Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][N:5]1[CH:9]=[C:8]([CH2:10][O:11][Si:12]([CH2:17][CH3:18])([CH2:15][CH3:16])[CH2:13][CH3:14])[N:7]=[CH:6]1)[CH3:2].C([Li])CCC.CON(C)[C:27](=[O:29])[CH3:28].[Cl-].[NH4+]>C1COCC1>[CH2:1]([O:3][CH2:4][N:5]1[CH:9]=[C:8]([CH2:10][O:11][Si:12]([CH2:13][CH3:14])([CH2:17][CH3:18])[CH2:15][CH3:16])[N:7]=[C:6]1[C:27](=[O:29])[CH3:28])[CH3:2]
Reactant: CCOCn1cnc(CO[Si](CC)(CC)CC)c1
Reactant: CON(C)C(C)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOCn1cc(CO[Si](CC)(CC)CC)nc1C(C)=O
Temperature: -78 °C
Reaction time: 17 h

Procedure:
The compound (665 mg) obtained in (3) was dissolved in THF (20 mL), and cooled to −78° C. while stirring under an argon atmosphere. To the present solution was added dropwise n-butyl lithium (2.69 M hexane solution, 1.50 mL) slowly using a syringe, followed by stirring at the same temperature for 30 minutes. Then, N-methoxy-N-methylacetamide (0.50 mL) was added using a syringe, and stirring was continued for 17 hours while the temperature was raised to room temperature. A saturated aqueous ammonium chloride solution was added to the reaction solution to terminate the reaction, followed by extraction with ethyl acetate. The combined extract was washed with saturated brine, dried over anhydrous sodium sulfate, and subsequently the solvent was distilled off under reduced pressure. The resulting residue was purified by flash chromatography (ethyl acetate/hexane=5%→30%) using silica gel column (product name: SNAP Cartridge KP-Sil 50 g, manufactured by Biotage, Ltd.) to afford the title compound (520 mg).
Reaction SMILES: C[Si](C#CC1C=CN=CC=1)(C)C.CCCC[Sn](O[Sn](CCCC)(CCCC)CCCC)(CCCC)CCCC.[CH2:40]([Sn:44]([C:53]#[C:54][C:55]1[CH:60]=[CH:59][N:58]=[CH:57][CH:56]=1)([CH2:49][CH2:50][CH2:51][CH3:52])[CH2:45][CH2:46][CH2:47][CH3:48])[CH2:41][CH2:42][CH3:43].C(C1C=CN=CC=1)#C.[N:69]([CH2:72][C:73]1[CH:78]=[C:77]([C:79]([F:82])([F:81])[F:80])[CH:76]=[C:75]([C:83]([F:86])([F:85])[F:84])[CH:74]=1)=[N+:70]=[N-:71]>C1COCC1.C[Si](C)(C)[O-].[K+]>[F:80][C:79]([F:81])([F:82])[C:77]1[CH:78]=[C:73]([CH:74]=[C:75]([C:83]([F:86])([F:84])[F:85])[CH:76]=1)[CH2:72][N:69]1[C:54]([C:55]2[CH:56]=[CH:57][N:58]=[CH:59][CH:60]=2)=[C:53]([Sn:44]([CH2:45][CH2:46][CH2:47][CH3:48])([CH2:49][CH2:50][CH2:51][CH3:52])[CH2:40][CH2:41][CH2:42][CH3:43])[N:71]=[N:70]1
Reactant: CCCC[Sn](C#Cc1ccncc1)(CCCC)CCCC
Reactant: [N-]=[N+]=NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: C#Cc1ccncc1
Agent: CCCC[Sn](CCCC)(CCCC)O[Sn](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)C#Cc1ccncc1
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccncc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
Add potassium trimethylsilanolate (0.651 g, 4.56 mmol, 90% purity) in one portion to a solution of 4-[(trimethylsilanyl)ethynyl]pyridine (40.0 g, 228 mmol, Ziessel, R., et al. J. Org. Chem. 1996, 61, 6535) and bis(tributyltin) oxide (95.2 g, 160 mmol) in THF (400 mL) while keeping the temperature between 25-30° C. with a water bath. After approximately 1 hour, concentrate the solution by rotary evaporation (50° C.) to give an oil containing 78-85% 4-[(tributylstannanyl)ethynyl]pyridine, 15-22% 4-ethynylpyridine and excess bis(tributyltin) oxide. Add 1-azidomethyl-3,5-bis(trifluoromethyl)benzene (73.7 g, 274 mmol) to the oil and heat at 110° C., distilling off any volatiles required to achieve the desired temperature. Heat the solution until the reaction is complete by 1H-NMR analysis (approximately 22 h). After cooling to 50° C., dilute the reaction mixture with heptane (600 mL) and stir at room temperature. Filter the mixture to remove the solids. Purify the mixture by pouring the heptane solution on a silica gel column (810 g silica gel in a 2 L fritted-glass funnel) and elute sequentially with heptane (5.2 L), 1:10 EtOAc:heptane (5.1 L), and 1:3 EtOAc:heptane (12.6 L). Combine the fractions containing product and concentrate by rotary evaporation to give 124 g (82% yield) of the title compound; mp 61.9-63.1° C.; Analysis for C28H36F6N4Sn: Calcd: C, 50.86; H, 5.49; N, 8.47. Found: C, 51.08, H, 5.61; N, 8.50.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:12]([CH:15]([CH3:17])[CH3:16])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:18]([NH:20][CH2:21][CH3:22])[CH3:19]>CN(C)C=O>[CH2:18]([N:20]([CH2:21][CH3:22])[C:2]1[C:3]2[N:4]([C:12]([CH:15]([CH3:17])[CH3:16])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:19]
Reactant: CC(C)c1nnc2c(Cl)nc3ccccc3n12
Reactant: CCNCC
Solvent: CN(C)C=O
Product: CCN(CC)c1nc2ccccc2n2c(C(C)C)nnc12
Yield: 75 %

