Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:29][O:30][C:31]1[C:32](=[O:55])[C:33]([CH3:54])=[C:34]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([O:50][C:51](=[O:53])[CH3:52])=[C:45]([CH:49]=2)[C:46](O)=[O:47])[C:35](=[O:39])[C:36]=1[O:37][CH3:38]>C(Cl)Cl>[CH3:29][O:30][C:31]1[C:32](=[O:55])[C:33]([CH3:54])=[C:34]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([O:50][C:51](=[O:53])[CH3:52])=[C:45]([CH:49]=2)[C:46]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)=[O:47])[C:35](=[O:39])[C:36]=1[O:37][CH3:38]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(NC(=O)c2cc(CC3=C(C)C(=O)C(OC)=C(OC)C3=O)ccc2OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.1 %

Procedure:
Ethyl 4-aminobenzoate (0.265 g, 1.604 mmol), triethylamine (0.162 g, 1.604 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.271 g, 1.604 mmol) were added to a methylene chloride solution (50 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:1) and then recrystallized from ether to obtain the titled compound (0.165 g, 0.316 mmol, 59%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19]([OH:21])=O)=[CH:5]2.[CH3:22][C:23]1[C:28]([NH2:29])=[CH:27][CH:26]=[C:25]([N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:24]=1>>[CH3:22][C:23]1[C:28]([NH:29][C:19]([C:6]2[N:7]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)[C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)=[O:21])=[CH:27][CH:26]=[C:25]([N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:24]=1
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Reactant: Cc1nc(N2CCCC2)ccc1N
Product: Cc1nc(N2CCCC2)ccc1NC(=O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Yield: 48.3 %

Procedure:
The process is carried out according to the method described in example 5.3, using 0.4 g (1.39 mmol) of 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid (example 1.1) and 0.32 g (1.81 mmol) of 2-methyl-6-(pyrrolidin-1-yl)-3-aminopyridine (compound no. Vd), described in step 9.2. 0.3 g of the expected product is thus isolated.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH:13]=[CH2:14])=[C:10]([OH:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:16]([Al](CC(C)C)CC(C)C)C(C)C.C(I)I.[OH-].[Na+]>C(Cl)Cl>[CH:13]1([CH2:12][C:11]2[C:2]([OH:1])=[C:3]([CH:8]=[CH:9][C:10]=2[OH:15])[C:4]([O:6][CH3:7])=[O:5])[CH2:16][CH2:14]1
Reactant: C=CCc1c(O)ccc(C(=O)OC)c1O
Reactant: CC(C)C[Al](CC(C)C)CC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ICI
Product: COC(=O)c1ccc(O)c(CC2CC2)c1O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
The compound of Example 5 (1.0 g, 4.8 mMol) was dissolved in methylene chloride (20cm3) and transferred to a 100 ml three-neck round bottom flask under an argon atmosphere at 0° C. Triisobutylaluminum (2.95 g, 3.76 ml, 14.9 mmol) was added dropwise via a dropping funnel. The reaction mixture was stirred for about 20 minutes while maintaining the temperature at 0° C., then methylene iodide (1.67 g, 0.5 ml, 6.2 mmol) was added via syringe, and the reaction mixture was stirred at room temperature for about four hours then slowly poured into an ice cold solution of 10% sodium hydroxide. The aqueous layer was extracted twice with about 25 ml of methylene chloride, and all of the organic fractions were combined, dried over magnesium sulfate and concentrated in vacuo to give the product.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([O:12][CH3:13])=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>CN(C)C=O>[CH3:13][O:12][C:8]1[CH:9]=[N:10][C:11]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[N:3][C:2]=2[NH:27][CH2:26][C:25]1[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=1
Reactant: COc1ccc(CN)cc1
Reactant: COc1cnc2c(Cl)nccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CNc2nccc3cc(OC)cnc23)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 90.1 %

