Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:31])[C:3]1[C:4]2[N:5]([C:9]([C:12]3[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]([NH:20][CH:21]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29]O)[CH:24]=4)[CH3:22])[N:13]=3)=[CH:10][N:11]=2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.C(=O)([O-])O.[Na+].[N-:51]=[N+:52]=[N-:53].[Na+]>C(Cl)(Cl)Cl.CN(C)C=O>[N:51]([CH2:29][C:25]1[CH:24]=[C:23]([CH:21]([NH:20][C:14]2[N:13]=[C:12]([C:9]3[N:5]4[CH:6]=[CH:7][CH:8]=[C:3]([CH:2]([F:31])[F:1])[C:4]4=[N:11][CH:10]=3)[C:17]([C:18]#[N:19])=[CH:16][N:15]=2)[CH3:22])[CH:28]=[CH:27][CH:26]=1)=[N+:52]=[N-:53]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(Nc1ncc(C#N)c(-c2cnc3c(C(F)F)cccn23)n1)c1cccc(CO)c1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CC(Nc1ncc(C#N)c(-c2cnc3c(C(F)F)cccn23)n1)c1cccc(CN=[N+]=[N-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
125 mg of the 4-[8-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl]-2-({1-[3-(hydroxymethyl)phenyl]ethyl]amino]pyrimidin-5-carbonitrile [101-1] and 259 μL of N,N-diisopropylethylamine were dissolved in 3 mL of chloroform, then 69 μL of methanesulfonyl chloride was added under an ice-cold condition, and stirred at the same temperature for 30 minutes. Thereto, a saturated aqueous solution of sodium hydrogen carbonate was added, and extracted with chloroform. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The insolubles were filtered and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was dissolved in 3 mL of N,N-dimethylformamide. Thereto, 97 mg of sodium azide was added, and stirred at 80° C. for 1 hour. The reaction solution was cooled back to room temperature, then a saturated aqueous solution of sodium hydrogen carbonate was added, and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The insolubles were filtered and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative thin-layer chromatography, and 87 mg of 2-({1-[3-(azidomethyl)phenyl)ethyl}amino)-4-[8-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-5-carbonitrile [102-1] was obtained as a light brown oily product.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]3[O:18][CH2:19][C:20](=[O:22])[NH:21][C:16]=3[N:15]=[C:14]([CH3:23])[N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[O:24]1[CH2:28][CH:25]1[CH2:26][OH:27]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC=CC=1>[OH:24][CH:25]([CH2:26][OH:27])[CH2:28][N:21]1[C:20](=[O:22])[CH2:19][O:18][C:17]2[C:12]([N:9]3[CH2:10][CH2:11][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8]3)=[N:13][C:14]([CH3:23])=[N:15][C:16]1=2
Reactant: CCOC(=O)N1CCN(c2nc(C)nc3c2OCC(=O)N3)CC1
Reactant: OCC1CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: c1ccccc1
Product: CCOC(=O)N1CCN(c2nc(C)nc3c2OCC(=O)N3CC(O)CO)CC1
Reaction time: 5 h
Yield: 83 %

Procedure:
A suspension containing 0.96 g of 4-(4-ethoxycarbonyl-1-piperazinyl)-2-methyl-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-7-one (Example 1), 0.44 g of 2,3-epoxy-1-propanol, 0.0966 g of tetra(n-butyl)-ammonium bromide and 20 ml of abs. benzene is boiled under stirring for 5 hours and left to stand at room temperature overnight. The crystals are filtered, washed with diisopropyl ethyl and dried to give 0.98 g (83%) of the product, m.p.: 146°-148° C.
Reaction SMILES: [OH-].[Li+].[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:14]([CH:25]=2)[C:15]([O:17]CC2C=CC=CC=2)=[O:16])[CH2:6][CH2:5]1.Cl>C1COCC1.O.C(OCC)(=O)C>[CH3:3][N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:11]=[CH:12][C:13]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:14]([CH:25]=2)[C:15]([OH:17])=[O:16])[CH2:8][CH2:9]1
Reactant: CN1CCN(c2ccc(OCc3ccccc3)c(C(=O)OCc3ccccc3)c2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(OCc3ccccc3)c(C(=O)O)c2)CC1

