Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[S:9]1[CH2:15][C:13](=[O:14])[NH:12][C:10]1=[S:11].C([O-])(=O)C.[Na+].O>C(O)(=O)C>[CH3:1][C:2]1[O:6][C:5]([CH:7]=[C:15]2[S:9][C:10](=[S:11])[NH:12][C:13]2=[O:14])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=O)o1
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(C=C2SC(=S)NC2=O)o1
Yield: 89.1 %

Procedure:
A mixture of 5.51 g (50.0 mmol) of 5-methylfuran-2-carboxaldehyde (purchased from Wako Junyaku Kogyo), 6.66 g (50.0 mmol) of rhodanine (purchased from Tokyo Kasei) 12.3 g (150 mmol) of anhydrous sodium acetate (purchased from Kokusan Kagaku) in 35 ml of acetic acid (purchased from Wako Junyaku Kogyo) was refluxed for 30 minutes, cooled and added to 500 ml of water, and the precipitate was collected, washed with water, ethanol and ether in order and dried to give 10.04 g (yield: 89.1%) of of (5-methylfurfurylidene)rhodanine as an orange brown crystalline.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([Cl:4])=[O:3].[CH2:7]([OH:10])[C:8]#[CH:9].N1C=CC=CC=1>C(Cl)Cl>[Cl:4][C:2](=[O:3])[C:1]([O:10][C:7]#[C:8][CH3:9])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C#CCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC#COC(=O)C(=O)Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 100 ml of methylene chloride were dissolved 10 g (79 mmol) of oxalyl chloride, to which a solution of 4.4 g (79 mmol) of propargyl alcohol and 6.4 ml (79 mmol) of pyridine dissolved in 30 ml of methylene chloride was slowly added dropwise over 1 hour with cooling with ice. The resulting mixture was stirred for 30 minutes at room temperature to produce propynyl chloroglyoxylate in the reaction system. Subsequently, a solution of 14.5 g (79 mmol) of pentafluorophenol and 6.4 ml (79 mmol) of pyridine dissolved in 30 ml of methylene chloride was slowly added dropwise to the reaction system with cooling with ice. The resulting mixture was stirred for 1 hour at room temperature and then filtered, washed with water, dried over anhydrous magnesium sulfate and concentrated. The thus obtained crude product was purified by crystallization to obtain 2.1 g of 2-propynyl pentafluorophenyl oxalate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16](Br)=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:14]=3)=[CH:11][C:10]([C:24]([F:27])([F:26])[F:25])=[N:9]2)[CH:5]=[CH:4][C:3]=1[S:28]([NH2:31])(=[O:30])=[O:29].C([Sn](CCCC)(CCCC)[C:37]1[N:38]=[CH:39][S:40][CH:41]=1)CCC.[Cl-].[Li+]>O1CCOCC1.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>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([C:37]4[N:38]=[CH:39][S:40][CH:41]=4)=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:14]=3)=[CH:11][C:10]([C:24]([F:27])([F:26])[F:25])=[N:9]2)[CH:5]=[CH:4][C:3]=1[S:28]([NH2:31])(=[O:30])=[O:29]
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(Br)c(C(F)(F)F)c2)cc1F
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(-c3cscn3)c(C(F)(F)F)c2)cc1F
Temperature: 25 °C
Yield: 18 %

