Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:17]([C:18](=[O:20])[CH3:19])=[CH:16][C:5]2[O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][C:4]=2[CH:3]=1.C[O-].[Na+].[CH:24](OCC)=O>COCCOC.O>[NH:1]1[C:2]2[CH:3]=[C:4]3[O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][C:5]3=[CH:16][C:17]=2[C:18](=[O:20])[CH:19]=[CH:24]1
Reactant: CCOC=O
Reactant: CC(=O)c1cc2c(cc1N)OCCOCCOCCO2
Agent: C[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=c1cc[nH]c2cc3c(cc12)OCCOCCOCCO3
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
To a solution of 1-(3-Amino-6,7,9,10,12,13-hexahydro-5,8,11,14-tetraoxa-benzocyclododecen-2-yl)-ethanone (108 mmol, 29.3 g) in DME (700 ml) was added sodium methoxide (432 mmol, 23.35 g). The mixture was stirred for 30 minutes. Ethyl formate (540 mmol, 44 ml) was added and the mixture was stirred overnight. (Additional sodium methoxide may be needed if reaction is not complete as monitored by LC/MS.) After the reaction was completion, the mixture was diluted with water (40 ml) and acidified to neutral with 1M HC 1. The precipitate was filtered and washed with water, dried in vacuo to afford 22 g (72%) of 7,8,10,11,13,14-Hexahydro-1H-6,9,12,15-tetraoxa-1-aza-cyclododeca[b]naphthalen-4-one. 1HNMR (400 MHz, DMSO) δ 8.58 (s, 1H), 7.52 (s, 1H), 7.22 (s, 1H), 7.12 (m, 1H), 4.35 (s, 4H), 3.87 (d, 4H), 3.62 (s, 4H). LC/MS Calcd for (M+H)+292.3. found 292.5.
Reaction SMILES: [CH2:1]([C:5]1[O:9][N:8]=[C:7]([CH3:10])[CH:6]=1)[C:2]([CH3:4])=[O:3].[CH3:11][C:12]1[O:17][C:16](=[O:18])[CH2:15][CH2:14][CH:13]=1.C(=O)([O-])[O-].Cl>C(#N)C>[CH3:10][C:7]1[CH:6]=[C:5]([CH2:1][C:2](=[O:3])[CH2:4][C:16](=[O:18])[CH2:15][CH2:14][CH2:13][C:12](=[O:17])[CH3:11])[O:9][N:8]=1
Reactant: CC(=O)Cc1cc(C)no1
Reactant: CC1=CCCC(=O)O1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: CC(=O)CCCC(=O)CC(=O)Cc1cc(C)no1
Temperature: 0 °C
Yield: 80.9 %

Procedure:
1.39 g of 5-acetonyl-3-methylisoxazole, 1.68 g of 3,4-dihydro-6-methyl-2H-pyran-2-one and 3.42 g of cecium carbonate were added to 20 ml of acetonitrile to heat at reflux for 3 hours. After returning to room temperatrure, the reaction solution was poured into 100 ml of ice water with hydrochloric acid added, and extracted with ethyl acetate. The organic layer was washed with water and then with saturated salt water, and dried over magnesium sulfate. The solvent was concentrated under reduced pressure. The obtained crude product was purified on silica gel column chromatography to give 2.03 g of the title compound as a colorless viscous liquid.
Reaction SMILES: O=C(C)[CH2:3][CH2:4][S:5][Sn:6]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH2:9][CH3:10].S1C=CC=C1CC(O)=O.[CH3:29][S:30](C=C)(=[O:32])=[O:31].[Sn]=O>>[CH3:29][S:30]([CH2:3][CH2:4][S:5][Sn:6]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH2:9][CH3:10])(=[O:32])=[O:31]
Reactant: C=CS(C)(=O)=O
Reactant: CCCC[Sn](CCCC)(CCCC)SCCC(C)=O
Agent: O=C(O)Cc1cccs1
Agent: O=[Sn]
Product: CCCC[Sn](CCCC)(CCCC)SCCS(C)(=O)=O
Yield: 41 %