Procedure:
4-Chloro-1-isopropyl-[1,2,4]-triazolo[4,3-a]quinoxaline (1.0 g., 0.004 mole), the product of Example 6, and 900 mg. (0.012 mole) of diethylamine in N,N-dimethylformamide (15 ml.) were stirred at room temperature for 4 hours. The reaction mixture was poured over ice and the precipitate was separated by means of filtration, washed with water and placed on a column of silica gel (175 ml.) and finally eluted with chloroform. The eluant was evaporated in vacuo to afford 850 mg. (75% yield) of pure 4-diethylamino-1-isopropyl-[1,2,4]triazolo[4,3-a]quinoxaline as a white solid (m.p. 93°-95° C.). Mass spectrum: m/e, 283 (P). The pure product (100 mg.) was then distilled in vacuo (0.1 mm) at 140° to 150° C. to afford the analytical sample (80 mg.), m.p. 94°-96° C.
Reaction SMILES: [O:1]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:14]=[C:15]([CH2:20][CH2:21][OH:22])[CH:16]=[C:17]([F:19])[CH:18]=3)[CH2:8][CH2:7]2)[CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:30]([C:33]1[S:34][C:35]([C:38](O)=[O:39])=[CH:36][N:37]=1)([CH3:32])[CH3:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:19][C:17]1[CH:18]=[C:13]([CH:14]=[C:15]([CH2:20][CH2:21][OH:22])[CH:16]=1)[CH2:12][N:9]1[CH2:10][CH2:11][C:6]2([O:1][CH2:2][CH2:3][N:4]([C:38]([C:35]3[S:34][C:33]([CH:30]([CH3:32])[CH3:31])=[N:37][CH:36]=3)=[O:39])[CH2:5]2)[CH2:7][CH2:8]1
Reactant: CC(C)c1ncc(C(=O)O)s1
Reactant: OCCc1cc(F)cc(CN2CCC3(CC2)CNCCO3)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)c1ncc(C(=O)N2CCOC3(CCN(Cc4cc(F)cc(CCO)c4)CC3)C2)s1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)-5-fluorophenyl)ethanol (example 55, step c) (0.153 g) in DMF (7 mL) was treated with triethylamine (0.208 mL) followed by 2-isopropylthiazole-5-carboxylic acid (example 55, step b) (0.085 g). The mixture was cooled to 0° C. and HATU (0.245 g) was added. The reaction mixture was stirred for 2 hours at 20° C. The mixture was partitioned between ethyl acetate and brine, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 2.5% methanol in dichloromethane with 1% triethylamine as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.130 g.
Reaction SMILES: [C:1]([C@@H:3]1[NH:6][C:5](=[O:7])[C@H:4]1[NH:8]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[CH:2].N1C=CC=CC=1.[S:34](=[O:37])(=[O:36])=[O:35].C(O)=O>ClCCl>[NH2:8][C@H:4]1[C@H:3]([C:1]#[CH:2])[N:6]([S:34]([OH:37])(=[O:36])=[O:35])[C:5]1=[O:7]
Reactant: C#C[C@@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=S(=O)=O
Solvent: c1ccncc1
Solvent: O=CO
Solvent: ClCCl
Product: C#C[C@H]1[C@H](N)C(=O)N1S(=O)(=O)O

