Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C[CH2:4][O:5][C:6]([CH:8](P(OCC)(OCC)=O)[CH3:9])=[O:7].[C:18]([N:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C1COCC1>[CH3:4][O:5][C:6](=[O:7])[C:8](=[C:28]1[CH2:29][CH2:30][N:25]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:26][CH2:27]1)[CH3:9]
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C)=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 60% NaH (2.005 g; 50.00 mmol) in anhydrous THF (100 mL), under an atmosphere of argon, was added triethyl 2-phosphonopropionate (10.73 mL; 50.00 mmol), at such a rate as to keep the reaction temperature below 30° C. The resulting mixture was stirred at room temperature for a further 1 hr. A solution of N-Boc-4-piperidone (9.965 g; 50.00 mmol), in anhydrous THF (50 mL), was added dropwise over five minutes. The resulting clear solution was stirred at ambient temperature for ˜1 hr. The reaction was quenched by the addition of water (100 mL). The resulting mixture was partitioned, the aq layer extracted once with EtOAc and the combined organics washed with saturated brine. The organics were dried over MgSO4, filtered and evaporated to a colourless oil; 14.76 g. (˜quantitative yield). This was used in the next stage without further purification. 1H NMR δ 1.19 (t, 3H), 1.36 (s, 9H), 1.77 (s, 3H), 2.25-2.37 (m, 2H), 2.51-2.56 (m, 2H), 3.22-3.44 (m, 4H), 4.11 (q, 2H). MS m/e [MH—(CO2, C4H8)]+=184.31.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[C:18]([S:24][CH2:25][CH3:26])[CH:17]=1.S(=O)(O)[O-].[Na+].C(=O)(O)[O-].[Na+]>O.CC(N(C)C)=O>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([C:11]([F:12])([F:13])[F:14])=[CH:8][CH:7]=3)[N:1]=2)=[C:18]([S:24][CH2:25][CH3:26])[CH:17]=1
Reactant: CCSc1cc(Cl)ccc1C=O
Reactant: NC(=O)c1ccc(C(F)(F)F)cc1N
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCSc1cc(Cl)ccc1-c1nc2cc(C(F)(F)F)ccc2c(=O)[nH]1
Temperature: 150 °C
Reaction time: 15 h
Yield: 80.7 %

Procedure:
A mixture of 1.0 g of 2-amino-4-trifluromethylbenzamide, 944 mg of 4-chloro-2-ethylsulfanylbenzaldehyde, 765 mg of sodium bisulfite and 4 ml of DMA was stirred at 150° C. for 15 hours. A saturated aqueous sodium bicarbonate solution and water were added to the cooled reaction mixture, and the precipitated solid was filtered. The resulting solid was washed with water and n-hexane and then dried to obtain 1.46 g of 2-(4-chloro-2-ethylsulfanylphenyl)-7-trifluoromethyl-3H-quinazolin-4-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:28]#[N:29])[C:9]2[CH:14]=[CH:13][C:12]([N:15]3[C:20](=[O:21])[NH:19][C:18](=[O:22])[C:17](C(O)=O)=[N:16]3)=[CH:11][C:10]=2OC)=[CH:4][CH:3]=1.SC[C:32](O)=[O:33]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[C:20](=[O:21])[NH:19][C:18](=[O:22])[CH:17]=[N:16]3)=[C:13]([O:33][CH3:32])[CH:14]=2)[C:28]#[N:29])=[CH:4][CH:3]=1
Reactant: O=C(O)CS
Reactant: COc1cc(-n2nc(C(=O)O)c(=O)[nH]c2=O)ccc1C(C#N)c1ccc(Cl)cc1
Solvent: O
Product: COc1cc(C(C#N)c2ccc(Cl)cc2)ccc1-n1ncc(=O)[nH]c1=O
Temperature: 175 °C