Procedure:
To a solution of 8-chloro-3-methoxy-1,7-naphthyridine (1 g, 5.14 mmol) in N,N-dimethylformamide (10.28 mL) was added potassium carbonate (1.42 g, 10.28 mmol) followed by 4-methoxybenzylamine (1.47 ml, 11.3 mmol). The reaction was stirred at 100° C. for 24 hours and then concentrated to generate a brown residue. This was partitioned between ethyl acetate and water. The organic layer was concentrated and purified by silica-gel chromatography, eluting with 1-5% methanol in DCM, to provide the title compound (1.37 g, 4.63 mmol) as a tan solid. LC/MS (ESI+) m/z=296 (M+H).
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:22][C:23]1[CH:24]=[C:25]([C:33]([OH:35])=O)[CH:26]=[N:27][C:28]=1[O:29][CH:30]([CH3:32])[CH3:31].O[NH:37]/[C:38](=[N:55]\[H])/[C:39]1[CH:47]=[C:46]2[C:42]([C:43]([CH2:48][CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:44][NH:45]2)=[CH:41][CH:40]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:22][C:23]1[CH:24]=[C:25]([C:33]2[O:35][N:55]=[C:38]([C:39]3[CH:47]=[C:46]4[C:42]([C:43]([CH2:48][CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:44][NH:45]4)=[CH:41][CH:40]=3)[N:37]=2)[CH:26]=[N:27][C:28]=1[O:29][CH:30]([CH3:31])[CH3:32]
Reactant: Cc1cc(C(=O)O)cnc1OC(C)C
Reactant: [H]/N=C(\NO)c1ccc2c(CCC(=O)OCC)c[nH]c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCOC(=O)CCc1c[nH]c2cc(-c3noc(-c4cnc(OC(C)C)c(C)c4)n3)ccc12
Reaction time: 0.5 h
Yield: 46.4 %

Procedure:
EDCI (590 mg) and HOBT (507 mg) were added to a solution of 5-methyl-6-[(1-methylethyl)oxy]-3-pyridinecarboxylic acid (300 mg) in THF (5 mL) at RT. The resulting solution was stirred for 30 mins. Ethyl 3-{6-[(Z)-(hydroxyamino)(imino)methyl]-1H-indol-3-yl}propanoate (D107) (845 mg) in THF (5 mL) was added and the reaction mixture was stirred at RT for 2 hours. TBAF (1.6 g) was then added. The reaction vessel was sealed and heated in Biotage Initiator using initial normal to 120° C. for 2 hours. After cooling, the reaction was quenched with water, and extracted with EtOAc for 3 times. The combined organic solution was washed with brine, dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was purified by column chromatography (20% EtOAc in hexane) to afford ethyl 3-[6-(5-{5-methyl-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoate (D111) (310 mg) as a pale yellow solid. MS (ES): C24H26N4O4 requires 434; found 435.2 (M+H+).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10])=[O:2].Br[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(O)C>[CH3:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:4][C:3]=1[CH:1]=[O:2]
Reactant: Brc1cccnc1
Reactant: COc1ccc(B(O)O)cc1C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cccnc2)cc1C=O
Yield: 32 %

Procedure:
N1 is prepared according to a method similar to Method A. Commercially available 3-formyl-4-methoxyphenylboronic acid (1.66 g, 9.22 mmol) is dissolved in 56 mL toluene and 14 mL ethanol. 3-Bromopyridine (0.98 mL, 10.2 mmol) is added followed by cesium carbonate (3.0 g, 9.21 mmol). Nitrogen is bubbled through the mixture for 10 minutes, then palladium tetrakistriphenylphosphine (0.53 g, 0.46 mmol) is added and nitrogen bubbling is resumed for another ten minutes. The mixture is heated to reflux for 5 hours. The mixture is allowed to cool and is filtered through Celite. The Celite pad is washed with ethyl acetate and methylene chloride. The filtrate is pumped dry and the residue is chromatographed on silica gel using a gradient elution of methanol/methylene chloride. 2-Methoxy-5-pyridin-3-yl-benzaldehyde (N1) is obtained (0.635 g, 2.98 mmol; 32% yield).
Reaction SMILES: [Br-:1].[NH2:2][N+:3]1[CH:7]=[CH:6][N:5]([CH2:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[C:4]=1[CH2:15][CH3:16].[CH3:17][N:18]([CH3:27])[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1>C(O)(=O)C>[Br-:1].[CH3:17][N:18]([CH3:27])[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[N:2][N+:3]2[CH:7]=[CH:6][N:5]([CH2:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:12])[CH3:13])[C:4]=2[CH2:15][CH3:16])=[CH:21][CH:20]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CCc1n(CC(=O)C(C)(C)C)cc[n+]1N
Agent: [Br-]
Solvent: CC(=O)O
Product: CCc1n(CC(=O)C(C)(C)C)cc[n+]1N=Cc1ccc(N(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2.38 g (8.2 mmol) of 1-amino-2-ethyl-3-(3,3-dimethyl-2-oxobutyl)imidazolium bromide are dissolved in 30 ml of glacial acetic acid, whereupon the solution is treated with 1.22 g (8.2 mmol) of p-dimethylaminobenzaldehyde. After stirring at room temperature 48 hours the product is recrystallized by the addition of ether, chromatographed on 20 g of silica gel (particle size 0.063-0.200 mm) while eluting with methylene chloride/methanol (19:1 v/v) and recrystallized from ethanol/ether. There is obtained 1-[[4-(dimethylamino)benzylidene]amino]-2-ethyl-3-(pivaloylmethyl)imidazolium bromide of melting point 188°-189°.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.[CH3:18][CH2:19][O:20][C:21]([CH2:23][CH:24]1[C:29](=O)[CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:22]>>[Cl:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[C:25]3[CH:24]([CH2:23][C:21]([O:20][CH2:19][CH3:18])=[O:22])[CH2:29][CH2:28][CH2:27][C:26]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:5][CH:4]=1
Reactant: NN(Cc1ccc(Cl)cc1)c1ccccc1
Reactant: CCOC(=O)CC1CCCCC1=O
Agent: Cl
Product: CCOC(=O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1ccccc21