Procedure:
(S)-(trans)-4-ethynyl-2-oxo-3-[(triphenylmethyl)amino]azetidine (404 mg) and 560 mg of a complex of pyridine and sulfur trioxide are added to a 25 ml flask. After the flask is flushed with nitrogen, 4.0 ml of dry pyridine is added and the mixture is heated at 80°-85° C. for 3 hours. The mixture is added to a rapidly stirred mixture of 4.0 ml of concentrated hydrochloric acid, 50 ml of water, and 50 ml of ethyl acetate. The pH is adjusted to 3.15 with sodium carbonate. The water layer is separated and extracted once with ethyl acetate. The combined organic layer is washed once with saturated aqueous sodium chloride, dried over sodium sulfate and filtered. Solvent removal in vacuo gives a foam which is taken up in 10 ml of dichloromethane. Formic acid (98%, 8 ml) is added, and after 15 minutes the mixture is concentrated to 4 ml and 10 ml of dichloromethane is added to give a solid suspended in solution. Filtration gives 100 mg of the title compound as a solid (obvious discoloration with melting >180° C.).
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([NH:10][CH2:11][C:12]1[CH:13]=[C:14]([CH:32]=[CH:33][CH:34]=1)[O:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[NH:23][CH2:24][CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])=[O:9])([CH3:6])([CH3:5])[CH3:4].O.Cl>O1CCCC1.C(O)C>[C:3]([O:7][C:8]([NH:10][CH2:11][C:12]1[CH:13]=[C:14]([CH:32]=[CH:33][CH:34]=1)[O:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[NH:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)CCCNc1ccc(Cl)cc1Oc1cccc(CNC(=O)OC(C)(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1cccc(Oc2cc(Cl)ccc2NCCCC(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
Aqueous 1 N sodium hydroxide solution (15 ml, 15 mmols) was added to a solution of ethyl 4-[2-[3-(tert-butoxycarbonylaminomethyl)phenoxy]-4-chlorophenyl]aminobutyrate (4.6 g, 10 mmols) in tetrahydrofuran (15 ml) and ethanol (15 ml). The resulting mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, which was acidified with 1 N hydrochloric acid added thereto, and then extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure to give an amorphous solid of 4-[2-[3-(tert-butoxycarbonylaminomethyl)phenoxy]-4-chlorophenyl]aminobutyric acid (4.1 g, 95%).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:16]=[C:15]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C:8]([O:10]CC)=[O:9].CCO.Cl>O>[Cl:3][C:4]1[CH:16]=[C:15]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)COc1ccc(-c2ccco2)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)COc1ccc(-c2ccco2)cc1Cl

Procedure:
0.40 g (10.00 mmol) NaOH in 5 mL water was added to a solution of 0.280 g (2.672 mmol) ethyl (2-chloro-4-furan-2-yl-phenoxy)-acetate (130a) in 20 mL abs. EtOH and the mixture was stirred for 16 h at RT. The reaction mixture was diluted with water and acidified to pH 1 with semiconc. aqueous HCl. The precipitate was filtered off, washed with water and dried in a HV.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[C:11]2[CH:16]=[C:15]([CH2:17][CH3:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=3)[C:11]3[CH:16]=[C:15]([CH2:17][CH3:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: CCc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(Cl)nc2s1
Product: CCc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-n3ccnc3C)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-ethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-ethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[C:15]([F:21])[CH:14]=1)[N:8]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:7][CH2:6]2.C(Cl)Cl>CO.C(Cl)Cl>[C:22]1([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([OH:2])[CH:4]=3)[CH:9]2[C:13]2[CH:18]=[C:17]([F:19])[C:16]([F:20])=[C:15]([F:21])[CH:14]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc2c(c1)CCN(c1ccccc1)C2c1cc(F)c(F)c(F)c1
Solvent: ClCCl
Solvent: CO
Product: Oc1ccc2c(c1)CCN(c1ccccc1)C2c1cc(F)c(F)c(F)c1

