Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([C:16]#[N:17])=[C:4]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1.[CH:23]([Sn](CCCC)(CCCC)CCCC)=[CH2:24].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[NH2:1][C:2]1[N:3]=[C:4]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[C:5]([C:16]#[N:17])=[C:6]([CH:23]=[CH2:24])[N:7]=1
Reactant: N#Cc1c(OS(=O)(=O)C(F)(F)F)nc(N)nc1-c1ccco1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C=Cc1nc(N)nc(-c2ccco2)c1C#N
Yield: 3.8 %

Procedure:
To a stirred solution of 250 mg (0.75 mmol) trifluoromethanesulfonic acid 2-amino-5-cyano-6-furan-2-yl-pyrimidin-4-yl ester in 15 ml dioxane under argon at room temperature were added 0.22 ml (0.75 mmol) vinyltributylstannane, 86 mg (0.07 mmol) tetrakis(triphenyl-phosphine)palladium(O) and 1.5 ml (3.0 mmol) 2M aqueous sodium carbonate solution. The reaction mixture was heated at reflux for 16 h, then concentrated in vacuo. The residue was partitioned between ethyl acetate and water and the organic phase washed with brine, dried over sodium sulfate, and concentrated in vacuo. Flash chromatography (1/1 ethyl acetate/hexane) followed by trituration in ether afforded 6 mg (4%) 2-amino-4-furan-2-yl-6-vinyl-pyrimidine-5-carbonitrile as a white crystalline solid. ES-MS m/e (%): 213 (M+H+, 100). Also obtained (as a by-product) was 3 mg (2%) 2-amino-4-ethyl-6-furan-2-yl-pyrimidine-5-carbonitrile as a yellow crystalline solid. ES-MS m/e (%): 215 (M+H+, 100).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=3)[CH2:13][CH:12]([C:27]([OH:29])=O)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:31]=[C:32]([NH2:38])[CH2:33][S:34]([CH3:37])(=[O:36])=[O:35]>>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([C:23]([F:24])([F:26])[F:25])[CH:17]=3)[CH2:13][CH:12]([C:27]3[O:29][N:38]=[C:32]([CH2:33][S:34]([CH3:37])(=[O:36])=[O:35])[N:31]=3)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1
Reactant: CS(=O)(=O)CC(N)=NO
Reactant: Cc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(O)CC3)C2)cc1C(F)(F)F
Product: Cc1ccc(C2CC(c3nc(CS(C)(=O)=O)no3)CN(C(=O)N3CCC(O)CC3)C2)cc1C(F)(F)F

Procedure:
100 mg (0.24 mmol) of the compound from Example 163A and 55 mg (0.36 mmol) of N′-hydroxy -2-(methylsulphonyl)ethanimidamide were reacted according to the General Method 2. Yield: 72 mg (56% of theory)
Reaction SMILES: C(NC1N=C(C(=O)C(SC)=O)C=CC=1)=O.[OH-].[Na+].[CH:18]([NH:20][C:21]1[N:26]=[C:25]([C:27](=O)[C:28]([OH:30])=[O:29])[CH:24]=[CH:23][CH:22]=1)=[O:19].Cl.[CH2:33]([O:36][NH2:37])[CH2:34][CH3:35].Cl>CO>[CH:18]([NH:20][C:21]1[N:26]=[C:25]([C:27](=[N:37][O:36][CH2:33][CH2:34][CH3:35])[C:28]([OH:30])=[O:29])[CH:24]=[CH:23][CH:22]=1)=[O:19]
Reactant: CCCON
Reactant: O=CNc1cccc(C(=O)C(=O)O)n1
Agent: CSC(=O)C(=O)c1cccc(NC=O)n1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCON=C(C(=O)O)c1cccc(NC=O)n1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
A mixture of S-methyl 2-(6-formamidopyridin-2-yl)thioglyoxylate (4.48 g.), methanol (20 ml.) and 1 N aqueous solution of sodium hydroxide (20 ml.) was stirred for 50 minutes at ambient temperature to give a solution containing 2-(6-formamidopyridin-2-yl)glyoxylic acid. To the solution was added O-propylhydroxylamine hydrochloride (2.23 g.), and the mixture was stirred for 35 minutes at the same temperature. The reaction mixture was adjusted to pH 7 with hydrochloric acid and the methanol was distilled off. The remaining aqueous mixture was washed with ethyl acetate, and ethyl acetate was added thereto and then adjusted to pH 1 with 10% hydrochloric acid. The ethyl acetate layer was separated, washed with water, dried over magnesium sulfate, treated with activated charcoal and then the solvent was distilled off. Thus obtained product was washed with a mixture of diethyl ether and diisopropyl ether and then dried to give 2-(6-formamidopyridin-2-yl)-2-propoxyiminoacetic acid (syn isomer) (1.76 g.), mp 140° to 142° C. (dec.).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21]C)=[O:20])[CH2:15][CH2:14]1)[C:7]([C:23]([F:26])([F:25])[F:24])=[CH:6]2.B(Br)(Br)Br.O>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]([OH:21])=[O:20])[CH2:15][CH2:14]1)[C:7]([C:23]([F:26])([F:25])[F:24])=[CH:6]2
Reactant: COC(=O)C1CCN(c2nc3ccc(OC)cc3cc2C(F)(F)F)CC1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C(O)C1CCN(c2nc3ccc(O)cc3cc2C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 20 h
Yield: 9.4 %