Procedure:
Following the procedure of Example 1, but using 1-(4-chlorobenzyl)-1-(phenyl)hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound was prepared.
Reaction SMILES: [C:1]([N:4]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:11]=[C:10]([CH3:25])[C:9]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:39])C=1>ClCCCl>[C:1]([N:4]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[O:18][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[N+:11]([O-:39])=[C:10]([CH3:25])[C:9]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1c(C)nc2cccc(OC3CCCCC3)c2c1N(C(C)=O)C(C)=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCCl
Product: CCOC(=O)c1c(N(C(C)=O)C(C)=O)c2c(OC3CCCCC3)cccc2[n+]([O-])c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
To a solution of ethyl 4-(N-acetylacetamido)-5-(cyclohexyloxy)-2-methylquinoline-3-carboxylate (Example 132b, 100 mg, 0.24 mmol) in DCE (5 mL) was added mCPBA (163 mg, 0.73 mmol). The reaction mixture was stirred at room temperature overnight under N2. The solvent was removed under reduce pressure, and the residue was purified by chromatography on silica gel eluting with 0-100% EtOAc/Hexanes gradient to give the title compound as an orange oil (100 mg, 97%). MS 429 (MH+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]([OH:12])=[CH:10][C:9]([C:13]([F:16])([F:15])[F:14])=[N:8]1.Cl[C:18]1[N:19]=[N:20][CH:21]=[C:22]([O:24][CH3:25])[CH:23]=1.C1(C)C=CC=CC=1.N1C(C)=CC=CC=1C>ClCCl>[CH3:25][O:24][C:22]1[CH:23]=[C:18]([O:12][C:11]2[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[N:8]=[C:9]([C:13]([F:16])([F:14])[F:15])[CH:10]=2)[N:19]=[N:20][CH:21]=1
Reactant: COc1cnnc(Cl)c1
Reactant: Oc1cc(C(F)(F)F)nn1C1CCCCO1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: Cc1cccc(C)n1
Product: COc1cnnc(Oc2cc(C(F)(F)F)nn2C2CCCCO2)c1
Yield: 59.3 %

Procedure:
1-(Tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-1H-pyrazol-5-ol (2.37 g, 0.010 mole), 3-chloro-5-methoxypyridazine (1.39 g, 0.0096 mole), toluene (60 mL), and 2,6 lutidine (1.5 g, 0.014 mole) were heated and held at reflux for 3 hours. The mixture was cooled, diluted with 100 mL of dichloromethane, and washed with 1% hydrochloric acid followed by 1% sodium hydroxide solution. The washed solution was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel using ethyl acetate/cyclohexane to give 5-methoxy-3-[[1-(tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]oxy]pyridazine (1.96 g, 59% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:11]2[C:6](=[CH:7][C:8]([C:15](=O)[CH3:16])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[C:5]([CH:18]([CH3:20])[CH3:19])=[CH:4][CH2:3]1.[CH3:22][CH2:23][O:24][C:25]([CH:27](P(OCC)(OCC)=O)[F:28])=[O:26].C([N-]C(C)C)(C)C.[Li+]>C1COCC1>[F:28]/[C:27](=[C:15](/[C:8]1[CH:7]=[C:6]2[C:11]([C:2]([CH3:1])([CH3:21])[CH2:3][CH:4]=[C:5]2[CH:18]([CH3:19])[CH3:20])=[CH:10][C:9]=1[O:12][CH2:13][CH3:14])\[CH3:16])/[C:25]([O:24][CH2:23][CH3:22])=[O:26]
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: CCOc1cc2c(cc1C(C)=O)C(C(C)C)=CCC2(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)/C(F)=C(/C)c1cc2c(cc1OCC)C(C)(C)CC=C2C(C)C