Procedure:
To a stirred solution of 2-fluoro-4-[5-[4-bromo-3-(trifluoromethyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (308 mg, 0.58 mmol) in dioxane (5 ml) was added 4-(tributylstannyl)thiazole (260 mg, 0.70 mmol), tetrakis(triphenylphosphine)palladium (67 mg, 0.058 mmol), lithium chloride (61 mg, 1.45 mmol), and the mixture was heated at reflux temperature for 16 hours. The reaction mixture was cooled down to room temperature, and diluted with ethyl acetate. The whole was washed with saturated potassium fluoride aqueous solution, and the precipitate was removed by filteration through celite. The resulting solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:2) to give title compound (56 mg, 18% yield).
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([C:7]2[N:12]3[CH:13]=[CH:14][N:15]=[C:11]3[CH:10]=[C:9]([C:16]([O:18][CH3:19])=[O:17])[N:8]=2)[CH:4]=[N:3]1.[CH:20]1([CH:23]=[CH:24][C:25]#[N:26])[CH2:22][CH2:21]1.CN(C=O)C.C1CCN2C(=NCCC2)CC1>CCOC(C)=O>[C:25]([CH2:24][CH:23]([N:2]1[CH:6]=[C:5]([C:7]2[N:12]3[CH:13]=[CH:14][N:15]=[C:11]3[CH:10]=[C:9]([C:16]([O:18][CH3:19])=[O:17])[N:8]=2)[CH:4]=[N:3]1)[CH:20]1[CH2:22][CH2:21]1)#[N:26]
Reactant: COC(=O)c1cc2nccn2c(-c2cn[nH]c2)n1
Reactant: N#CC=CC1CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1cc2nccn2c(-c2cnn(C(CC#N)C3CC3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 35.3 %

Procedure:
In a 100 mL flask, methyl 5-(1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine-7-carboxylate hydrochloride (0.300 g, 1.07 mmol) and 3-cyclopropylacrylonitrile (Preparation B; 0.300 g, 3.22 mmol) were suspended in DMF (5.36 mL, 1.07 mmol) and DBU (0.722 mL, 4.83 mmol) added in one portion. The reaction mixture was stirred at ambient temperature for 15 hours. The reaction mixture was diluted in EtOAc and washed with water and brine. The combined organic layers were dried over MgSO4, filtered, and concentrated down to a yellow oil. Purification of the crude material by silica chromatography using a gradient of 50-100% EtOAc afforded methyl 5-(1-(2-cyano-1-cyclopropylethyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine-7-carboxylate (0.127 g, 0.378 mmol, 35.2% yield) as a yellow oil. MS (apci) m/z=337.2 (M+H).
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:26]=[CH:25][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.[SiH4].C([Si]([O:45][C:46]1[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH:54]2[CH2:56][O:55]2)=[CH:48][CH:47]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[CH2:21]([N:20]([CH2:23][CH3:24])[C:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:56][C@H:54]([OH:55])[CH2:53][O:52][C:49]3[CH:50]=[CH:51][C:46]([OH:45])=[CH:47][CH:48]=3)=[CH:26][CH:25]=2)[CH2:13][CH2:14]1)=[O:19])[CH3:22]
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)C(=O)N1CCC(Nc2ccc(CCN)cc2)CC1
Agent: [SiH4]
Solvent: O=CO
Product: CCN(CC)C(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 24.2 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N,N-diethyl-1-piperidinecarboxamide formate (0.37 g, 1.01 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane silane (0.367 g, 0.909 mmol) according to Procedure G to give the title compound (eluant: 20:1 chloroform-methanol) (0.159 g, 0.22 mmol).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([NH2:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[F:11]F.C(=O)([O-])O.[Na+].C(OCC)(=O)C>FC(F)(F)C(O)=O>[NH2:1][C:2]1[C:3]([C:8]([NH2:10])=[O:9])=[N:4][C:5]([F:11])=[CH:6][N:7]=1
Reactant: NC(=O)c1nccnc1N
Reactant: FF
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1nc(F)cnc1N
Temperature: 0 °C