Procedure:
This compound was prepared analogously to (5), starting from thiolacetic acid and methylvinylsulphone, leading to the intermediate sulphone (47%), treating subsequently with the tin oxide to give the required product (6) (41%). All spectroscopic and analytical data were consistent with the proposed structures.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[N:11][NH:12]2)=[CH:8][CH:7]=1)=[O:4].[F:15][C:16]1[CH:28]=[CH:27][C:19]([CH2:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:18][CH:17]=1>C(OCC)C>[F:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][CH:21]2[CH2:22][CH2:23][N:24]([CH2:2][C:3]([NH:5][C:6]3[CH:14]=[C:13]4[C:9]([CH:10]=[N:11][NH:12]4)=[CH:8][CH:7]=3)=[O:4])[CH2:25][CH2:26]2)=[CH:27][CH:28]=1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Reactant: O=C(CCl)Nc1ccc2cn[nH]c2c1
Solvent: CCOCC
Product: O=C(CN1CCC(Cc2ccc(F)cc2)CC1)Nc1ccc2cn[nH]c2c1

Procedure:
The title compound is prepared from 2-chloro-N-(1H-indazol-6-yl)-acetamide and 4-(4-fluoro-benzyl)-piperidine according to the method described in Example 142b. Melting Point: 135-137° C. (diethylether)
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[CH:22]=[CH:21][C:20](I)=[CH:19][N:18]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[CH3:24][C:25]1[C:29](C(B(O)O)=O)=[C:28]([CH3:35])[O:27][N:26]=1>C(=O)([O-])[O-].[Na+].[Na+].COCCOC.C(OCC)(=O)C.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>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[CH:22]=[CH:21][C:20]([C:29]5[C:25]([CH3:24])=[N:26][O:27][C:28]=5[CH3:35])=[CH:19][N:18]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1noc(C)c1C(=O)B(O)O
Reactant: Ic1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1
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: COCCOC
Solvent: CCOC(C)=O
Product: Cc1noc(C)c1-c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1

Procedure:
A mixture of 3-cyclobutyl-7-[(5-iodo-2-pyridinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine (E207) (252 mg, 0.6 mmol), 3,5 dimethyl-4-isoxazoyl boronic acid (168 mg, 1.2 mmol) and tetrakis(triphenylphosphine)palladium(0) in 2M sodium carbonate solution (5 ml) and ethylene glycol dimethyl ether (10 ml) was stirred at reflux for 14 hours. The reaction mixture was diluted with ethyl acetate and washed with a saturated solution of sodium bicarbonate, water, brine and dried (sodium sulfate). The organic layer was filtered, concentrated in vacuo and the resulting residue was purified by column chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (0.5:4.5:95) to afford the title compound (E222); MS (ES+) m/e 390 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:7][C:8]2([OH:25])[CH2:13][CH2:12][N:11]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:28]N(C)P(N(C)C)(N(C)C)=O.CI>C1COCC1.OS([O-])(=O)=O.[Na+]>[CH:1]1([CH2:7][C:8]2([O:25][CH3:28])[CH2:13][CH2:12][N:11]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: CCOC(=O)c1ccc(N2CCC(O)(CC3CCCCC3)CC2)cc1
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)c1ccc(N2CCC(CC3CCCCC3)(OC)CC2)cc1
Temperature: 50 °C

Procedure:
A solution of EXAMPLE 1F (380 mg) in THF (5 mL) was treated with NaH (96 mg, 60% dispersion in mineral oil), heated to 50° C. for 2 hours, and treated with hexamethylphosphoramide (1 mL) followed by MeI (1 mL). The reaction mixture was refluxed overnight, cooled to 0° C., and diluted with saturated aqueous NaHSO4 solution (10 mL). The resulting two-phase mixture was separated, the aqueous phase was extracted twice with ether, and the combined organic layers washed with water and brine. After drying over MgSO4, the mixture was concentrated in vacuo and purified by silica gel chromatography eluting with 15% ethyl acetate in hexanes.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:11][CH3:12])=[N:5][C:6](C)=[N:7][C:8]=1S)#[N:2].O.[NH2:14][NH2:15]>C(O)C>[C:1]([C:3]1[C:4]([NH:11][CH3:12])=[N:5][C:6]([NH:14][NH2:15])=[N:7][CH:8]=1)#[N:2]
Reactant: CNc1nc(C)nc(S)c1C#N
Reactant: NN
Solvent: CCO
Solvent: O
Product: CNc1nc(NN)ncc1C#N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 5-cyano-4-methylamino-2-methyl-sulfanyl-pyrimidine (25.86 g) from Example 3 and hydrazine hydrate (52 mL) in ethanol (250 mL) was heated at reflux with stirring for 3 hours. The reaction mixture was cooled to room temperature and the insoluble product was collected by filtration, washed with cold aqueous ethanol (1:1) to give 23 g of the title compound. Crystallization from ethanol afforded an analytically pure sample of 5-cyano-2-hydrazino-4-methylamino-pyrimidine, mp 247°-249° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[C:6](O)=[O:7].S(Cl)([Cl:25])=O>ClC(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[C:6]([Cl:25])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C(CCCBr)(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: ClC(Cl)Cl
Product: O=C(Cl)C(CCCBr)(c1ccc(F)cc1)c1ccc(F)cc1