Procedure:
To a solution of methyl 1-(6-methoxy-3-(trifluoromethyl)quinolin-2-yl)piperidine-4-carboxylate (300 mg, 0.815 mmol) in DCM (5 mL) was added BBr3 (0.4 mL, 4.08 mmol) dropwise at 0° C. The mixture was stirred at 0° C. for 20 hours. Water (10 mL) was added to the mixture dropwise at 0° C. The mixture was concentrated in vacuo, then diluted with EtOAc (150 mL), filtered and concentrated in vacuo. Purification by prep-HPLC (0.1% TFA as additive) to give Compound IV-41 (26 mg, yield 9.4%) as a solid. 1H NMR (MeOD 400 MHz): δ 8.51 (s, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.41 (dd, J=8.8, 2.8 Hz, 1H), 7.21 (d, J=2.8 Hz, 1H), 3.55-3.49 (m, 2H), 3.13-3.02 (m, 2H), 2.58-2.49 (m, 1H), 2.09-2.00 (m, 2H), 1.93-1.82 (m, 2H). MS (ESI): m/z 340.7 [M+H]+.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].CCCCCC.[N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[CH2:22][O:23][C:24]1[CH:33]=[C:32]2[C:27]([CH2:28]CCC2=O)=[CH:26][CH:25]=1.O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.CCOCC>[CH2:4]=[C:3]1[C:26]2[CH:25]=[C:24]([O:23][CH2:22][C:13]3[CH:14]=[CH:15][C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:12]=3)[CH:33]=[CH:32][C:27]=2[CH2:28][CH2:1][CH2:2]1
Reactant: [Li]CCCC
Reactant: O=C1CCCc2ccc(OCc3ccc4ccccc4n3)cc21
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: O
Solvent: CCOCC
Product: C=C1CCCc2ccc(OCc3ccc4ccccc4n3)cc21
Reaction time: 0.75 h
Yield: 24 %

Procedure:
To a suspension of 3.6 g (10.1 mmol) of methyltriphenylphosphonium bromide in 50 mL tetrahydrofuran under nitrogen at -50° C. is added n-butyllithium (10 mm as a hexane solution (2.1 M)). After 45 minutes, a solution of 3.0 g (9.90 mmol) of 3,4-dihydro-7-(2-quinolinylmethoxy)-1(2H)-naphthalenone, prepared according to Example 1A above, in 50 mL tetrahydrofuran is added dropwise and the reaction mixture is allowed to slowly come to room temperature. After three days, 50 mL water and 50 mL ether is added. The organic layer is separated, dried over magnesium sulfate and evaporated to 5.0 g of crude product. Chromatography accords 1.3 g (44%) of the desired product. Recrystallization from hexane gives 0.70 g (24%) of white crystals mp 56°-58° C.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:13][C@H:14]2[CH2:18][CH2:17][CH2:16][C@@H:15]2[NH:19][C:20](=[O:33])[C:21]2C=CC=CC=2C2ON=C(C)N=2)=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:8]=1)[CH3:2].Cl.C(C1C(N[C@H]2CCC[C@@H]2N)=NC=C(C(F)(F)F)N=1)C.[N:54]1[CH:59]=[CH:58][CH:57]=[N:56][C:55]=1[C:60]1C(C(O)=O)=[N:62][CH:63]=[CH:64][CH:65]=1>>[CH2:1]([C:3]1[C:4]([NH:13][C@H:14]2[CH2:18][CH2:17][CH2:16][C@@H:15]2[NH:19][C:20]([C:21]2[C:60]([C:55]3[N:54]=[CH:59][CH:58]=[CH:57][N:56]=3)=[CH:65][CH:64]=[CH:63][N:62]=2)=[O:33])=[N:5][CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[N:8]=1)[CH3:2]
Reactant: O=C(O)c1ncccc1-c1ncccn1
Reactant: CCc1nc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1NC(=O)c1ccccc1-c1nc(C)no1
Agent: CCc1nc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1N
Agent: Cl
Product: CCc1nc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1NC(=O)c1ncccc1-c1ncccn1