Procedure:
In 9 mL of trifluoroacetic acid was dissolved 0.3 g of 3-amino-2-pyrazinecarboxamide. At an ice-cooled temperature, 10% fluorine gas (a fluorine gas diluted with nitrogen gas) was introduced into the solution at a rate of 45 ml per minute for a period of 22 minutes. After stirring the mixture at an ice-cooled temperature for 17 minutes, the temperature was elevated to room temperature. The reaction mixture was added to a mixture of 30 mL of saturated aqueous solution of sodium hydrogen carbonate and 30 mL of ethyl acetate, and the organic layer was separated. The remaining aqueous layer was acidified with 6 mol/L hydrochloric acid and then extracted with 20 ml of ethyl acetate. The organic layers thus obtained were united, washed successively with 10 mL of water and 10 mL of saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent: n-hexane:ethyl acetate=2:1] to obtain 0.015 g of 3-amino-6-fluoro-2-pyrazinecarboxamide as a light yellow-colored solid product.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14](F)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>C(OCC)(=O)C>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(=O)N1CCC(C(=O)c2ccc(F)cc2)CC1
Solvent: CCOC(C)=O
Product: CC(=O)N1CCC(C(=O)c2ccc(N3CCOCC3)cc2)CC1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A mixture consisting of 3.73 g of 1-acetyl-4-(4-fluorobenzoyl)piperidine and 2.6 ml of morpholine was stirred at 100° C. for 24 hours and the reaction mixture was then dissolved in 100 ml of ethyl acetate. The solution was washed with a saturated aqueous solution of sodium hydrogen carbonate and water in that order and the organic layer was dried over anhydrous magnesium sulfate. The solvent was then removed and the residual oil was purified by silica gel column chromatography (eluent: methanol:dichloromethane=1:19, v/v) to give 2.4 g of the title compound as oil.
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[CH:7]=[C:8]([C:13]2([C:27]([F:30])([F:29])[F:28])[O:17][N:16]=[C:15]([C:18]3[CH:19]=[C:20]([N+:24]([O-])=O)[CH:21]=[CH:22][CH:23]=3)[CH2:14]2)[CH:9]=[C:10]([Cl:12])[CH:11]=1>C(O)C.[Fe]>[Cl:5][C:6]1[CH:7]=[C:8]([C:13]2([C:27]([F:29])([F:28])[F:30])[O:17][N:16]=[C:15]([C:18]3[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=3)[NH2:24])[CH2:14]2)[CH:9]=[C:10]([Cl:12])[CH:11]=1
Reactant: O=[N+]([O-])c1cccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1cccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.2 %

Procedure:
To an aqueous 2.5% acetic acid solution (1 ml) was added an iron powder (10-20 mesh; 192 mg). To the mixture was added a suspension of 3-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]nitrobenzene (232 mg) obtained by Reference Production Example 1 in ethanol (1.5 ml) at 75° C. After stirring at the same temperature for 15 minutes, an additional iron powder (300 mg) was added thereto, and the mixture was stirred at room temperature for 1 hour. After cooling to room temperature, the reaction mixture was filtrated and washed with ethyl acetate. Then, the filtrate was extracted with water and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 3-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]aniline (198 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14](C(OC(C)(C)C)=O)[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[N:24])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:16]=[CH:17][C:18]([O:21][CH2:22][C:23]#[N:24])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(N(C(=O)OC(C)(C)C)c2ccc(OCC#N)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CCOc1ccc(NC2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.8 %

Procedure:
To a stirred solution of 4-[tert-butoxycarbonyl-(5-cyanomethoxy-pyridin-2-yl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (0.90 g, 2.1 mmol, 1.0 equiv) in dichloromethane (15 mL) was added 90% trifluoroacetic acid (1.69 mL, 2.37 g, 19 mmol, 9.0 equiv) drop by drop and the reaction mixture stirred at rt for 16 h. It was then poured into ice water and the pH adjusted to 9-10 by addition of a sat. solution of potassium carbonate. The solution was extracted three times with a mixture of dichloromethane/isopropanol (4:1). The combined organic layers were concentrated by evaporation under reduced pressure to give 0.15 g (30%) of the title compound as yellow oil. MS (ISP): 233.0 [M+H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=[O:18])[CH2:8][C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[N+](=[CH2:23])=[N-]>CO.CCOCC>[CH3:23][O:18][C:7]1[NH:6][C:5]2[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][C:4]=2[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9](=[O:17])[CH:8]=1
Reactant: O=C1CC(=O)N(c2ccccc2)c2cc(Cl)ccc2N1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Product: COC1=CC(=O)N(c2ccccc2)c2cc(Cl)ccc2N1
Reaction time: 1 h