Procedure:
Lithium hydroxide (17.25 mg, 0.72 mmol) was added to a stirred solution of phenylmethyl 5-(4-methyl-1-piperazinyl)-2-[(phenylmethyl)oxy]benzoate (may be prepared as described in Description 39; 100 mg, 0.24 mmol) in a mixture of THF:water (3:1, 10 ml). The mixture was heated to reflux for 12 h and then diluted with ethyl acetate (50 ml). 10% aqueous HCl was added to the mixture to adjust the pH to 2. The organic phase was isolated, washed with brine, dried over magnesium sulphate, and concentrated to give a white solid. The product was purified using Comflash to yield the title compound. 50 mg.
Reaction SMILES: [C:1]([OH:12])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:13][N:14]([CH2:16][CH2:17]O)[CH3:15].Cl.CN(C)CCCN=C=NCC.Cl>ClCCl>[C:1]([O:12][CH2:17][CH2:16][N:14]([CH3:15])[CH3:13])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CN(C)CCO
Reactant: CCCCCCC/C=C/C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCCCCCC/C=C/C(=O)OCCN(C)C
Reaction time: 8 h

Procedure:
trans-2-Decenoic acid (170 mg, 1 mmol) and N,N-dimethylaminoethanol (90 mg, 1 mmol) were dissolved in anhydrous dichloromethane (10 ml) and, under stirring in an ice bath, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (211 mg, 1.1 mmol) (Sigma-Aldrich) was added thereto. After stirring in an ice bath for 1 hour and then at room temperature for 8 hours, the reaction solution was poured over a diluted hydrochloric acid solution followed by extracting with chloroform. The chloroform layer was concentrated to give the aimed compound as a light brown oily product.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[O:8][N:7]=1)=[O:5])C.[OH-].[Na+].Cl>O1CCCC1>[C:17]([C:14]1[CH:13]=[CH:12][C:11]([C:9]2[O:8][N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=2)=[CH:16][CH:15]=1)#[N:18]
Reactant: CCOC(=O)c1cc(-c2ccc(C#N)cc2)on1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2cc(C(=O)O)no2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 5-(4-cyano-phenyl)-isoxazole-3-carboxylic acid ethyl ester (100 mg) and 1 N aqueous NaOH solution (1.24 mL) in tetrahydrofuran (4.5 mL) is stirred at room temperature for 3 h. The reaction mixture is acidified with 3 N hydrochloric acid and concentrated in vacuo. The residue is triturated with water; the precipitate is filtered off and dried to give the title compound. LC (method 3): tR=1.01 min; Mass spectrum (ESI+): m/z=215 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.Cl.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](Cl)=[O:16].[NH2:18][C:19]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([S:36]([CH2:39][CH3:40])(=[O:38])=[O:37])=[CH:32][CH:31]=2)=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH2:39]([S:36]([C:33]1[CH:32]=[CH:31][C:30]([O:29][C:26]2[CH:27]=[CH:28][C:19]([NH:18][C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=3)=[O:16])=[C:20]([CH:25]=2)[C:21]([O:23][CH3:24])=[O:22])=[CH:35][CH:34]=1)(=[O:38])=[O:37])[CH3:40]
Reactant: CCS(=O)(=O)c1ccc(Oc2ccc(N)c(C(=O)OC)c2)cc1
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)c1ccc(Oc2ccc(NC(=O)c3ccccn3)c(C(=O)OC)c2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 54.6 %

Procedure:
With cooling with ice, 4.4 ml of triethylamine and 2.8 g of picolinic acid chloride hydrochloride were added to a chloroform (30 ml) solution of 2.65 g of methyl 2-amino-5-[4-(ethylsulfonyl)phenoxy]benzoate, and stirred at room temperature for 90 minutes. Aqueous saturated sodium hydrogencarbonate solution was added to the reaction liquid, extracted with chloroform, and the organic layer was washed with saturated saline water. After dried, the solvent was evaporated away under reduced pressure, and the residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=2/1 to 1/1) to obtain 1.9 g of the entitled compound as a creamy white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].C(=O)([O-])[O-].[Na+].[Na+].Cl.Cl[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]Cl>C(O)CCC>[F:1][C:2]1[CH:3]=[C:4]([N:5]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: Nc1ccc(F)c(F)c1
Reactant: ClCCNCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: Fc1ccc(N2CCNCC2)cc1F
Temperature: 120 °C
Reaction time: 1 h