Procedure:
To a stirred solution of 29.5 parts of α-(3-bromopropyl)-4-fluoro-α-(4-fluorophenyl)benzeneacetic acid in 300 parts of trichloromethane were added 28.8 parts of thionyl chloride and the whole was stirred and refluxed for 3 hours. The reaction mixture was evaporated, yielding 30 parts of α-(3-bromopropyl)-4-fluoro-α-(4-fluorophenyl)-benzeneacetyl chloride as a residue.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[C:28](O)(=[O:31])[CH2:29][CH3:30]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: CCC(=O)O
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (95 mg, 82%), MS (ISP) m/z=387.4 [(M+H)+], mp 192.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (132 mg, 0.3 mmol) and propionic acid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][O:10][C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]1=2.S(C1C=CC(C)=CC=1)(O[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(#N)C>[CH3:35][N:34]([CH3:36])[C:31]1[CH:32]=[CH:33][C:28]([CH2:27][CH2:26][N:1]2[CH2:5][CH2:4][CH2:3][C@@H:2]2[CH2:6][N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][O:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]2=3)=[CH:29][CH:30]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(N(C)C)cc2)cc1
Reactant: c1ccc2c(c1)COc1ccccc1N2C[C@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CN(C)c1ccc(CCN2CCC[C@@H]2CN2c3ccccc3COc3ccccc32)cc1
Temperature: 90 °C

Procedure:
(R)-5,11-dihydro-5-(2-pyrrolidinylmethyl)dibenzo[b,e][1,4]oxazepine (Preparation Example 1) (420 mg, 1.5 mmol), 2-(4-dimethylaminophenyl)ethyl tosylate (640 mg, 2 mmol), sodium carbonate (210 mg, 2 mmol) and sodium iodide (30 mg, 0.2 mmol) were added to acetonitrile (20 ml), and the mixture was heated under reflux at 90° C. for 14 hours. The solvent was evaporated under reduced pressure, and the residue was partitioned in ethyl acetate and water. The organic layer was washed with water and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was treated by the column chromatography and then eluted with dichloromethane and then with dichloromethane/2 M methanolic ammonia (50:1) as the eluents. A suitable fraction was collected, and the solvent was evaporated under reduced pressure to obtain the title compound in the form of a light yellow oil (240 mg, 37%).
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[C:16]([O:17][CH3:18])=[N:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:19])[CH:13]=2)[N:8]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:6][C:7]1[C:16]([O:17][CH3:18])=[N:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:19])[CH:13]=2)[N:8]=1
Reactant: COc1ccc(CNc2nc3ccc(C)cc3nc2OC)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1nc2cc(C)ccc2nc1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.5 %