Procedure:
A mixture of 4.2 parts of 2-[4-[(4-chlorophenyl)cyanomethyl]3-methoxyphenyl]-2,3,4,5-tetrahydro-3,5-dioxo-1,2,4-triazine-6-carboxylic acid and 13 parts of 2-mercaptoacetic acid is stirred and heated for 2 hours at 175° C. After cooling, 150 parts of water are added. The aqueous phase is decanted and the remaining oil is stirred in water. The whole is treated with sodium hydrogen carbonate. The product is extracted with a mixture of trichloromethane and methanol (90:10 by volume). The extract is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions are collected and the eluent is evaporated in vacuo. The residue is crystallized from 8 parts of acetonitrile. The product is filtered off, washed with 2,2'-oxybispropane and dried, yielding α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-3-methoxybenzeneacetonitrile (intermediate 2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7](O)=[O:8].Cl.[CH3:14][NH:15][O:16][CH3:17].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]([N:15]([O:16][CH3:17])[CH3:14])=[O:8])[CH:10]=[CH:11][CH:12]=1
Reactant: O=C(O)C=Cc1cccc(Br)c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C=Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.4 %

Procedure:
3-Bromocinnamic acid (15.3 g, 67.3 mmol), N,O-dimethylhydroxylamine hydrochloride (7.9 g, 80.8 mmol), HOBT (18.2 g, 134.7 mmol), EDAC (25.8 g, 134.7 mmol) and triethylamine (18.7 mL, 134.68 mmol) were added to dichloromethane (500.0 mL). The reaction mixture was stirred at room temperature for 16 hours, quenched with a saturated solution of ammonium chloride, and then extracted with dichloromethane three times. The combined extract was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3) to give 14.8 g of the titled compound as a yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([OH:11])[CH:3]=1.[C:12]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
To a solution of 4-fluoro-2-hydroxy-1-nitrobenzene (5.0 g, 31.8 mmol) in DMF (10 mL) was added K2CO3 (13.1 g, 95.4 mmol). The reaction mixture was stirred at RT for 1 h followed by addition of methyl iodide (9.93 g, 69.9 mmol) and the reaction mixture was stirred at 60° C. for 2 h. The reaction mass was concentrated and quenched in water. The reaction mass was basified with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 4.5 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.93 (s, 3H), 6.97 (t, J=7.8 Hz, 1H), 7.31 (d, J=8.7 Hz, 1H), 8.02 (s, 1H).
Reaction SMILES: [C:1](OC(OCC)OCC)(=O)C.[CH3:12][C:13]([NH:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]2[N:27]=[N:28][N:29]=[C:19]2[C:18]=1[NH2:30])([CH3:15])[CH3:14].[OH-].[Na+]>C(O)(=O)C>[CH3:15][C:13]([N:16]1[C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]3[N:27]=[N:28][N:29]=[C:19]3[C:18]=2[N:30]=[CH:1]1)([CH3:12])[CH3:14]
Reactant: CC(C)(C)Nc1c(N)c2nnnn2c2ccccc12
Reactant: CCOC(OCC)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(C)(C)n1cnc2c1c1ccccc1n1nnnc21

Procedure:
Diethoxymethyl acetate (1.9 mL) was added dropwise to a solution of N5-(1,1-dimethylethyl)tetrazolo[1,5-a]quinoline-4,5-diamine (1.5 g, 5.9 mmole, Example 19) in acetic acid (15 mL). The reaction mixture was heated on a steam bath for 1 hour then made basic with sodium hydroxide. The resulting precipitate was isolated by filtration then recrystallized from ethanol to provide 6-(1,1-dimethylethyl)-6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline, m.p. 224-226° C. Analysis: Calculated for C14H14N6: %C, 63.13; %H, 5.29; %N, 31.56; Found: %C, 62.90; %H, 5.44; %N, 11.52.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([OH:10])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[K+].[CH3:13][N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1>CO>[CH3:13][N:14]1[CH2:15][CH:16]=[C:17]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[C:6]([OH:10])[CH:5]=3)[NH:1][CH:2]=2)[CH2:18][CH2:19]1
Reactant: CN1CCC(=O)CC1
Reactant: Oc1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN1CC=C(c2c[nH]c3ccc(O)cc23)CC1
Temperature: 70 °C
Yield: 66.5 %