Procedure:
As described in General Procedure F-1, 1-(4,4-dimethyl-6-ethoxy-1-isopropyl-3,4-dihydronaphthalen-7-yl)ethanone (Compound A-24, 240 mg, 0.840 mmol) and triethyl 2-fluoro-2-phosphonoacetate (0.51 mL, 2.52 mmol) were reacted with lithium diisopropylamide (2.60 mmol) in THF (2 mL) to produce the title compound after purification by flash column chromatography (silica gel, 97:3 hexane/ethyl acetate).
Reaction SMILES: Cl.[F:2][C@@:3]12[C@:16]3([CH3:17])[C:11](=[CH:12][C:13](=[O:18])[CH:14]=[CH:15]3)[C@@H:10]([F:19])[CH2:9][C@H:8]1[C@@H:7]1[CH2:20][C@@H:21]3[C@:25]([C:26](=[O:32])[CH2:27][O:28][C:29](=[O:31])[CH3:30])([C@@:6]1([CH3:33])[CH2:5][C@@H:4]2[OH:34])[CH2:24][NH:23][CH2:22]3.[N:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37][C:36]=1[CH:45]=O.C(N(CC)CC)C.C(O)=O>C(#N)C>[F:2][C@@:3]12[C@:16]3([CH3:17])[C:11](=[CH:12][C:13](=[O:18])[CH:14]=[CH:15]3)[C@@H:10]([F:19])[CH2:9][C@H:8]1[C@@H:7]1[CH2:20][C@@H:21]3[C@:25]([C:26](=[O:32])[CH2:27][O:28][C:29](=[O:31])[CH3:30])([C@@:6]1([CH3:33])[CH2:5][C@@H:4]2[OH:34])[CH2:24][N:23]([CH2:45][C:36]1[CH:37]=[CH:38][C:39]2[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:35]=1)[CH2:22]3
Reactant: O=Cc1ccc2ccccc2n1
Reactant: CC(=O)OCC(=O)[C@@]12CNC[C@@H]1C[C@H]1[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]12C
Agent: Cl
Solvent: O=CO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)[C@@]12CN(Cc3ccc4ccccc4n3)C[C@@H]1C[C@H]1[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]12C
Yield: 54.6 %

Procedure:
A solution of intermediate 6 (200 mg, 0.400 mmol), quinoline-2-carbaldehyde (251 mg, 1.600 mmol), triethylamine (61 mL, 0.440 mmol) and formic acid (263 μL, 3.20 mmol), in acetonitrile (4 ml) is irradiated with microwaves (130° C., 20 minutes). The reaction mixture was partitioned between AcOEt and 5% NaHCO3 solution. The organic layers were then washed with brine, dried over Na2SO4 and filtered. The solvent was evaporated and the crude was purified by silica gel chromatography (DCM/MeOH 99:1) to give compound 11 (132 mg, 54.6% yield).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[CH3:14][NH2:15].O>C(Cl)Cl>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:15][CH3:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Reactant: CN
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(CBr)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a chilled (0° C.) stirred solution of 4-(bromomethyl)-benzenesulfonylchloride (3.0 g, 11 mmol) in DCM (100 mL) was added methylamine hydrochloride (1.2 g, 12 mmol). After 30 minutes, water (100 mL) was added. The organic layer was separated, washed with brine (30 mL), and dried over sodium sulfate and concentrated in vacuo to afford 4-bromomethyl-N-methyl-benzenesulfonamide.
Reaction SMILES: Br[C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:27][CH:26]=2)O1>>[F:14][C:13]([F:16])([F:15])[C:10]1[CH:11]=[CH:12][C:7]([N:4]2[CH:5]=[N:6][C:2]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:27][CH:26]=3)=[N:3]2)=[CH:8][CH:9]=1
Reactant: COC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: FC(F)(F)c1ccc(-n2cnc(Br)n2)cc1
Product: COC(=O)Cc1ccc(-c2ncn(-c3ccc(C(F)(F)F)cc3)n2)cc1