Procedure:
To 2-(2,4-dimethoxybenzylamino)-3-methoxy-6-methylquinoxaline (4.48 g, 13.2 mmol), 30 ml of 50% trifluoroacetic acid in dichloromethane was added at room temperature. The resulting mixture was stirred at room temperature for 18 hours and concentrated under the reduced pressure to remove the solvent. The residue was neutralized with saturated sodium bicarbonate solution and then NaCl solution was added thereto. The product was extracted with dichloromethanee and the organic layer was dried over MgSO4. After concentration under the reduced pressure, the crude product was purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (3:1) mixture and concentration gave 2.01 g of the titled compound (yield, 81%).
Reaction SMILES: Br[CH:2](Br)[C:3]1[CH:4]=[C:5]([C:10]2[C:14]([Cl:15])=[C:13]([O:16][CH:17]([F:19])[F:18])[N:12]([CH3:20])[N:11]=2)[CH:6]=[CH:7][C:8]=1[Cl:9].S(=O)(=O)(O)[OH:23]>>[Cl:15][C:14]1[C:10]([C:5]2[CH:6]=[CH:7][C:8]([Cl:9])=[C:3]([CH:2]=[O:23])[CH:4]=2)=[N:11][N:12]([CH3:20])[C:13]=1[O:16][CH:17]([F:19])[F:18]
Reactant: O=S(=O)(O)O
Reactant: Cn1nc(-c2ccc(Cl)c(C(Br)Br)c2)c(Cl)c1OC(F)F
Product: Cn1nc(-c2ccc(Cl)c(C=O)c2)c(Cl)c1OC(F)F
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
At 85° C., 4.65 g (10 mmol) of 3-(3-dibromomethyl-4-chloro-phenyl)-4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazole were introduced a little at a time into 7 ml of concentrated sulfuric acid. The reaction solution was then stirred at 100° C. for 5 minutes, then stirred into 40 ml of ice-water. The solid product formed was filtered off and dried. Yield: 3.0 g;
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].Cl[C:20](=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>ClCCl>[C:13]1([C:11]2[O:12][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:9][CH:10]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: NCC(=O)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ncc(-c2ccccc2)o1
Temperature: 25 °C
Yield: 21.8 %

Procedure:
Triethylamine (1.08 mL; 7.69 mmol) was added to a mixture of 2-amino-1-phenylethanone hydrochloride (0.550 g; 3.08 mmol) and ethyl 2-chloro-2-oxoacetate (0.369 mL; 3.23 mmol) in dichloromethane (10 mL) at 0° C. The reaction mixture was then stirred at room temperature for 22 hand diluted with dichloromethane (40 mL). The organic layer was washed successively with a saturated aqueous solution of sodium carbonate, and water. The organic layer was dried over magnesium sulfate and was concentrated under reduced pressure. The crude residue was dissolved in phosphorus (V) oxychloride (10 mL) and the solution was refluxed for 4 hours. After cooling, the volatiles were removed under reduced pressure and the residue was dissolved in dichloromethane. The organic layer was then carefully washed with a saturated aqueous solution of sodium carbonate, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent 15 to 100% dichloromethane in heptane) to afford 0.146 g (22% overall yield) of ethyl 5-phenyloxazole-2-carboxylate as a solid.
Reaction SMILES: F[C:2]1C=C(OC2N=CC=C3C=CN(C)C=23)C=CC=1N.[NH:20]1[C:24]2=[C:25]([O:29][C:30]3[CH:35]=[CH:34][C:33]([NH:36][C:37]([NH:39][C:40](=[O:48])[CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[S:38])=[CH:32][C:31]=3[F:49])[N:26]=[CH:27][CH:28]=[C:23]2[CH:22]=[CH:21]1>>[F:49][C:31]1[CH:32]=[C:33]([NH:36][C:37]([NH:39][C:40](=[O:48])[CH2:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[S:38])[CH:34]=[CH:35][C:30]=1[O:29][C:25]1[N:26]=[CH:27][CH:28]=[C:23]2[CH:22]=[CH:21][N:20]([CH3:2])[C:24]=12
Reactant: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2nccc3cc[nH]c23)c(F)c1
Reactant: Cn1ccc2ccnc(Oc3ccc(N)c(F)c3)c21
Product: Cn1ccc2ccnc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c21
Yield: 87 %

Procedure:
Starting from the compound 265 and following the procedure described above for the synthesis of compound 262a (scheme 59, step 4, example 218), title compound 262b was obtained in 87% yield as an off-white solid. 1H NMR (DMSO-d6) δ (ppm): 12.40(s, 1H), 11.78(s, 1H), 7.83(dd, 1H, J1=10.95 Hz, J2=1.9 Hz), 7.56(d, 1H, 2.7 Hz), 7.49(d, 1H, J=5.5 Hz), 7.43-7.39(m, 2H), 7.37-7.33(m, 4H), 7.31-7.26(m, 2H), 6.52(d, 1H, J2=2.9 Hz), 4.11(s, 3H), 3.84(s, 2H), MS (m/z): 435.1(M+H) (found).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]2[N:6]=[C:7]([N:9]3[CH2:12][CH:11]([OH:13])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:16][N:17]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[N:18]1.C1CCC(P(C2C(C3C=CC=CC=3)=CC=CC=2)C2CCCCC2)CC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1.C(O)C>[CH3:16][N:17]1[CH:21]=[C:20]([C:2]2[CH:15]=[CH:14][C:5]3[N:6]=[C:7]([N:9]4[CH2:12][CH:11]([OH:13])[CH2:10]4)[S:8][C:4]=3[CH:3]=2)[CH:19]=[N:18]1
Reactant: OC1CN(c2nc3ccc(Br)cc3s2)C1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: C1COCCO1
Solvent: CCO
Product: Cn1cc(-c2ccc3nc(N4CC(O)C4)sc3c2)cn1
Temperature: 150 °C