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-{[3-ethyl-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-2-(3-methyl-1,2,4-oxadiazol-5-yl)benzamide (Example 149) from (1S,2S)-1-N-[3-ethyl-5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 41; 450 mg, 1.64 mmol) and 3-(pyrimidin-2-yl)pyridine-2-carboxylic acid (CAS number 1228431-21-7; 330 mg, 1.64 mmol) to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:23]1[CH:28]=[CH:27][CH2:26][CH2:25][CH2:24]1>C(Cl)(Cl)Cl.O>[Br:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28][O:23]1
Reactant: C1=COCCC1
Reactant: Brc1ncnc2[nH]cnc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: Brc1ncnc2c1ncn2C1CCCCO1
Temperature: 20 °C
Reaction time: 18 h
Yield: 95.4 %

Procedure:
A solution of 6-bromo-9H-purine (2.0 g, 10 mmol) and p-toluenesulfonic acid monohydrate (190 mg, 1.0 mmol) in chloroform (45 mL) at 0° C. was treated with dihydropyran (1.4 mL, 15 mmol) and stirred at 20° C. for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with saturated sodium bicarbonate, water and brine, dried with sodium sulfate, filtered, and concentrated to give a crude residue. Purification by flash column chromatography using ethyl acetate in hexanes (0%-70%) gave the desired product (2.7 g, 94%). LCMS for C10H12BrN4O (M+H)+: m/z=283.0, 285.0; Found: 283.0, 285.0.
Reaction SMILES: [F-].[Cs+].CC1C=CC(S([O:13][CH2:14][C@@H:15]2[O:17][CH2:16]2)(=O)=O)=CC=1.[Cl:18][C:19]1[C:24]([NH:25][C:26]2[C:35]3[C:30](=[CH:31][C:32](F)=[CH:33][C:34]=3[O:36][CH:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[N:29]=[CH:28][N:27]=2)=[C:23]2[O:44][CH2:45][O:46][C:22]2=[CH:21][CH:20]=1>CN(C=O)C>[Cl:18][C:19]1[C:24]([NH:25][C:26]2[C:35]3[C:30](=[CH:31][C:32]([O:13][CH2:14][C@@H:15]4[O:17][CH2:16]4)=[CH:33][C:34]=3[O:36][CH:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[N:29]=[CH:28][N:27]=2)=[C:23]2[O:44][CH2:45][O:46][C:22]2=[CH:21][CH:20]=1
Reactant: Fc1cc(OC2CCOCC2)c2c(Nc3c(Cl)ccc4c3OCO4)ncnc2c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: Clc1ccc2c(c1Nc1ncnc3cc(OC[C@H]4CO4)cc(OC4CCOCC4)c13)OCO2
Temperature: 70 °C
Yield: 76.6 %

