=O)NC(=O)OCc1ccccc1
Product: CC(C)(CC(=O)NC1CCc2ccccc2N(CCCc2ccccc2)C1=O)NC(=O)OCc1ccccc1

Procedure:
Prepared from 3-benzyloxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3-yl]-butanamide (Example 51, Step A) and 3-phenylpropyl bromide by the procedure described in Example 3, Step A. 1H NMR (200 MHz, CDCl3): 1.38 (s,6H), 1.82 (m,4H), 2.4-2.9 (m,7H), 3.45 (m,1H), 4.36 (m,1H), 5.02 (s,2H), 5.64 (s,1H), 6.69 (d,8 Hz,1H), 6.9-7.4 (m,14H). FAB-MS: calculated for C32H37N3O4 527; found 528 (M+H,100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH2:12][CH2:13][NH:14][CH2:15][CH:7]1[C:6](=[O:16])[NH:5]2.[CH:17]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)=[CH2:18]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH2:12][CH2:13][N:14]([CH2:18][CH2:17][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH2:15][CH:7]1[C:6](=[O:16])[NH:5]2
Reactant: C=Cc1ccncc1
Reactant: O=C1Nc2cc(F)ccc2N2CCNCC12
Product: O=C1Nc2cc(F)ccc2N2CCN(CCc3ccncc3)CC12

Procedure:
Treating 2.3 g. of 8-fluoro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxaline-5(6H)-one with 9.0 g. of 4-vinylpyridine in the manner shown in Example 1, there was obtained 1.5 g. of the title compound as the dihydrochloride salt, m.p. 230°-233° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](Br)=[CH:7][CH2:8][N+:9]([O-:17])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.C(NCC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:45][N:46]([CH3:50])[CH2:47][C:48]#[CH:49]>[Pd](Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([C:49]#[C:48][CH2:47][N:46]([CH3:50])[CH3:45])=[CH:7][CH2:8][N+:9]([O-:17])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: [O-][N+]1=C(c2ccccc2)c2cc(Cl)ccc2C(Br)=CC1
Reactant: C#CCN(C)C
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CN(C)CC#CC1=CC[N+]([O-])=C(c2ccccc2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 3.5 g (10 mmole) of 8-chloro-5-bromo-1-phenyl-3H-2-benzazepine-2-oxide, 40 ml of 98% diethylamine, 40 ml of dimethylformamide, 44.3 mg (0.25 mmole) of palladium chloride, 131.2 mg (0.5 mmole) of triphenylphosphine, 47.6 mg (0.25 mmole) of cuprous iodide and 16 ml of 1-dimethylamino-2-propyne was stirred at room temperature under nitrogen for 24 hr. The mixture was concentrated at reduced pressure to dryness. An ether solution of the residue containing petroleum ether was washed with water followed by dilute cold hydrochloric acid. The aqueous solution was separated, made alkaline with dilute cold sodium hydroxide and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. The residue crystallized from a mixture of ether and petroleum ether to give a tan solid, mp 121°-123° C. Recrystallization from ether gave tan prisms, mp 124°-125° C.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[S:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[N:10][C:9]=2[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=2)[CH:5]=[CH:4][N:3]=1.[C:30]1([SH:36])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])O.[Na+]>>[CH3:29][C:25]1[CH:24]=[C:23]([C:9]2[N:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([S:36][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:7]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: Sc1ccccc1
Reactant: Cc1cccc(-c2nc(-c3ccc(S(C)(=O)=O)cc3)sc2-c2ccnc(F)c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cccc(-c2nc(-c3ccc(S(C)(=O)=O)cc3)sc2-c2ccnc(Sc3ccccc3)c2)c1
Temperature: 150 °C
Reaction time: 10 h
Yield: 70.3 %

Procedure:
A mixture of 5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazole (0.40 g, 0.94 mmol) and thiophenol (1.0 mL, 9.7 mmol) was stirred at 150° C. for 10 hours. After the reaction mixture was cooled to room temperature, a saturated aqueous solution of sodium hydrogencarbonate was added, the resulting mixture was extracted with ethyl acetate and washed with water. This extract was dried and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate, 1:1) and recrystallized from ethanol to obtain 0.34 g (yield 70%) of the title compound.
Reaction SMILES: [F:1][CH2:2][C:3]([C:7]1[O:11][N:10]=[C:9]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)[CH:8]=1)([CH3:6])[CH2:4][F:5].[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[O:34][CH2:35][CH2:36][O:37][CH3:38])[N:30]=[CH:29][N:28]=[C:27]2[O:39][C:40]1[CH:41]=[C:42]([CH:44]=[CH:45][CH:46]=1)[NH2:43]>CN(C)C1C=CN=CC=1.C1COCC1>[F:5][CH2:4][C:3]([C:7]1[O:11][N:10]=[C:9]([NH:12][C:13]([NH:43][C:42]2[CH:44]=[CH:45][CH:46]=[C:40]([O:39][C:27]3[C:26]4[C:31](=[CH:32][C:33]([O:34][CH2:35][CH2:36][O:37][CH3:38])=[C:24]([O:23][CH3:22])[CH:25]=4)[N:30]=[CH:29][N:28]=3)[CH:41]=2)=[O:21])[CH:8]=1)([CH3:6])[CH2:2][F:1]
Reactant: CC(CF)(CF)c1cc(NC(=O)Oc2ccccc2)no1
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(CF)CF)on4)c3)c2cc1OC
Yield: 37 %

Procedure:
The title compound was prepared as described in Example 162B, using phenyl 5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate as described in Example 162A (0.089 g, 0.3 mmol), 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (0.102 g, 0.3 mmol), and 4-(dimethylamino)pyridine (0.03 g) in THF (6 mL), to afford 1-[5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl]-3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}urea as solid (0.061 g, 37%). 1H NMR (300 MHz, DMSO-d6) δ 9.71 (s, 1H), 9.01 (s, 1H), 8.56 (s, 1H), 7.58 (m, 2H), 7.42 (m, 2H), 7.27 (d, 1H), 6.98 (d, 1H), 6.77 (s, 1H), 4.71 (s, 2H), 4.56 (s, 2H), 4.35 (m, 2H), 3.99 (s, 3H), 3.77 (m, 2H), 3.56 (s 3H), 1.28 (s, 3H); LC-MS (ESI) m/z 544 (M+H)+.