Procedure:
The title compound was prepared as described in Example 3 using 3-bromo-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazole (C1b) and methyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (C2) and isolated as a white solid (2.3 g, 81%): 1H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 8.23-8.16 (m, 2H), 8.08 (d, J=8.2 Hz, 2H), 8.03-7.96 (m, 2H), 7.49-7.38 (m, 2H), 3.78 (s, 2H), 3.65 (s, 3H); 19F NMR (376 MHz, DMSO-d6) δ −60.82; ESIMS m/z 362 ([M+H]+).
Reaction SMILES: CC([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9]C=2)[C:5]=1[OH:14])=O.C1C2CC(=[O:22])C(C2)C1.N1CCCC1>C1(C)C=CC=CC=1>[O:14]1[C:5]2[C:6](=[CH:11][CH:12]=[CH:13][CH:4]=2)[CH2:7][CH2:8][CH:9]1[OH:22]
Reactant: CC(=O)c1ccc2ccccc2c1O
Reactant: O=C1CC2CCC1C2
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: OC1CCc2ccccc2O1
Reaction time: 10 h

Procedure:
A solution was prepared by dissolving 10 g (0.054 mole) of 1-hydroxy-2-acetonaphthone, 6.6 g (0.06 mole) of norcamphor and 8 g (0.113 mole) of pyrrolidine in 300 cc of toluene. The solution was boiled for 10 hours and water was separated. After termination of the reaction, toluene was removed under reduced pressure, and the remaining chromanone compound was crystallized with acetone. Then, the chromanone compound was dissolved in 200 cc of methanol, and sodium boron hydride was gradually added to the solution to form a chromanol compound. Then, 7.47 g of the chromanol compound was heated at 150° C. to 160° C. together with 4.5 g of anhydrous copper sulfate in a carbon dioxide current for 10 minutes and the obtained viscous liquid was purified by the chromatography on silica gel to obtain 6.3 g of a chromene compound of the following formula: ##STR70##
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:15]([O:17]C)=[O:16])[CH:8]=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.O>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[CH:14]=1)[C:15]([OH:17])=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(C(=O)OC)cc(C(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(C(=O)O)cc(C(C)(C)C)c1
Reaction time: 4 h
Yield: 104.4 %

Procedure:
To a solution of dimethyl 5-tert-butylisophthalate (93.3 g, 0.373 mol) in MeOH (610 mL) was added a solution of sodium hydroxide (14.9 g, 0.373 mol) in water (41 mL) at 25 ° C. The mixture was allowed to stir at this temperature for 4 h and then concentrated. The residue was suspended in 1M H2SO4 and filtered. The solid was washed with water and dried under vacuum to give 3-tert-butyl-5-(methoxycarbonyl)benzoic acid (92 g) as a white solid which was used without purification. 1H NMR (400 MHz, d6-DMSO) δ: 8.35 (s, 1H), 8.20 (m, 2H), 3.85 (s,3H), and 1.30 (s, 9H). LCMS: ES− 235.4.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26][C:27]2([C:31]([O:33][CH3:34])=[O:32])[CH2:30][CH2:29][CH2:28]2)/[C:9]1=[O:35])=O)(C)(C)C.[F:36][C:37]1[CH:38]=[CH:39][C:40]([CH3:52])=[C:41]([CH:43]=[N:44][C:45]([O:47][Si](C)(C)C)=[CH2:46])[CH:42]=1.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:35])[C:10]3([CH:18]([C:19]4[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=4[O:26][C:27]4([C:31]([O:33][CH3:34])=[O:32])[CH2:30][CH2:29][CH2:28]4)[CH2:46][C:45](=[O:47])[NH:44][CH:43]3[C:41]3[CH:42]=[C:37]([F:36])[CH:38]=[CH:39][C:40]=3[CH3:52])[C:11]2=[CH:12][CH:13]=1
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Reactant: COC(=O)C1(Oc2ccc(Cl)cc2/C=C2\C(=O)N(C(=O)OC(C)(C)C)c3cc(Cl)ccc32)CCC1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1(Oc2ccc(Cl)cc2C2CC(=O)NC(c3cc(F)ccc3C)C23C(=O)Nc2cc(Cl)ccc23)CCC1
Temperature: 60 °C
Yield: 11.5 %