Procedure:
Caesium fluoride (0.46 g) and (2R)-(−)-glycidyl tosylate (0.275 g) were added in turn to a solution of 4-(6-chloro-2,3-methylenedioxyanilino)-7-fluoro-5-tetrahydropyran-4-yloxyquinazoline (0.416 g) in DMF (5 ml) and the reaction mixture was stirred and heated to 60° C. for 2 hours and to 70° C. for a further 1.5 hours. The mixture was evaporated and the residue was partitioned between ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic layer was washed with water and with brine, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using a 49:1 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound (0.36 g); NMR Spectrum: (CDCl3) 1.9–2.1 (m, 2H), 2.2–2.3 (m, 2H), 2.8 (m, 1H), 2.98 (m, 1H), 3.42 (m, 1H), 3.6–3.7 (m, 2H), 3.95–4.1 (m, 3H), 4.45 (m, 1H), 4.8 (m, 1H), 6.02 (s, 2H), 6.59 (m, 12H), 6.72 (d, 1H), 6.81 (d, 1H), 6.97 (d, 1H), 8.5 (s, 1H), 9.27 (s, 1H); Mass Spectrum: M+H+ 472 and 474.
Reaction SMILES: CS[CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[NH:5][C:4]1=[O:17]>C(O)(=O)C.[Zn]>[O:17]=[C:4]1[CH2:3][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[NH:5]1
Reactant: CCOC(=O)c1ccc2c(c1)C(SC)C(=O)N2
Agent: [Zn]
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc2c(c1)CC(=O)N2
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a solution of the compound obtained in Step A (0.1448 mol) in glacial acetic acid (700 ml) there is added powdered zinc (0.8690 mol). The two-phase mixture is stirred at 40° C. for 8 hours. The reaction mixture is filtered and the filtrate is then evaporated to dryness. The residue is stirred in water overnight and filtered and the precipitate obtained is washed with water. The product is taken up in toluene and then evaporated to dryness, and is then taken up in ether, filtered, washed with ether and then dried in vacuo at 40° C. under P2O5 to yield the title product, which is used directly in the next Step.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:28][CH2:27][C:10]2[C:11]3[C:12](Br)([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:13]([F:19])([F:18])[CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[CH2:28][CH2:27][C:10]2[C:11]3[CH:12]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:13]([F:18])([F:19])[CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2ccc3c(c2CC1)C(Br)(c1cccnc1)C(F)(F)C3
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCc2ccc3c(c2CC1)C(c1cccnc1)C(F)(F)C3
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 65.4 %

Procedure:
Into a 500 ml flask, the product from step (b) (15.2 mmol) dissolved in toluene (100 ml) was placed. The flask was purged with Ar, followed by the addition of tributyltin hydride (8.36 ml, 31.11 mmol). The reaction mixture was placed in a pre-heated (110° C.) oil bath and stirred for 20 minutes. The reaction mixture was cooled, quenched with saturated aqueous Na2CO3, and extracted with EtOAc (3×). The combined EtOAc extracts were washed with brine, dried over Na2SO4, and solvent evaporated in vacuo to give the crude product. Purification by silica-gel chromatography (gradient elution: 0 to 15% DCM w/20% MeOH, 1% NH4OH in DCM:) gave the sub-title compound as a yellow oil (3.7 g). 1H NMR (300 MHz, CDCl3) δ 8.54-8.52 (m, 1H); 8.37-8.33 (m, 1H); 7.23-7.21 (m, 2H); 7.15-7.09 (m, 2H); 4.67 (d, J=19.2, 1H); 4.14-4.08 (m, 2H); 3.69-3.60 (m, 1H); 3.53-3.48 (m, 2H); 3.42-3.34 (m, 2H); 3.21-3.10 (m, 1H); 2.92-2.87 (m, 2H); 2.65-2.58 (m, 1H); 2.52-2.44 (m, 1H); 1.32-1.20 (m, 3H); MS: ESI (positive): 373 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH2:12][C:13]#[N:14])=[C:10]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[C:11]([CH2:12][C:13]#[N:14])=[C:10]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(CC#N)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1CC#N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 23.7 %

Procedure:
To 4.0 g of methyl 2-chloro-3-cyanomethyl-4-methanesulfonylbenzoate and 50 ml of methanol, 5 ml of an aqueous solution containing 0.72 g of sodium hydroxide (93%) was gradually added. The mixture was stirred for 15 minutes at room temperature. Then, the reaction mixture was neutralized with diluted hydrochloric acid, methanol was distilled off under reduced pressure and the concentrated solution was extracted with chloroform. After washing the extract with water and drying it, chloroform was distilled off to obtain 0.9 g of the desired product. Melting point: 169°-172° C.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([OH:13])=[C:5]([C:9]([CH3:12])=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:23][O:24][CH2:25]Cl>ClCCl>[CH2:1]([C:3]1[C:4]([O:13][CH2:23][O:24][CH3:25])=[C:5]([C:9]([CH3:12])=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCc1ccc(C)c(C(=O)O)c1O
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1ccc(C)c(C(=O)O)c1OCOC
Temperature: 25 °C
Reaction time: 8 h
Yield: 111.7 %