Procedure:
A mixture of 1-(6-bromobenzo[d]thiazol-2-yl)azetidin-3-ol (Reference Example 1, 1.426 g, 5.0 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (CAS #761446-44-0, 1.248 g, 6.0 mmol), dichlorobis(triphenylphosphine)palladium (II) (0.140 g, 0.20 mmol), and (2-biphenyl)dicyclohexylphosphine (0.070 g, 0.20 mmol) in 1:1 dioxane/ethanol (12 mL) was treated with deoxygenated 1 M aqueous Na2CO3 (6.0 mL). The reaction mixture was then heated under microwave irradiation at 150° C. for 10 minutes. The reaction mixture was then diluted with dichloromethane (30 mL) and filtered through a pad of diatomaceous earth that was subsequently rinsed with 9:1 dichloromethane/methanol. The filtrate was concentrated under reduced pressure and the residue was treated with acetonitrile (20 mL) to provide a slurry that was filtered. The filter cake was treated with 4:1 methanol/water (5 mL) and the resulting slurry was filtered. The filter cake was rinsed with 4:1 methanol/water (3 mL), then dried under vacuum to provide 1-(6-(1-methyl-1H-pyrazol-4-yl)benzo[d]thiazol-2-yl)azetidin-3-ol. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.82-3.91 (m, 2H), 3.85 (s, 3H), 4.31 (t, J=8 Hz, 2H), 4.62-4.72 (m, 1H), 5.86-5.91 (m, 1H), 7.43 d, J=8 Hz, 1H), 7.48 (dd, J=1, 8 Hz, 1H), 7.82 (d, J=1 Hz, 1H), 7.96 (d, J=1 Hz, 1H), 8.07 (s, 1H); MS (DCI/NH3) m/z 287 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.C1(C)C(S(O[CH2:19][CH:20]2[CH2:25][O:24][C:23]([CH3:27])([CH3:26])[O:22][CH2:21]2)(=O)=O)=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN1CCCC1=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:19][CH:20]2[CH2:25][O:24][C:23]([CH3:27])([CH3:26])[O:22][CH2:21]2)=[CH:4][N:3]=1
Reactant: Oc1cnc(Cl)nc1
Reactant: Cc1ccccc1S(=O)(=O)OCC1COC(C)(C)OC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC1(C)OCC(COc2cnc(Cl)nc2)CO1
Temperature: 70 °C
Reaction time: 3.5 h
Yield: 74.1 %

Procedure:
To 2.53 g (19.4 mmol) of 2-chloro-5-hydroxypyrimidine, a solution of 5.95 g (19.8 mmol) of 5-(toluenesulfonyloxymethyl)-2,2-dimethyl-1,3-dioxane in 11 ml of N-methylpyrrolidone and 6.50 g (19.9 mmol) of cesium carbonate were added, and the reaction mixture was stirred at 70° C. for 3.5 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate twice. The obtained organic layers were combined, washed with water and saturated sodium chloride aqueous solution in order and dried with anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. tert-Butyl methyl ether was added to the obtained residue, and the precipitate was obtained by filtration to provide 3.72 g of the title compound as a white solid (yield: 74%).
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:6]=[C:7](I)[CH:8]=[CH:9][CH:10]=1)#[N:2].[F:12][C:13]1[CH:14]=[C:15]([O:28][CH2:29][C:30]#[CH:31])[CH:16]=[C:17]([C:19]2([O:26][CH3:27])[CH2:23][CH2:22][CH2:21][CH:20]2[O:24][CH3:25])[CH:18]=1.N1CCCCC1>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.C1(C)C=CC=CC=1>[C:1]([CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:31]#[C:30][CH2:29][O:28][C:15]2[CH:16]=[C:17]([C:19]3([O:26][CH3:27])[CH2:23][CH2:22][CH2:21][CH:20]3[O:24][CH3:25])[CH:18]=[C:13]([F:12])[CH:14]=2)[CH:8]=[CH:9][CH:10]=1)#[N:2]
Reactant: C#CCOc1cc(F)cc(C2(OC)CCCC2OC)c1
Reactant: N#CCOc1cccc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: COC1CCCC1(OC)c1cc(F)cc(OCC#Cc2cccc(OCC#N)c2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.3 %