Procedure:
The title compound was prepared by analogy to Example 48 except that 6-methoxy-2-phenyl-1-(3,4,5-trifluoro-phenyl)-1,2,3,4-tetrahydroisoquinoline was used instead of 6-methoxy-1-(4-methoxy-phenyl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline, and neat CH2Cl2 to 10% MeOH/CH2Cl2 was used as eluent for flash chromatography purification.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:25]=[C:26]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:27]=1)[CH2:8][C@H:9]1[CH2:14][C@H:13]([C:15]2[O:19][NH:18][C:17](=[O:20])[CH:16]=2)[CH2:12][CH2:11][N:10]1C(OC)=O)([CH3:4])([CH3:3])[CH3:2].Br>>[C:28]([C:26]1[CH:25]=[C:7]([CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:27]=1)[CH2:8][C@H:9]1[CH2:14][C@H:13]([C:15]2[O:19][NH:18][C:17](=[O:20])[CH:16]=2)[CH2:12][CH2:11][NH:10]1)([CH3:30])([CH3:31])[CH3:29]
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1cc(C(C)(C)C)cc(C(C)(C)C)c1
Agent: Br
Product: CC(C)(C)c1cc(C[C@H]2C[C@H](c3cc(=O)[nH]o3)CCN2)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.7 %

Procedure:
Trans-Methyl 2-(3,5-di-tert-butylbenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (155 mg, 0.36 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 3 mL, 17.13 mmol) and the mixture stirred at room temperature overnight. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx III, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-(trans-2-(3,5-di-tert-butylbenzyl)piperidin-4-yl)isoxazol-3(2H)-one (69 mg, 51%). 1H NMR (600 MHz, DMSO) δ 1.26 (s, 18H), 1.45-1.53 (m, 1H), 1.69-1.87 (m, 3H), 2.58-2.72 (m, 3H), 2.83-2.93 (m, 2H), 3.09-3.16 (m, 1H), 5.64 (s, 1H), 6.99 (d, 2H), 7.18-7.23 (m, 1H). HRMS Calculated for [C23H34N2O2+H]+: 371.2698. Found: 371.2688
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Li]CCCC.[OH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=O)[CH3:19])=[CH:14][CH:13]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1.C1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:18]([C:15]1[CH:16]=[CH:17][C:12]([OH:11])=[CH:13][CH:14]=1)=[CH2:19]
Reactant: c1ccsc1
Reactant: CC(=O)c1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Li]CCCC
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: C=C(c1ccc(O)cc1)c1cccs1
Temperature: -78 °C
Reaction time: 2 h
Yield: 11.5 %

Procedure:
A solution of thiophene (0.60 mL, 7.5 mmol) in THF (15 mL) was cooled to −78° C., BuLi solution (2.5 M in hexanes, 3.0 mL, 7.5 mmol) was added dropwise, after 1 h at −78° C., a solution of 1-(4-hydroxy-phenyl)-ethanone (1.0 g, 7.34 mmol) was added. The slurry mixture was stirred at −78° C. for 2 h, then slowly warmed to rt. The reaction was quenched with saturated aqueous NH4Cl, extracted with ethyl acetate, the extract was washed with brine, dried over MgSO4 and concentrated to give yellow oil residue. To the above oil residue was added benzene (10 mL) and catalytic amount of TsOH. The mixture was heated with Dean-Stark trap for 15 min, then concentrated 4-(1-Thiophen-2-yl-vinyl)-phenol (170 mg, 11.5%) was obtained after flash column chromatography (20%–40% ethyl acetate-hexanes). MS Found: (M+H)+=203.
Reaction SMILES: [CH3:1][C:2]1[C:11]([NH:12][C:13](=[S:21])OC2C=CC=CC=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:22][C:23]1[CH:24]=[C:25]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:26]=[C:27]([F:29])[CH:28]=1>>[CH3:1][C:2]1[C:11]([NH:12][C:13]([N:33]2[CH2:32][CH2:31][N:30]([C:25]3[CH:24]=[C:23]([F:22])[CH:28]=[C:27]([F:29])[CH:26]=3)[CH2:35][CH2:34]2)=[S:21])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1nc2ccccc2cc1NC(=S)Oc1ccccc1
Reactant: Fc1cc(F)cc(N2CCNCC2)c1
Product: Cc1nc2ccccc2cc1NC(=S)N1CCN(c2cc(F)cc(F)c2)CC1
Yield: 74 %