Procedure:
A mixture of E/Z-6-chloro-3-[5-chloro-2-(1-methoxycarbonyl-cyclobutoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (1.5 g, 2.9 mmol) and 1-(5-fluoro-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (10 mmol) prepared in Example 4 in toluene (10 mL) was heated at 60° C. for 3 h. To the mixture was added TFA (5 mL), and the resultant solution was stirred at room temperature for 20 min, then concentrated in vacuo. The residue was partitioned between ethyl acetate and diluted aqueous NaOH solution. The organic layer was separated, washed with water, dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash chromatography to give the title compound as white solid (200 mg).
Reaction SMILES: ClC1C=C(N[C@H](C2CC2)C(N[C@@H]2CCCN(C(OC(C)(C)C)=O)C2)=O)C=C(F)C=1.[Cl:30][C:31]1[CH:32]=[C:33]([NH:38][CH2:39][C:40]([NH:42][C@@H:43]2[CH2:48][CH2:47][CH2:46][N:45]([C:49](OC(C)(C)C)=O)[CH2:44]2)=[O:41])[CH:34]=[C:35]([Cl:37])[CH:36]=1.NC1C(C#N)=C(Cl)N=CN=1.[Cl:66][C:67]1[C:68]([NH2:74])=[N:69][CH:70]=[N:71]C=1Cl>>[NH2:74][C:68]1[N:69]=[CH:70][N:71]=[C:49]([N:45]2[CH2:46][CH2:47][CH2:48][C@@H:43]([NH:42][C:40](=[O:41])[CH2:39][NH:38][C:33]3[CH:34]=[C:35]([Cl:37])[CH:36]=[C:31]([Cl:30])[CH:32]=3)[CH2:44]2)[C:67]=1[Cl:66]
Reactant: Nc1ncnc(Cl)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)CNc2cc(Cl)cc(Cl)c2)C1
Agent: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)[C@H](Nc2cc(F)cc(Cl)c2)C2CC2)C1
Agent: N#Cc1c(N)ncnc1Cl
Product: Nc1ncnc(N2CCC[C@@H](NC(=O)CNc3cc(Cl)cc(Cl)c3)C2)c1Cl

Procedure:
The title compound of Example 140 was prepared in similar manner as described in Example 134 except the key intermediate (R)-tert-butyl 3-((R)-2-(3-chloro-5-fluorophenylamino)-2-cyclopropylacetamido)piperidine-1-carboxylate was replaced with (R)-tert-butyl 3-(2-(3,5-dichlorophenylamino)acetamido)piperidine-1-carboxylate and the 4-amino-6-chloropyrimidine-5-carbonitrile was substituted for 5,6-dichloropyrimidin-4-amine. 1H NMR (300 MHz, CD3OD) δ 7.91 (s, 1H), 6.51-6.63 (m, 1H), 6.34 (d, J=1.51 Hz, 2H), 3.93-4.10 (m, 1H), 3.47-3.57 (m, 3H), 3.20-3.31 (m, 2H), 2.76-3.01 (m, 1H), 1.72-1.85 (m, 2H), 1.54-1.67 (m, 2H). EIMS (m/z): calcd. for C17H19Cl3N6O (M+1H) 431. found 431.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([N+:16]([O-])=O)=[CH:14][C:13]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].[Sn](Cl)Cl.N>C(O)C.Cl.O>[NH2:16][C:15]1[C:9]2[S:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[N:11][C:10]=2[CH:12]=[C:13]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:14]=1
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc([N+](=O)[O-])c2s1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: N
Solvent: CCO
Solvent: O
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(N)c2s1
Temperature: 80 °C
Yield: 162.2 %

Procedure:
A stirred suspension of 1-Ethyl-3-(7-nitro-5-pyridin-3-yl-benzothiazol-2-yl)-urea (25 mg, 0.0728 mmol) in ethanol (0.5 ml) and concentrated hydrochloric acid (0.5 ml) was treated with tin (II) chloride (69 mg, 0.364 mmol) and heated at 80° C. for 5 h. After cooling to ambient temperature, the mixture was diluted with water (50 ml) and made alkaline (pH 11) by the addition of concentrated ammonia. The 1-(7-Amino-5-pyridin-3-yl-benzothiazol-2-yl)-3-ethyl-urea was extracted with ethyl acetate (3×50 ml) which was dried (MgSO4) and the solvent removed in vacuo to give an off-white solid (37 mg) which was used without further purification.