Procedure:
To a solution of 1H-indol-5-ol (18.60 g, 0.14 mol) in methanol (250 ml), stirring at room temperature under nitrogen, was slowly added potassium hydroxide (31.4 g, 0.56 mol) in methanol (100 mL). 1-methyl-4-piperidone (29.0 mL, 0.24 mol) was added dropwise to the black solution. The reaction mixture was heated at 70° C. for 8 hours, cooled to room temperature, concentrated in vacuo. The resulting residue was directly purified on silica gel. Elution with a 9:1 mixture of dichloromethane and 7 N ammonia in methanol provided 21.25 g (62%) of the title compound as a tan solid: mp=182-185° C.; 1H NMR (400 MHz, dmso-d6): 10.78 (br s, 1H), 8.64 (s, 1H), 7.22 (d, 1H, J=2.4 Hz), 7.13 (d, 1H, J=8.8 Hz), 7.10 (d, 1H, J=1.6 Hz), 6.59 (dd, 1H, J=8.8, 1.2 Hz), 5.94 (br s, 1H), 3.02-2.98 (m, 2H), 2.52 (br t, 2H, J=5.6 Hz), 2.48-2.42 (m, 2H), 2.24 (s, 3H); MS (APCI): m/e 229.1 (M+1).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)[C:4]([CH3:6])=[O:5].[C:16]([O:22][CH2:23]Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>C(#N)C>[C:16]([O:22][CH2:23][O:12][C:11]([C:10]1[CH:14]=[CH:15][C:7]([CH2:3][C:4](=[O:5])[CH3:6])=[CH:8][CH:9]=1)=[O:13])(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CC(=O)Cc1ccc(C(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)Cc1ccc(C(=O)OCOC(=O)C(C)(C)C)cc1

Procedure:
Sodium hydride (0.48 g) was added to 4-acetonylbenzoic acid (3.56 g) in acetonitrile and the solution refluxed for 1/2 hour. Chloromethyl pivalate (3.02 g) was then added and the mixture refluxed for 22 hours. Acetonitrile was removed, the residue partitioned between ether and water and the organic layer separated and washed with sodium bicarbonate solution (x2). The ether layer was dried (MgSO4) and evaporated to give the title compound which was crystallised and recrystallised from hexane. τ (CDCl3) 8.77 (9H, s), 7.82 (3H, s), 6.25 (2H, s), 4.02 (2H, s), 2.73 (2H, d, J=9 Hz), 1.96 (2H, d, J=9 Hz).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[C:7]1([S:13]([C:16]2[C:17]([S:27][CH3:28])=[N:18][N:19]3[C:24](Cl)=[CH:23][C:22]([CH3:26])=[N:21][C:20]=23)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CN(C=O)C>[C:7]1([S:13]([C:16]2[C:17]([S:27][CH3:28])=[N:18][N:19]3[C:24]([NH:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])=[CH:23][C:22]([CH3:26])=[N:21][C:20]=23)(=[O:15])=[O:14])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccccc1
Reactant: CN(C)CCN
Solvent: CN(C)C=O
Product: CSc1nn2c(NCCN(C)C)cc(C)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 113.4 %

Procedure:
0.088 g (1 mmol) of 2-dimethylaminoethylamine was added to a solution of 0.17 g (0.5 mmol) of 3-benzenesulphonyl-7-chloro-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine in 3 ml of DMF and stirred at 60° for 2 hrs. The reaction solution was cooled to RT and evaporated in a high vacuum. The residue was partitioned between 2N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2, and the combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (SiO2, CH2Cl2/MeOH 19:1) and crystallization from EtOH yielded 0.23 g (73%) of N-(3-benzenesulphonyl-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-yl)-N′,N′-dimethyl-ethane-1,2-diamine as colorless crystals, m.p. 190-191°.
Reaction SMILES: [NH:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH2:5][N:4]=1)[NH2:2].Cl.[CH3:18][C:19]([CH3:21])=O>>[C:19](=[N:2][NH:1][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH2:5][N:4]=1)([CH3:21])[CH3:18]
Reactant: CC(C)=O
Reactant: COc1cc2c(cc1OC)C(NN)=NCC2
Agent: Cl
Product: COc1cc2c(cc1OC)C(NN=C(C)C)=NCC2