Procedure:
To 11.4 g of 7-chloro-5-phenyl-1H-1,5-benzodiazepine-2,4-dione stirred in 150 ml methanol is added, dropwise, approximately 2.1 g of diazomethane in ether. After addition is complete, the reaction is stirred for 1 hour and filtered. The filtrate is evaporated and the residue diluted with a small amount of ether. The suspension is filtered and the filtrate evaporated to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:21]([C:22](=O)/[CH:23]=[CH:24]/N(C)C)=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([N:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.S(O)(O)(=O)=O.[NH2:34][C:35]([NH2:37])=[NH:36]>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:21]([C:22]3[CH:23]=[CH:24][N:34]=[C:35]([NH2:37])[N:36]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([N:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N=C(N)N
Reactant: CN(C)/C=C/C(=O)c1c(-c2cccc(Br)c2)nn2c(N3CCCC3)cccc12
Agent: O=S(=O)(O)O
Product: Nc1nccc(-c2c(-c3cccc(Br)c3)nn3c(N4CCCC4)cccc23)n1
Yield: 61 %

Procedure:
In a similar manner as described in Example 1 from (2E)-1-[2-(3-bromophenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one (500 mg, 1.1 mmol) and guanidine sulfate, 4-[2-(3-bromophenyl)-7-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine (300 mg, 61%) was obtained as a yellow solid. 1H NMR (d6-DMSO): δ 8.03 (d, 1H), 7.87 (d, 1H), 7.81 (s, 1H), 7.70–7.62 (m, 2H), 7.46 (t, 1H), 7.35 (t, 1H), 6.58 (broad s, 2H), 6.26 (d, 1H), 6.22 (d, 1H), 3.75 (m, 4H), 1.98 (m, 4H); MS m/z 435 (M+1); Anal. Caled. for C21H19N6Br: C, 57.94; H, 4.40; N. 19.31. Found: C, 57.91; H, 4.51; N, 19.07.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].Cl[CH2:7][SiH2:8][CH:9]([O:12][CH3:13])[O:10][CH3:11].[SiH4]>[Br-].C([P+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:4][CH2:7][SiH2:8][CH:9]([O:12][CH3:13])[O:10][CH3:11])(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: COC(OC)[SiH2]CCl
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: COC(OC)[SiH2]COC(C)=O
Temperature: 150 °C
Reaction time: 3 h

Procedure:
A mixture of 10.7 L of Hydroseal G 400 H(═HSB, C17-C21 hydrocarbon mixture, see above) and 5.97 kg (72.8 mol) of sodium acetate was heated up for one hour at 150° C./2 mbar (for drying). The heating was switched off, the vacuum was broken with nitrogen and 450 g (1.32 mol) of tetrabutylphosphonium bromide (=phase transfer catalyst) were added and the temperature was adjusted to 120° C. Under agitation, 10.24 kg (66.2 mol) of (chloromethyl)dimethoxymethylsilane (=a silane of formula II) were metered in over 2 hours. The mixture was stirred at the same temperature for a further 3 hours. The product was distilled out through a sieve plate column; the product (acetoxymethyl)dimethoxymethylsilane was obtained at 53-54 mbar (head), 70-73° C. (head) and 100-125° C. (pot) in the distillate (10.8 kg, 60.6 mol, 92% of theory; purity 99.5% (GC area %)) as a colorless liquid. The solvent, sodium chloride, excess sodium acetate and the phase transfer catalyst in the form of the chloride, bromide and acetate salt of tetrabutylphosphonium remained in the residue (18.5 kg in total).
Reaction SMILES: [Br:1]Br.[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:12])[CH3:11]>C(O)(=O)C>[Br:1][CH2:11][C:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[Br:3])=[O:12]
Reactant: BrBr
Reactant: CC(=O)c1ccccc1Br
Solvent: CC(=O)O
Product: O=C(CBr)c1ccccc1Br
Temperature: 25 °C