Procedure:
Phenyl N-(2-methylquinolin-3-yl)thiocarbamate and 1-(3,5-difluorophenyl)piperazine were reacted by the same way with the example 125 to obtain the titled compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1.[NH:11]1[CH:15]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:19]([O:18][C:16]([C:14]1[CH:15]=[N:11][N:12]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=2)[CH:13]=1)=[O:17])[CH3:20]
Reactant: OCc1ccc(CCl)cc1
Reactant: CCOC(=O)c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cnn(Cc2ccc(CO)cc2)c1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of (4-Chloromethyl-phenyl)-methanol (600 mg, 3.8 mmol), ethyl 1H-pyrazole-4-carboxylate (537 mg, 3.8 mmol) and potassium carbonate (2.6 g, 19 mmol) in 30 mL acetone was stirred at 50° C. for 3 h. The mixture was filtrated and concentrated in vacuo. The crude was purified by preparative HPLC (Waters Sunfire Prep C18 PBD 5 um, 30×100 mm, 5 to 100% ACN and 0.1% TFA, flow 40 ml/min) to yield the title compound. LCMS (method A) RtA=1.403 min; [M+H]+=261.0.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][N:28]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(NC(C)C)(C)C>O1CCOCC1.[Cu]I>[N:28]1[CH:27]=[C:32]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:31]=[N:30][CH:29]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Brc1ccncn1
Agent: [Cu]I
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: CC(C)NC(C)C
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3ncc(C#Cc4cncnc4)c3n2)cc1
Temperature: 23 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a flask was added 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (159 mg, 0.45 mmol), 4-Bromopyrimidine (87 mg, 0.55 mmol, commercially available [CAS 4595-59-9]), PdCl2(NCPh)2 (13 mg, 7 mol %), and CuI (10 mg, 12 mol %). The flask was charged with Ar, then 3 mL of dioxane (degassed with Ar), tri-(tert-butyl)phosphine (0.12 mL of a 0.25M soln in dioxane, 33 mol %), and diisopropylamine (0.15 mL) were added. The r×n mixture was stirred at 23° C. under Ar overnight, then filtered through a pad of Si-gel, concentrated, purified by Si-gel chromatography (EtOAc/heptane 5-40:95-60) to give an orange solid. Recrystallization from EtOAc/heptane (1:2) yielded the product as an orange solid (131 mg, 68%). MS (ISP) 434.1 [(M+H)+]; mp 175° C.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([O:10][CH3:11])[CH:5]=1.O.[NH2:14][NH2:15]>C(O)C>[CH3:11][O:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][N:7]=1)[C:3]([NH:14][NH2:15])=[O:2]
Reactant: NN
Reactant: COC(=O)c1ccnc(OC)c1
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)NN)ccn1
Temperature: 75 °C
Reaction time: 12 h
Yield: 80.3 %

Procedure:
2-Methoxy-isonicotinic acid methyl ester (23.0 g, 137 mmol) and hydrazine hydrate (8.95 g, 178 mmol) were dissolved in ethanol and stirred at 75° C. for 12 hours. The reaction mixture was concentrated and the remaining solid was tritiated in hexanes/ether (80:20), filtered and dried to afford the title compound as a solid (18.4 g, 80%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:28])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10](=[O:21])[C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:8]2)=[O:4].[Br:29]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:28])=[C:7]2[C:12](=[C:13]([Br:29])[N:14]=1)[N:11]([CH2:15][CH:16]([CH2:17][CH3:18])[CH2:19][CH3:20])[C:10](=[O:21])[C:9]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[CH:8]2)=[O:4]
Reactant: CCC(CC)Cn1c(=O)c(-c2ccccc2)cc2c(O)c(C(=O)OC)ncc21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCC(CC)Cn1c(=O)c(-c2ccccc2)cc2c(O)c(C(=O)OC)nc(Br)c21
Yield: 64.1 %