Procedure:
In a manner similar to that of Example 25, condensation of 1-hydrazino-6,7-dimethoxy-3,4-dihydroisoquinoline (7.0 g.) and acetone (100 ml.) and treatment of the reaction mixture with hydrochloric acid afforded 1-(2-isopropylidenehydrazino)-6,7-dimethoxy-3,4-dihydroisoquinoline (I: X = X' = CH3, Y = Y' = H, Z = Z' = CH3O) hydrochloride (7.55 g., m.p. 211.5°-213° C. with decomposition).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=3)[C:19]([O:21]C)=[O:20])=[O:15])=[C:9]([C:26](=[O:43])[NH:27][C:28]3[CH:32]=[CH:31][N:30]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=4)[N:29]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+]>O1CCCC1.O>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=3)[C:19]([OH:21])=[O:20])=[O:15])=[C:9]([C:26](=[O:43])[NH:27][C:28]3[CH:32]=[CH:31][N:30]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:40])([F:41])[F:42])[CH:34]=4)[N:29]=3)[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2ccn(-c3cccc(C(F)(F)F)c3)n2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2ccn(-c3cccc(C(F)(F)F)c3)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.8 %

Procedure:
Into a 100-mL round bottom flask, was placed a solution of methyl 3-((4-(piperidin-1-yl)-2-((1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)carbamoyl)phenyl)carbamoyl)benzoate (300 mg, 0.51 mmol, 1.00 equiv) in tetrahydrofuran (30 mL), water (5 mL), and lithium hydroxide hydrate (300 mg, 12.50 mmol, 24.62 equiv). The resulting solution was stirred overnight at room temperature. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The solution was adjusted to pH 2 with hydrochloric acid 1 mol/L). The resulting solution was extracted with 3×30 mL of ethyl acetate and the organic layers combined, washed with 1×30 mL of brine, and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 300 mg of crude product as a gray solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:22]=[CH:21][C:9]2[CH2:10][CH2:11][CH:12]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:13][C:8]=2[C:7]=1[CH2:23][CH2:24][CH3:25].[I-:26].[Na+]>C(C(C)=O)C>[I:26][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:22]=[CH:21][C:9]2[CH2:10][CH2:11][CH:12]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:13][C:8]=2[C:7]=1[CH2:23][CH2:24][CH3:25]
Reactant: [I-]
Reactant: CCCc1c(OCCCCl)ccc2c1OC(CCC(=O)OCC)CC2
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCCc1c(OCCCI)ccc2c1OC(CCC(=O)OCC)CC2

Procedure:
Ethyl 7-(3-chloropropoxy)-3,4-dihydro-8-propyl-2H-1-benzopyran-2-propanoate (3.2 g, 9.042 mmol) and sodium iodide (13.6 g, 9.042 mmol) were added to 200 ml of methyl ethyl ketone and the reaction mixture was heated to reflux overnight. The solvent was removed under vacuum and 100 ml water was added. The solution was extracted 3 times with ethyl acetate. The combined extracts were dried and filtered, and the solvent was removed under vacuum to give the product as a brown oil.
Reaction SMILES: Br[C:2]1[C:3]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[CH:4][C:5]([O:8][C:9]2[C:14]3[N:15]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[S:17][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[F:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[C:3]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[CH:4][C:5]([O:8][C:9]3[C:14]4[N:15]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[S:17][C:13]=4[CH:12]=[CH:11][CH:10]=3)=[N:6][CH:7]=2)=[CH:35][CH:34]=1
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)c(Br)cn3)cccc2s1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)c(-c4ccc(F)cc4)cn3)cccc2s1

Procedure:
To a mixture of N-{4-[5-bromo-4-(4-trifluoromethyl-phenyl)-pyridin-2-yloxy]-benzothiazol-2-yl}-acetamide, (Example 145(b)), (51 mg, 0.1 mmol) and 4-fluorophenylboronic acid (18 mg, 0.13 mmol, Aldrich) in dioxane (1 mL) was added Pd(PPh3)4 (6 mg, 0.005 mmol, Aldrich) and aqueous Na2CO3 (16 mg in 0.2 mL of water). The reaction mixture was heated in microwave synthesizer at 1600C for 30 min. Purification by silica gel chromatography (EtOAc/hexanes) gave the title compound as a white solid. MS (ESI, pos. ion) m/z: 524 (M+1). Mp: 112.3-130.1° C.
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:12][CH2:11][CH:10]([CH2:13][O:14][CH:15]=[CH2:16])[CH2:9][CH2:8]1)(=O)=O.CS(C)=O.[C-:21]#[N:22].[Na+]>>[CH:15]([O:14][CH2:13][CH:10]1[CH2:11][CH2:12][CH:7]([CH2:6][C:21]#[N:22])[CH2:8][CH2:9]1)=[CH2:16]
Reactant: [C-]#N
Reactant: C=COCC1CCC(COS(C)(=O)=O)CC1
Agent: [Na+]
Solvent: CS(C)=O
Product: C=COCC1CCC(CC#N)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.2 %