Procedure:
Bromine (40.3 g, 0.25 mol) was added dropwise to a solution of 2′-Bromoacetophenone (50.0 g, 0.25 mol) in acetic acid (500 ml) over 1.5 hours at 15-20° C. The solution was then allowed to warm to room temperature and concentrated under reduced pressure to yield a crude product that was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]4[N:16]=[C:17]([NH2:27])[S:18][C:19]=4[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:26])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:28]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][NH:40][CH:41]=2)O1>>[NH:39]1[CH:38]=[C:37]([C:2]2[CH:3]=[CH:4][C:5]3[C:11]4[S:12][C:13]([C:15]5[N:16]=[C:17]([NH2:27])[S:18][C:19]=5[C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[Cl:26])=[CH:14][C:10]=4[CH2:9][CH2:8][O:7][C:6]=3[CH:28]=2)[CH:41]=[N:40]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: Nc1nc(-c2cc3c(s2)-c2ccc(Br)cc2OCC3)c(-c2ccccc2Cl)s1
Product: Nc1nc(-c2cc3c(s2)-c2ccc(-c4cn[nH]c4)cc2OCC3)c(-c2ccccc2Cl)s1

Procedure:
Following the procedure of Example 44, 4-(8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-5-(2-chlorophenyl)thiazol-2-amine and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole were reacted to give 262. MS: (ESI+) 477.1
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[H][H].[CH3:9][CH:10]([OH:25])[CH:11]([OH:24])[C:12]1[N:17]=[C:16]2[C:18]([N:20]=[C:21]([NH2:23])[NH:22][C:15]2=[N:14][CH:13]=1)=[O:19].Cl>[Pt]=O>[CH3:9][CH:10]([OH:25])[CH:11]([OH:24])[CH:12]1[NH:17][C:16]2[C:18]([N:20]=[C:21]([NH2:23])[NH:22][C:15]=2[NH:14][CH2:13]1)=[O:19]
Reactant: [H][H]
Reactant: CC(O)C(O)c1cnc2[nH]c(N)nc(=O)c2n1
Agent: O=[Pt]
Agent: Cl
Agent: O=C([O-])[O-]
Product: CC(O)C(O)C1CNc2[nH]c(N)nc(=O)c2N1

Procedure:
There was dispersed 500 mg of platinum oxide into 250 ml of 10% aqueous solution of potassium carbonate, and then the catalyst was activated with hydrogen gas. Then, 250 ml of 10% aqueous solution of potassium carbonate containing 5.0 g of biopterin was added to the above dispersion. After the catalytic reduction was conducted by agitating the resulting mixture for 5 hours under normal temperature and normal pressure in a hydrogen atmosphere, the reaction mixture was adjusted to pH 1 by adding 2N hydrochloric acid. The catalyst was filtered off from the reaction mixture to give tetrahydrobiopterin solution having a (6R)/(6S) ratio of 80/20 as measured by HPLC.
Reaction SMILES: C[C@@H:2]1[C:6]2[NH:7][C:8]([B:10]3[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]3)=[CH:9][C:5]=2[C:4](=[O:19])[NH:3]1.N1C=CC2C(=O)NCC1=2>>[CH3:15][C:13]1([CH3:16])[C:12]([CH3:17])([CH3:18])[O:11][B:10]([C:8]2[NH:7][C:6]3[CH2:2][NH:3][C:4](=[O:19])[C:5]=3[CH:9]=2)[O:14]1
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Agent: O=C1NCc2[nH]ccc21
Product: CC1(C)OB(c2cc3c([nH]2)CNC3=O)OC1(C)C