Procedure:
3,4-Difluoro-aniline (1 g, 7.7 mmol) was dissolved in dry n-butanol (10 mL) and dry sodium carbonate (3.2 g, 30 mmol) was added to it and the reaction mixture stirred for 1 hour under nitrogen. Bis(2-chloroethyl) amine hydrochloride (1.38 g, 7.7 mmol) in nBuOH (10 mL) were then added to the mixture via a syringe. The reaction was then heated at 120° C. for 48 h. The nBuOH was evaporated in vacuo and the residue was extracted with ethyl acetate. Drying of the organic layer with Na2SO4 followed by concentration afforded the crude product. Purification using flash column chromatography (chloroform/methanol) afforded 1-(3,4-Difluoro-phenyl)-piperazine as an off white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[C:5]([NH:7][C:8]1[C:9]([CH3:19])=[N:10][NH:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.P(Cl)(Cl)(Cl)=O>ClCCl.CO>[CH3:19][C:9]1[C:8]2[N:7]=[C:5]([C:4]3[CH:20]=[CH:21][CH:22]=[C:2]([CH3:1])[CH:3]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]=2[NH:11][N:10]=1
Reactant: Cc1cccc(C(=O)Nc2c(C)n[nH]c2-c2ccccc2)c1
Solvent: CO
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1cccc(-c2nc3c(C)n[nH]c3c3ccccc23)c1
Reaction time: 4 h

Procedure:
The preparation took place in analogy to example 34 (D) using 404 mg of 3-methyl-N-(3-methyl-5-phenyl-1H-pyrazol-4-yl)-benzamide, except 10 ml of phosphorous oxychloride was used and the reaction was stirred for 4 hrs. Trituration of the residue with dichloromethane/methanol (95/5) gave the title compound as an off white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[OH:22].Cl[CH:24]([C:29]([O:31][CH3:32])=[O:30])[C:25]([O:27][CH3:28])=[O:26].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[O:22][CH:24]([C:29]([O:31][CH3:32])=[O:30])[C:25]([O:27][CH3:28])=[O:26]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Reactant: COC(=O)C(Cl)C(=O)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl)C(=O)OC
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
To a mixture of 20.0 g of 2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidin-1-yl)phenol, 10.8 g of dimethyl chloromalonate and 120 ml of N,N-dimethylformamide, 9.79 g of potassium carbonate were added and stirred at 70° C. for 1.5 hours. After the reaction mixture was cooled to room temperature, it was poured into a mixture of hydrochloric acid and ice and extracted with ethyl acetate. The organic layer was washed with 10% aqueous potassium carbonate solution and saturated brine subsequently, dried over anhydrous magnesium sulfate and concentrated. The residue was washed with methanol and diisopropyl ether to give 21.6 g of dimethyl [2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidin-1-yl)phenoxy]malonate.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[C:8]([CH:11]=1)[CH:9]=O)(=[O:3])[CH3:2].C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:9][C:8]=2[CH:11]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)COc1ccc(C(C)=O)cc1C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2cc(C(C)=O)ccc2o1
Yield: 40 %