Procedure:
4-[(Vinyloxy)methyl]cyclohexylmethyl methanesulfonate (1.43 g, 0.00576 mol) was dissolved in dimethyl sulfoxide (5 mL, 0.07 mol), and then sodium cyanide (1 g, 0.02 mol) was added. The reaction was stirred at 60° C. for 2 hours at 25° C. for 16 hours. The reaction was extracted with ethyl acetate and the extracts were washed with water, brine 3×, and then dried over MgSO4 and concentrated in vacuo. The product was purified via column chromatography on silica gel (20% ethyl acetate, 80% hexanes) to give 0.90 g of the desired product as a mixture of the two diastereomers. 1H NMR (400 MHz, CDCl3): δ 6.33-6.48 (m, 1H), 4.96-4.13 (m, 1H), 4.00-3.96 (m, 1H), 3.49-3.50 (m, 2H), 2.26 (d, 2H, J=6.8 Hz), 1.86-1.93 (m, 4H), 1.56-1.70 (m, 3H), 1.41-1.52 (m, 1H), 0.95-1.20 (m, 4H). (major isomer).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]=[C:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[OH:25])[N:9]=2)[CH2:4]1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][CH2:38][CH3:39])=[O:35]>C(Cl)Cl>[CH2:37]([O:36][C:34](=[O:35])[NH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]=[C:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[OH:25])[N:9]=2)[CH2:4]1)[CH2:38][CH3:39]
Reactant: Cc1ccc2c(N3CC[C@@H](CN)C3)nc(-c3ccccc3O)nc2c1
Reactant: CCCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCOC(=O)NC[C@@H]1CCN(c2nc(-c3ccccc3O)nc3cc(C)ccc23)C1
Temperature: -30 °C
Yield: 62.4 %

Procedure:
A solution of 2-(4-((S)-3-(aminomethyl)pyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (301 mg, 0.9 mmol) in CH2Cl2 (10 ml) was stirred under an N2 atmosphere. Triethylamine (0.25 mL, 1.8 mmol) was added, and the solution was cooled to −30° C. A 1 M propyl chloroformate solution (0.1 mL in 0.9 mL CH2Cl2, 0.9 mmol) was added, and the reaction mixture was allowed to warm to room temperature over a period of 30 minutes. After adding CH2Cl2 to the reaction mixture, it was washed 2 times with water, before it was dried over Na2SO4, filtered, and concentrated. Purification via silica gel chromatography using 0-20% EtOAc in CH2Cl2 gave propyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate (236 mg, 62%). LC/MS: m/z 421 (M+H)+ at 2.54 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.43 (dd, J=8.2, 1.8 Hz, 1H), 8.21 (d, J=8.7 Hz, 1H), 7.58 (s, 1H), 7.39-7.31 (m, 3H), 6.93-6.89 (m, 2H), 4.09-3.86 (m, 6H), 3.78-3.73 (m, 1H), 3.21-3.09 (m, 2H), 2.49 (s, 3H), 2.15-2.09 (m, 1H), 1.83-1.74 (m, 1H), 1.62-1.48 (m, 2H), 0.89-0.86 (m, 3H).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([O:11][C:12]2[C:20]3[N:19]=[C:18]([CH3:21])[N:17]([CH3:22])[C:16]=3[CH:15]=[C:14]([C:23]([OH:25])=O)[CH:13]=2)[CH2:3][CH2:2]1.[CH3:26][NH:27][CH2:28][CH2:29][OH:30].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([O:11][C:12]2[C:20]3[N:19]=[C:18]([CH3:21])[N:17]([CH3:22])[C:16]=3[CH:15]=[C:14]([C:23]([N:27]([CH2:28][CH2:29][OH:30])[CH3:26])=[O:25])[CH:13]=2)[CH2:3][CH2:2]1
Reactant: Cc1nc2c(OC3CCOc4ccccc43)cc(C(=O)O)cc2n1C
Reactant: CNCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2c(OC3CCOc4ccccc43)cc(C(=O)N(C)CCO)cc2n1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.9 %