Procedure:
This compound as a brown solid was prepared according to the procedure described for intermediate 705, using 5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (703) as the starting material. m/z (ESI, +ve) 248.7 (M+H)+).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1([OH:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.ClCCl.Cl[C:16]([CH3:24])([CH2:18][CH2:19][C:20](Cl)([CH3:22])[CH3:21])[CH3:17]>O>[OH:11][C:5]1[CH:10]=[CH:9][C:8]2[C:20]([CH3:22])([CH3:21])[CH2:19][CH2:18][C:16]([CH3:24])([CH3:17])[C:7]=2[CH:6]=1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Reactant: Oc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(O)ccc21
Temperature: 25 °C
Reaction time: 19 h

Procedure:
The synthesis process is as set forth in the chemical reaction formula below. The AlCl3 in the reaction path stands for aluminum chloride. Into phenol (1.02 g, 10.8 mmol) were added anhydrous dichloromethane (5 mL), aluminum chloride (144 mg, 1.08 mmol), and 2,5-dichloro-2,5-dimethylhexane (2.18 g, 11.9 mmol) followed by stirring at room temperature for 19 hours. The reaction solution was poured into cold water and extracted by ethyl acetate. The organic layer was washed by water, a saturated sodium hydrogen carbonate aq. solution, and a saturated saline solution, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by recrystallization in a solvent of hexane. The yield was 1.83 g (83%).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][CH3:3].[H-].[Na+].Cl[C:8]1[CH:9]=[CH:10][C:11]2[CH2:12][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:15][O:16][C:17]=2[N:18]=1.O>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:4][C:8]1[CH:9]=[CH:10][C:11]2[CH2:12][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:15][O:16][C:17]=2[N:18]=1)[CH2:2][CH3:3]
Reactant: CCCO
Reactant: CC(C)(C)OC(=O)N1CCOc2nc(Cl)ccc2C1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCOc1ccc2c(n1)OCCN(C(=O)OC(C)(C)C)C2
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 71 %

Procedure:
To a solution of 1-propanol (0.13 mL) in toluene (4 mL) was added sodium hydride (0.14 g), and the resulting mixture was stirred at 70° C. for 15 min under a nitrogen atmosphere. A mixture of tert-butyl 8-chloro-2,3-dihydropyrido[3,2-f][1,4]oxazepine-4(5H)-carboxylate (0.50 g), BINAP (0.033 g), Pd2(dba)3 (0.024 g) and toluene (4 mL) was added, and the resulting mixture was stirred at 100° C. for 2 hr under an argon atmosphere. The reaction solution was poured into water, and the resulting product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→40% ethyl acetate/hexane) to give tert-butyl 8-propoxy-2,3-dihydropyrido[3,2-f][1,4]oxazepine-4(5H)-carboxylate (0.38 g, 71%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.B(F)(F)F.[CH3:14][CH2:15]OCC.C([Mg]Br)C.[Cl-].[NH4+]>C(O[Ti](OCCC)(OCCC)OCCC)CC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([NH2:9])[CH2:15][CH2:14]2)=[N:6][CH:7]=1
Reactant: CCOCC
Reactant: N#Cc1ccc(Br)cn1
Agent: CCCO[Ti](OCCC)(OCCC)OCCC
Agent: CC[Mg]Br
Agent: FB(F)F
Product: NC1(c2ccc(Br)cn2)CC1
Reaction time: 3 h

Procedure:
To a mixture of 5-bromopicolinonitrile (1.82 g, 10.0 mmol), tetrapropoxytitanium (3.26 ml, 11.0 mmol) and boron trifluoride diethyl etherate (2.51 ml 20.0 mmol) at 0° C. was added ethylmagnesium bromide (1.0M in ether, 22 ml, 22.0 mmol) The resulting solution was allowed to stir at it for 3 h. Ammonium chloride solution was added and the solution was extracted with ethyl acetate for three times. The organic layers were collected and washed with brine and dried over sodium sulfate. After concentration the crude product was purified by SiO2 column.