Procedure:
To a mixture of 5-acetyl-2-(methoxycarbonyl) methoxybenzaldehyde (4.47 g) in toluene, a solution of 1,8-diazabicyclo[5.4.0]-7-undecene (1.30 g) in toluene (8 ml) was added dropwise for 15 hours at refluxing temperature. After being cooled, the resulting mixture was washed with water, dried lover magnesium sulfate and concentrated under reduced pressure. The resulting precipitates were washed with diethyl ether to give 5-acetyl-2-methoxycarbonylbenzofuran (1.65 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=[CH:41][C:4]=1[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[N:14](S(C3C=CC(C)=CC=3)(=O)=O)[C:15]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=4)[N:19]([CH3:30])[CH:18]=3)=[CH:16][C:9]=12.[OH-].[K+]>>[CH3:1][O:2][C:3]1[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=[CH:41][C:4]=1[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[NH:14][C:15]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=4)[N:19]([CH3:30])[CH:18]=3)=[CH:16][C:9]=12
Reactant: COc1ccc(CNCc2ccnc3c2cc(-c2cn(C)c4cc(OC)c(OC)cc24)n3S(=O)(=O)c2ccc(C)cc2)c(OC)c1
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(CNCc2ccnc3[nH]c(-c4cn(C)c5cc(OC)c(OC)cc45)cc23)c(OC)c1
Yield: 79 %

Procedure:
(2,4-Dimethoxybenzyl)[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]amine is prepared as described in Example 179a starting with 0.05 g of (2,4-dimethoxybenzyl)[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]amine instead of the [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl](4-trifluoromethylsulfanylbenzyl)amine used in Example 179a and 0.36 cm3 of 5N potassium hydroxide. 0.03 g of (2,4-dimethoxybenzyl)[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]amine is obtained, the characteristics of which are as follows:
Reaction SMILES: [C:1]([C:5]1[CH:39]=[CH:38][C:8]([C:9]([N:11]2[C@@H:15]([C:16]3[N:17]=[CH:18][S:19][CH:20]=3)[C@@H:14]([C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)[CH2:13][C@@:12]2([CH2:34][CH:35]([CH3:37])[CH3:36])[C:27]([O:29]C(C)(C)C)=[O:28])=[O:10])=[CH:7][C:6]=1[CH3:40])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>>[C:1]([C:5]1[CH:39]=[CH:38][C:8]([C:9]([N:11]2[C@@H:15]([C:16]3[N:17]=[CH:18][S:19][CH:20]=3)[C@@H:14]([C:21]3[CH:26]=[N:25][CH:24]=[CH:23][N:22]=3)[CH2:13][C@@:12]2([CH2:34][CH:35]([CH3:36])[CH3:37])[C:27]([OH:29])=[O:28])=[O:10])=[CH:7][C:6]=1[CH3:40])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(C(=O)N2[C@@H](c3cscn3)[C@@H](c3cnccn3)C[C@@]2(CC(C)C)C(=O)OC(C)(C)C)ccc1C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)N2[C@@H](c3cscn3)[C@@H](c3cnccn3)C[C@@]2(CC(C)C)C(=O)O)ccc1C(C)(C)C

Procedure:
The tert-butyl ester from stage A was deprotected with TFA in a similar manner to that described in Example 1. The compound was purified by SPE (C18) eluting with water followed by acetonitrile to afford the title compound as a solid.
Reaction SMILES: [Li+].[BH4-].CO.C([O:7][C:8](=O)[C:9]([CH3:39])([CH3:38])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][C:30]([C:33](OCC)=[O:34])([CH3:32])[CH3:31])[CH:24]=3)[S:22][CH2:21][CH2:20][CH2:19][S:18]2)[CH:12]=1)C.[NH4+].[Cl-]>C(Cl)Cl>[OH:7][CH2:8][C:9]([CH3:39])([CH3:38])[CH2:10][C:11]1[CH:12]=[C:13]([C:17]2([C:23]3[CH:24]=[C:25]([CH2:29][C:30]([CH3:32])([CH3:31])[CH2:33][OH:34])[CH:26]=[CH:27][CH:28]=3)[S:18][CH2:19][CH2:20][CH2:21][S:22]2)[CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)C(C)(C)Cc1cccc(C2(c3cccc(CC(C)(C)C(=O)OCC)c3)SCCCS2)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(CO)Cc1cccc(C2(c3cccc(CC(C)(C)CO)c3)SCCCS2)c1
Temperature: 25 °C
Yield: 85.2 %