Procedure:
To a stirred mixture of 4-(3,4-dihydro-2H-chromen-4-yloxy)-1,2-dimethyl-1H-benzimidazole-6-carboxylic acid (70 mg, 0.21 mmol, STEP 2) and 2-(methylamino)ethanol (31 mg, 0.41 mmol) in dimethylformamide (2 mL) were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) (67 mg, 0.35 mmol) and 1-hydroxybenzotriazole hydrate (HOBt) (60 mg, 0.41 mmol) at room temperature. After stirring at room temperature for 18 hours, the reaction mixture was quenched with sodium hydrogencarbonate aqueous solution (5 mL), and extracted with ethyl acetate (50 mL×2). The combined extracts were washed with brine, dried over sodium sulfate, and concentrated in vacuum. The residue was purified by column chromatography on silica gel (ethyl acetate:methanol=10:1 as an eluent). The residue was suspended with diethyl ether, and collected by filtration to afford the title compound as a white solid (24 mg, 24%):
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)=[O:7])=[CH:4][C:3]=1[N:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH2:31][CH2:32]Cl)([CH3:23])[CH3:22])[C:15]1=[O:34].[CH3:35][NH2:36]>C(#N)C>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)=[O:7])=[CH:4][C:3]=1[N:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]([CH3:22])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH2:31][CH2:32][NH:36][CH3:35])[CH3:23])[C:15]1=[O:34]
Reactant: CC(C)(Nc1nccn(-c2cc(C(=O)NC3CC3)ccc2Cl)c1=O)c1ccccc1OCCCl
Reactant: CN
Solvent: CC#N
Product: CNCCOc1ccccc1C(C)(C)Nc1nccn(-c2cc(C(=O)NC3CC3)ccc2Cl)c1=O
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A solution of 4-chloro-3-[3-({1-[2-(2-chloroethoxy)phenyl]-1-methylethyl}amino)-2-oxopyrazin-1(2H)-yl]-N-cyclopropylbenzamide (Example 330i, 0.22 g) dissolved in acetonitrile (3 mL) was treated with 40% aqueous methylamine (0.380 mL). The resulting mixture was stirred at 100° C. for 16 h in a sealed tube. The reaction mixture was filtered and purified by preparative HPLC (Phenominex Gemini column using a 95-5% gradient of aqueous 0.2% ammonia in acetonitrile as eluent). The fractions containing the desired compound were evaporated to afford the title compound (0.087 g).
Reaction SMILES: Br[C:2]1[N:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:9]([O:16][S:17]([C:20]2[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:27][NH:28][S:29]([CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])(=[O:31])=[O:30]>>[C:39]([O:38][C:37]([NH:36][CH2:35][CH2:34][CH2:33][CH2:32][S:29]([N:28]([C:2]1[N:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:9]([O:16][S:17]([C:20]2[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2)[CH3:27])(=[O:31])=[O:30])=[O:43])([CH3:42])([CH3:41])[CH3:40]
Reactant: COC(=O)c1nc(Br)c2cccnc2c1OS(=O)(=O)c1ccc(C)cc1
Reactant: CNS(=O)(=O)CCCCNC(=O)OC(C)(C)C
Product: COC(=O)c1nc(N(C)S(=O)(=O)CCCCNC(=O)OC(C)(C)C)c2cccnc2c1OS(=O)(=O)c1ccc(C)cc1

Procedure:
The title compound was prepared in a similar fashion as described in Example 2.1, starting from methyl 5-bromo-8-(tosyloxy)-1,6-naphthyridine-7-carboxylate (Example 12; 10.3 mmol) and tert-butyl 4-(N-methylsulfamoyl)butylcarbamate (Example 8) to obtain the target compound (3.43 gr).