Procedure:
A mixture of 1-(2-ethyl-butyl)-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (200 mg, 0.53 mmol) and N-bromosuccinimide (103 mg, 0.58 mmol) in CH2Cl2 (2 mL) was refluxed for 3 h. Solvent was evaporated in vacuo, and the residue was purified by silica gel chromatography (3-15% EtOAc/hexanes+1% AcOH) to give 156 mg of the title compound as a yellow solid. MS: (+) m/z 459.31, 461.13 (M+1, 79/81Br).
Reaction SMILES: [CH2:1]([C:3]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH3:18])[C:4]=1[N:5]([CH2:10]OC)[C:6](=[O:9])[CH2:7][Cl:8])[CH3:2].O=S(Cl)[Cl:21]>>[CH2:1]([C:3]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH3:18])[C:4]=1[N:5]([CH2:10][Cl:21])[C:6](=[O:9])[CH2:7][Cl:8])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCc1cccc(CC)c1N(COC)C(=O)CCl
Product: CCc1cccc(CC)c1N(CCl)C(=O)CCl

Procedure:
Ten (10.0) g of 2',6'-diethyl-N-(methoxymethyl)-2-chloroacetanilide (common name "alachlor") when refluxed with 60 ml of SOCl2 for periods from 12-24 hours gave little evidence of the formation of 2',6'-diethyl-N-(chloromethyl)-2-chloroacetanilide ("CMA"), the desired product.
Reaction SMILES: [Cl:1][S:2]([N:5]=C=O)(=[O:4])=[O:3].[S:8](Cl)(=[O:11])(=[O:10])[NH2:9].[CH2:13]([O:15][C:16](=[O:29])[CH2:17][NH:18][CH2:19][C:20]1[O:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[CH:24]=1)[CH3:14].Cl>C(Cl)Cl.C(N(CC)CC)C.C(O)=O>[S:2]([Cl:1])(=[O:4])(=[O:3])[NH2:5].[CH2:13]([O:15][C:16](=[O:29])[CH2:17][N:18]([CH2:19][C:20]1[O:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[CH:24]=1)[S:8](=[O:11])(=[O:10])[NH2:9])[CH3:14]
Reactant: CCOC(=O)CNCc1cc2ccccc2o1
Reactant: O=C=NS(=O)(=O)Cl
Agent: Cl
Agent: NS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O=CO
Solvent: ClCCl
Product: CCOC(=O)CN(Cc1cc2ccccc2o1)S(N)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stock of sulfamyl chloride was prepared by adding formic acid to chlorosulfonyl isocyanate. The sulfamyl chloride was added to a room temperature solution of 104 and triethyl amine in methylene chloride. The reaction was stirred at room temperature overnight. TLC (30% ethyl acetate/hexanes) showed a major spot and a minor product. The reaction was poured into 10% HCl, extracted with methylene chloride, dried over sodium sulfate, filtered, and concentrated to a thick yellow syrup. The crude syrup was adsorbed onto silica and purified by flash chromatography with 15-30% ethyl acetate/hexanes to obtain the final product 105 as a light yellow film.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][CH3:30])=[O:28])=[C:22]([Cl:31])[CH:21]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[C:32]#[N:33])C1C=CC=CC=1.C1(SC)C=CC=CC=1>FC(F)(F)C(O)=O>[Cl:31][C:22]1[CH:21]=[C:20]([O:19][C:13]2[C:12]3[C:17](=[CH:18][C:9]([OH:8])=[C:10]([C:32]#[N:33])[CH:11]=3)[N:16]=[CH:15][CH:14]=2)[CH:25]=[CH:24][C:23]=1[NH:26][C:27]([NH:29][CH3:30])=[O:28]
Reactant: CNC(=O)Nc1ccc(Oc2ccnc3cc(OCc4ccccc4)c(C#N)cc23)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: CNC(=O)Nc1ccc(Oc2ccnc3cc(O)c(C#N)cc23)cc1Cl
Temperature: 50 °C
Reaction time: 8 h
Yield: 109.1 %

Procedure:
After adding N-[4-(7-benzyloxy-6-cyanoquinolin-4-yloxy)-2-chlorophenyl]-N′-methylurea (968 mg) and thioanisole (3.7 ml) to trifluoroacetic acid (10 ml), the mixture was stirred overnight at 50° C. It was then concentrated under reduced pressure, ethyl acetate and aqueous sodium bicarbonate were added and the precipitated crystals were filtered out and washed with ethyl acetate to obtain the title compound (849 mg).