Procedure:
A solution of ethyl 2-hydroxy-6-methylbenzoic acid (4.56 g, 25.3 mmol) and diisopropylethylamine (13.2 mL, 76 mmol) in dry dichloromethane (30 mL) was cooled in an ice-bath. Chloromethyl methyl ether (3.83 mL, 50.6 mmol) was added slowly and the mixture was allowed to stand at 0° C., warming slowly to room temperature. After 36 hours a further portion of chloromethyl methyl ether (1.9 mL) was added and the mixture was left at room temperature overnight. The mixture was then washed with 10% citric acid, water and brine, dried and evaporated to give the title compound (6.34 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[N:7]([CH3:12])[N:6]=[C:5]2I.C([Mg]Cl)(C)C.[CH2:19]([Sn:23]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])Cl)[CH2:20][CH2:21][CH3:22]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[N:7]([CH3:12])[N:6]=[C:5]2[Sn:23]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cn1nc(I)c2cc(Cl)c(Cl)cc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2cc(Cl)c(Cl)cc12
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5,6-dichloro-3-iodo-1-methyl-1H-indazole (150 mg, 0.44 mmol) in THF (3 mL) at −10° C. (ice/acetone) was slowly added isopropylmagnesium chloride (2.0 M in THF, 0.26 mL, 0.52 mmol). The bright yellow heterogeneous reaction mixture was stirred at −10° C. for 15 min then tributylchlorostannane (0.14 mL, 0.52 mmol) was added dropwise. Stirring was continued at −10° C. for 30 min then at room temperature for 1 h. The reaction mixture was quenched with water and extracted with EtOAc (2×). The combined organics were dried over MgSO4 and concentrated to afford 5,6-dichloro-1-methyl-3-tributylstannanyl-1H-indazole as a pale yellow oil which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].CO[CH:12]=[C:13]1[C:18](=[O:19])[O:17][C:16]([CH3:21])([CH3:20])[O:15][C:14]1=[O:22]>CC(O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][CH:12]=[C:13]2[C:14](=[O:22])[O:15][C:16]([CH3:20])([CH3:21])[O:17][C:18]2=[O:19])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1ccc(N)cc1Br
Reactant: COC=C1C(=O)OC(C)(C)OC1=O
Solvent: CC(C)O
Product: Cc1ccc(NC=C2C(=O)OC(C)(C)OC2=O)cc1Br
Temperature: 90 °C
Yield: 84 %

Procedure:
To a vial charged with 3-bromo-4-methylaniline (1.00 g, 5.37 mmol) was added IPA (10.75 ml) and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (1.001 g, 5.37 mmol) respectively. The mixture was heated to 90° C. for 2 hrs, providing a brown solution which was cooled to room temperature, yielding an orange precipitate which was collected by vacuum filtration affording 5-(((3-bromo-4-methylphenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (1.535 g, 4.51 mmol, 84% yield). This solid was transferred to a 5-20 ml microwave vial and 9 ml (0.5M 1,2-dichlorobenzene) was added and the mixture irradiated at 225° C. for 15 min, affording conversion to desired product according to LC-MS. To the suspension was added diethyl ether (˜5 ml) to aid in product precipitation. The precipitate was collected via vacuum filtration and washed with ether, affording a brown solid as an isomeric mixture (560 mg). To the filtrate which had some precipitate forming was added heptane affording additional precipitate. This second crop was collected affording another 115 mg of product (53% yield total). m/z (ESI) 238.1/240.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:19])=[C:4]([CH:6]=[C:7]([CH3:18])[C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])[NH2:5].[F:20][C:21]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:22]=1[C:23]([N:25]=[C:26]=[O:27])=[O:24].CCCCCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([CH3:19])=[C:4]([NH:5][C:26]([NH:25][C:23](=[O:24])[C:22]2[C:28]([F:32])=[CH:29][CH:30]=[CH:31][C:21]=2[F:20])=[O:27])[CH:6]=[C:7]([CH3:18])[C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17]
Reactant: Cc1cc(N)c(C)c(Cl)c1Oc1ccc(Cl)cc1Cl
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: Cc1cc(NC(=O)NC(=O)c2c(F)cccc2F)c(C)c(Cl)c1Oc1ccc(Cl)cc1Cl
Yield: 96.8 %