Procedure:
To a suspension of LiBH4 (0.78 g, 35.8 mmol) in CH2Cl2 (55 mL) was added methanol (1.04 g, 32.5 mmol) at room temperature. After the addition of 229 (6.5 g, 12.3 mmol), the reaction mixture was heated to reflux for 6 h. After cooling to room temperature, saturated aqueous NH4Cl solution (20 mL) and CH2Cl2 (15 mL) were added and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2×10 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo to afford 230 (4.66 g, 85%) as an oil. 1H NMR (CDCl3): δ 7.42 (s br., 2H), 7.17 (m, 4H), 6.97 (m, 2H), 3.63 (s, 4H), 3.16 (s, 4H), 2.69 (m, 2H), 2.47 (m, 4H), 1.88 (m, 2H), 0.75 (s, 12H). 13C NMR (CDCl3): δ 142.39, 139.18, 131.69, 129.88, 128.05, 127.01, 71.12, 44.89, 43.74, 36.70, 29.63, 24.22.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[S:23](=[O:25])(=[O:24])[CH2:22][CH2:21][CH2:20][C:9]=2[N:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[N:12]=1)(=O)=O.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:31][CH:30]=1>>[Cl:19][C:15]1[CH:14]=[C:13]([C:11]2[N:12]=[C:7]([NH:28][C:29]3[CH:30]=[CH:31][C:32]([CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:33][CH:34]=3)[C:8]3[S:23](=[O:25])(=[O:24])[CH2:22][CH2:21][CH2:20][C:9]=3[N:10]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: O=S1(=O)CCCc2nc(-c3cccc(Cl)c3)nc(OS(=O)(=O)C(F)(F)F)c21
Product: CCOC(=O)Cc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2S(=O)(=O)CCC3)cc1
Yield: 77.5 %

Procedure:
Following general procedure H, 2-(3-chlorophenyl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl trifluoromethanesulfonate (1.0 g, 2.26 mmol) was reacted with ethyl 2-(4-aminophenyl)acetate (0.445 g, 2.49 mmol) to afford the title compound (0.827 g, 78%) as a light yellow solid. MW=471.96. APCI MS m/z 472 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:6]=[CH:5]2.[CH:19]1(B(O)O)[CH2:21][CH2:20]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CCOC(C)=O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH:19]1([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:6]=[CH:5]3)[CH2:21][CH2:20]1
Reactant: C[Si](C)(C)CCOCn1ncc2cc(Br)ccc21
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: C[Si](C)(C)CCOCn1ncc2cc(C3CC3)ccc21
Temperature: 100 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
A 250 ml 2-neck round-bottomed flask was charged with 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (2.5 g, 7.64 mmol), cyclopropylboronic acid (1.18 g, 13.7 mmol), palladium (II) acetate (85.7 mg, 0.38 mmol), tricyclohexylphosphine (214 mg, 0.764 mmol), potassium phosphate tribasic (3.24 g, 15.3 mmol), toluene (40 ml) and water (4 ml). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was cooled to room temperature and then diluted with EtOAc (100 ml) and water (20 ml). The mixture was extracted with EtOAc (100 mL). The organic layers were washed with water (20 mL) and brine (20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was absorbed onto SiO2 and purified by chromatography over SiO2 with EtOAc/CH2Cl2 (gradient: 0-10% EtOAc) to afford 1.7 g (77%) of 5-cyclopropyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazole as a light yellow oil. 1H NMR (300 MHz, CDCl3) δ: 7.93 (s, 1H), 7.48 (d, J=8.7 Hz, 1H), 7.44 (s, 1H), 7.19 (dd, J=8.5, 1.7 Hz, 1H), 3.53 (app t, J=8.3 Hz, 2H), 1.93-2.12 (m, 1H), 0.92-1.04 (m, 2H), 0.88 (app t, J=8.3 Hz, 2H), 0.64-0.78 (m, 2H), −0.07 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16](OC(SC)=S)[C:17]2([C:22]([O:24][CH3:25])=[O:23])[CH2:21][CH2:20][CH2:19][O:18]2)[CH:13]=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](Cl)(CCCC)CCCC)CCC.[F-].[K+]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=1)[CH2:16][C:17]1([C:22]([O:24][CH3:25])=[O:23])[CH2:21][CH2:20][CH2:19][O:18]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1(C(OC(=S)SC)c2cccc(CNC(=O)OC(C)(C)C)c2)CCCO1
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)C1(Cc2cccc(CNC(=O)OC(C)(C)C)c2)CCCO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 2-((3-{[(t-butoxycarbonyl)-amino]methyl}phenyl){[(methylsulfanyl)carbothioyl]oxy}-methyl)tetrahydro-2-furancarboxylate in 30 ml of toluene were added 1.55 g of tri-n-butyltin chloride and 0.03 g of 2,2-diazobis(isobutyronitrile) under an atmosphere of nitrogen gas, and the mixture was heated under reflux for 23 hours. After cooling to room temperature, 100 ml of saturated aqueous potassium fluoride was added. After stirring for 30 minutes, the mixture was extracted with 200 ml of ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography, to give 1.26 g of the title compound as a colorless oil.
Reaction SMILES: [CH:1]12[CH2:9][CH:5]([C:6]1([CH3:8])[CH3:7])C[CH2:3][CH:2]2C.[C:11]([OH:14])(=[O:13])[CH3:12].[O:15](O)O>C(Cl)(Cl)Cl>[C:11]([OH:14])(=[O:13])[CH3:12].[C:5]12([OH:15])[CH2:9][CH:1]([C:6]1([CH3:8])[CH3:7])[CH2:2][CH2:3][C:11]2([OH:14])[CH3:12]
Reactant: CC1CCC2CC1C2(C)C
Reactant: OOO
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC1(O)CCC2CC1(O)C2(C)C