Procedure:
A mixture of 3-cyanomethoxyphenyl iodide (0.355 g), tetrakis(triphenylphosphine)palladium (0.079 g) and toluene (7 ml) was stirred at ambient temperature for 15 minutes. To this mixture there were added in turn (1RS,2SR)-1-[5-fluoro-3-(2-propynyloxy)phenyl]-1,2-dimethoxycyclopentane (0.252 g), cuprous iodide (0.013 g) and piperidine (0.274 ml) and the mixture was stirred at ambient temperature for 2 hours. The mixture was partitioned between toluene and water. The organic layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO4) and evaporated. The residue was purified by column chromatography using methylene chloride as eluent. There was thus obtained (1RS,2SR)-1-[3-(3-(3-cyanomethoxyphenyl)prop-2-ynyloxy)-5-fluorophenyl-1,2-dimethoxycyclopentane (0.194 g, 35%), as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]([O:9]CC)=[O:8])[N:4]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([Cl:19])=[CH:14][N:13]=2)[N:3]=1.CO.[OH-].[Na+]>O>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[N:4]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([Cl:19])=[CH:14][N:13]=2)[N:3]=1
Reactant: CCOC(=O)c1cc(Br)nn1-c1ncc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(Br)nn1-c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.3 %

Procedure:
To a 100 mL flask, ethyl 3-bromo-1-(3,5-dichloropyridin-2-yl)-1H-pyrazole-5-carboxylate (2.0 g, 5.5 mmol), methanol (10 mL), water (10 mL) and sodium hydroxide (0.3 g, 5.5 mmol) were added. After being stirred at room temperature for 1 hour, the mixture reacted completely. The reaction mixture was concentrated by rotary evaporator to about 10 mL as a dark brown solution. Then water (40 mL) was added into the dark brown solution. The aqueous solution was extracted with ethyl ether (50 mL) and acidified with concentrated hydrochloric acid to pH of 4. The precipitate was isolated by filtration, washed with water (2×50 mL) and dried to give the product (0.97 g) as white solid in 48% yield.
Reaction SMILES: C([Li])CCC.BrC1[C:8]([F:17])=[C:9]([CH3:16])[C:10]([F:15])=[C:11]([F:14])[C:12]=1[F:13].CN(C=O)C1C=CC=CC=1.Cl.C([O:31][CH2:32][CH3:33])C>CCCCCC>[CH3:16][C:9]1[C:8]([F:17])=[C:33]([C:12]([F:13])=[C:11]([F:14])[C:10]=1[F:15])[CH:32]=[O:31]
Reactant: CCOCC
Reactant: Cc1c(F)c(F)c(F)c(Br)c1F
Agent: CN(C=O)c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Product: Cc1c(F)c(F)c(F)c(C=O)c1F

Procedure:
n-Butyl lithium (12.9 ml of a 1.6M solution in hexane) was added dropwise to a solution of 3-bromo-2,4,5,6-tetrafluorotoluene (5.0 g) in diethyl ether (40 ml) under an argon atmosphere whilst maintaining the mixture temperature within the range -60° to -70° C. When the addition was complete the mixture was stirred for a period of 1.5 hours at -70° C. after which a solution of N-methylformanilide (2.8 g) in diethyl ether (15 ml) was added and the resultant mixture allowed to attain the ambient temperature (ca. 25° C.). Dilute hydrochloric acid (25 ml) of a 2 N solution) was added to the well-stirred mixture after which the ethereal layer was separated, washed with water and dried over anhydrous magnesium sulphate. After removal of the solvent by evaporation under reduced pressure the residual oil was distilled to yield 3-methyl-2,4,5,6-tetrafluorobenzaldehyde (1.6 g) b.p. 78°-80° C./14 mm Hg. Infra red (liquid film): 1710, 1640, 1490, 1140 cm-1