Procedure:
Into a magnetically stirred solution of 3-chloro-4-(2,4-dichlorophenoxy)-2,5-dimethylaniline (1.5 grams, 4.73 mmol) prepared in Part B in toluene (15 milliliters) under nitrogen atmosphere was added neat 2,6-difluorobenzoyl isocyanate (1.3 grams, 7.10 mmol) and the mixture was refluxed for a period of 1 hour. The reaction mixture was allowed to cool and hexane (3 milliliters) was added to induce crystallization. The resultant precipitate was filtered and washed successively with hexane and toluene to give pure 1-[3-chloro-4-(2,4-dichlorophenoxy)-2,5-dimethylphenyl]-3-(2,6-difluorobenzoyl) urea (2.29 grams, 4.58 mmol, 97%) as a white solid having a melting point of 188° C.-190° C. Elemental analysis of the white solid indicated the following:
Reaction SMILES: [I:1][C:2]1[NH:6][C:5]([C:7]([O:9]CC)=[O:8])=[N:4][C:3]=1[CH3:12].[OH-].[Na+].Cl>CO.O>[I:1][C:2]1[NH:6][C:5]([C:7]([OH:9])=[O:8])=[N:4][C:3]=1[CH3:12]
Reactant: CCOC(=O)c1nc(C)c(I)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nc(C(=O)O)[nH]c1I
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of ethyl 5-iodo-4-methyl-1H-imidazole-2-carboxylate (compound 239.2, 200 mg, 0.71 mmol) in methanol (4 mL). A solution of sodium hydroxide (114 mg, 2.85 mmol) in water (2 mL) was added to the reaction. The reaction mixture was stirred for 2 h at 60° C. The pH of the solution was adjusted to 1-2 with hydrogen chloride (1 M). The resulting mixture was concentrated under reduced pressure. Methanol (5 mL) was added to the residue. The salt was filtered off and the filtrate was concentrated under reduced pressure to give 290 mg (crude) of the title compound as a white solid.
Reaction SMILES: [OH-].[K+].O1CCCCC1OC1CCCCO1.Cl[CH2:17][CH2:18][OH:19].[CH2:20]([OH:30])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH2:18]([OH:19])[CH2:17][O:30][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCO
Reactant: OCCCl
Agent: C1CCC(OC2CCCCO2)OC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCOCCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
44.88 g (800 mmol) of fine powdered potassium hydroxide is added to 32.93 g (200 mmol) of the tetrahydropyranyl ether of 2-chloroethanol, 1 g (3.6 mmol) of tetrabutylammonium chloride and 20 g (126.36 mmol) of decan-1-ol in 300 ml of toluene, and it is refluxed for 24 hours. Solid is filtered out, and the filtrate is evaporated to the dry state. 500 ml of ethanol/50 ml of 10% aqueous hydrochloric acid are added to the residue (oil) that is thus obtained, and it is stirred for one hour at room temperature. It is evaporated to the dry state in a vacuum, and the residue is chromatographed on silica gel (mobile solvent: hexane/acetone=20:1).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:16]([OH:18])=O)=[N:8][C:9]=2[O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH2:3][CH2:2]1.Cl.[S:20]1[CH:24]=[CH:23][N:22]=[C:21]1[C:25]1([NH2:29])[CH2:28][O:27][CH2:26]1>>[S:20]1[CH:24]=[CH:23][N:22]=[C:21]1[C:25]1([NH:29][C:16]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])[N:8]=2)=[O:18])[CH2:28][O:27][CH2:26]1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC(F)(F)F)n1
Reactant: NC1(c2nccs2)COC1
Agent: Cl
Product: O=C(NC1(c2nccs2)COC1)c1ccc(C2CC2)c(OCC(F)(F)F)n1

Procedure:
The title compound was synthesized in analogy to Example 280c, using 5-cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 301a) and 3-(thiazol-2-yl)oxetan-3-amine hydrochloride (Example 281b) as starting materials, MS (EI): m/e=400.1 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([OH:13])[C:10]2[CH2:9][C:8]([CH3:15])([CH3:14])[CH2:7][CH2:6][C:5]=2[N:4]=1.[CH3:16][NH:17][CH3:18]>C1COCC1>[CH3:16][N:17]([CH2:2][C:3]1[N:12]=[C:11]([OH:13])[C:10]2[CH2:9][C:8]([CH3:15])([CH3:14])[CH2:7][CH2:6][C:5]=2[N:4]=1)[CH3:18]
Reactant: CNC
Reactant: CC1(C)CCc2nc(CCl)nc(O)c2C1
Solvent: C1CCOC1
Product: CN(C)Cc1nc(O)c2c(n1)CCC(C)(C)C2
Temperature: 60 °C

Procedure:
To a solution of 2-(chloromethyl)-6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-ol (2.5 g, 11 mmol) in THF (10 mL) was added dimethyl amine (2M in THF, 16.5 mL, 33 mmol). The reaction mixture was heated (60° C.) for two hours and then partitioned between ethyl acetate and sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to provide 2-((dimethylamino)methyl)-6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-ol, which was used in step 3 without further purification. MS (ES) for C13H21N3O: 236 (MH+).