Procedure:
The mixture was extracted with 50% EtOAc/hexanes two times. The combined organic extract was washed with 10% NaHSO3 solution and water, dried over anhydrous Na2SO4 and concentrated to afford the crude product as a tan oil (2.85 g). The pinanediol acetate 3 was purified by silica gel chromatography, eluting with 5˜50% EtOAc/hex, to yield a nearly colorless oil (2.03 g, 84%) containing a small amount of a less polar pinane-keto-alcohol acetate byproduct. IR (CHCl3): 3450, 3000, 2927, 2870, 1730, 1475, 1455, 1388, 1370, 1230, 1128, 1042, and 605 cm−1. 1HNMR (400 MHz, CDCl3): δ 4.26-4.38 (m, 2H), 4.03-4.09 (m, 1H), 3.15 (s, 1H, OH), 2.89 (d, J=6.2 Hz, 1H, OH), 2.46-2.54 (m, 1H), 2.18-2.26 (m, 1H), 2.10 (t, J=5.8 Hz, 1H), 2.06(s, 3H), 1.92-2.05 (m, 2H), 1.79-1.87 (m, 1H), 1.63-1.70 (m, 1H), 1.38 (d, J=10.4 Hz, 1H), 1.27 (s, 3H), 0.94 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]([OH:15])=O)[C:11](=[O:12])[N:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[CH2:28]([NH2:31])[CH2:29][CH3:30]>C(Cl)(Cl)Cl>[CH2:28]([NH:31][C:13]([C:10]1[C:11](=[O:12])[N:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:7]2=[N:8][CH:9]=1)=[O:15])[CH2:29][CH3:30]
Reactant: Cc1cccn2c(=O)c(C(=O)O)cnc12
Reactant: CCCN
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCNC(=O)c1cnc2c(C)cccn2c1=O
Reaction time: 0.08 h
Yield: 70.7 %

Procedure:
A mixture containing 9.2 g (0.045 mol) of 9-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 7.05 mi (0.05 mol) of triethylamine in 280 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 3.7 ml (0.045 mol) of methyl chloroformate dissolved in 25 ml of chloroform is dropped to the above mixture at -21 0° C. during 10 minutes. After stirring for 5 minutes, 2.95 g (0.05 mol) of propylamine dissolved in 50 ml of chloroform are dropped to the above solution at a temperature between -21° C. and -19° C. during 45 minutes. The reaction mixture is stirred below -10° C. for 1 hour, then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 70 ml of 5% sodium hydrogen carbonate solution each, then 3 times with 70 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to give 7.8 g (70.7%) of the named compound as snow-white crystals after recrystallization from ethanol, m.p.: 138°-140° C.