Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([N:5]([CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH3:23])[CH:21]=2)[O:16][C:15]([CH3:25])([CH3:24])[CH2:14]1)[CH2:6][CH2:7][CH2:8][CH2:9][C:10](O)=[O:11])(=[O:4])=[O:3].C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:38][CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=1>C1COCC1>[N:42]1[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=1[CH2:40][CH2:39][NH:38][C:10](=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH3:23])[CH:21]=2)[O:16][C:15]([CH3:25])([CH3:24])[CH2:14]1
Reactant: Cc1ccc2c(c1)C(N(CCCCC(=O)O)S(C)(=O)=O)CC(C)(C)O2
Reactant: NCCc1ccccn1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)C(N(CCCCC(=O)NCCc1ccccn1)S(C)(=O)=O)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.8 %

Procedure:
A mixture of 0.5 g (1.4 mmol) of 5-[methylsulfonyl-(2,2,6-trimethylchroman-4-yl)amino]pentanoic acid (Example 10c) and 0.26 g (1.6 mmol) of CDI in 20 ml of THF is stirred at RT for 3 h. 0.2 g (1.6 mmol) of 2-(2-aminoethyl)-pyridine is then added and the mixture is stirred further overnight at RT. After concentrating the reaction mixture, the residue is taken up in EA and water, and the organic phase is washed 3 times with 2M sodium hydroxide solution. After drying over magnesium sulfate, concentration and purification by chromatography on silica gel using methylene chloride/methanol 9:1, 0. 0.33 g of 5-[methylsulfonyl-(2,2,6-trimethylchroman-4-yl)amino]-pentanoic acid (2-(2-pyridyl)ethyl)amide is obtained.
Reaction SMILES: [CH2:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][S:2]1(=[O:11])=[O:10].[Br:12]Br>C(Cl)(Cl)(Cl)Cl.[Fe]>[Br:12][C:9]1[C:4]2[CH2:3][S:2](=[O:10])(=[O:11])[CH2:1][C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: O=S1(=O)Cc2ccccc2C1
Reactant: BrBr
Agent: [Fe]
Solvent: ClC(Cl)(Cl)Cl
Product: O=S1(=O)Cc2cccc(Br)c2C1

Procedure:
1,3-Dihydrobenzo[c]thiophene 2,2-dioxide, previously described, is brominated with 1 equivalent of bromine in carbon tetrachloride solution in the presence of iron [CA 84, 89930 (1976)] at reflux until the bromine color disappears to give 4-bromo-1,3-dihydrobenzo[c]thiophene 2,2-dioxide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[NH:21][N:22]=[CH:23][CH:24]=1)=[CH:16][CH:15]=3.Cl[C:31]([O:33][CH2:34][CH2:35][O:36][CH3:37])=[O:32]>>[CH3:37][O:36][CH2:35][CH2:34][O:33][C:31]([N:22]1[CH:23]=[CH:24][C:20]([C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH3:25])[C:12]2[N:26]([CH3:29])[C:27](=[O:28])[C:9]([C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])=[CH:10][C:11]3=2)=[N:21]1)=[O:32]
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4ccn[nH]4)ccc3n(C)c21
Reactant: COCCOC(=O)Cl
Product: COCCOC(=O)n1ccc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)n1

Procedure:
The process is carried out as indicated in Example 99 above, with the compound from Example 39, 3-(2,4-dichlorophenyl)-1,9-dimethyl-6-(2H-pyrazol-3-yl)-1,9-dihydropyrido[2,3-b]indol-2-one and 2-methoxyethyl chloroformate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](=S)[NH:7][C:6]=2[CH:17]=1.[NH2:18][CH2:19][CH2:20][N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1>C(OCCO)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([NH:18][CH2:19][CH2:20][N:21]3[CH:25]=[CH:24][N:23]=[CH:22]3)=[N:7][C:6]=2[CH:17]=1
Reactant: NCCn1ccnc1
Reactant: S=C1Nc2cc(Cl)ccc2Nc2ccccc21
Solvent: CCOCCO
Product: Clc1ccc2c(c1)N=C(NCCn1ccnc1)c1ccccc1N2
Yield: 56.6 %

Procedure:
A solution of 0.6 g (2.3 mmol) of 8-chloro-5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-thione in 15 mL of 2-ethoxyethanol was treated with 0.6 mL (4.6 mmol) of 1-(2-aminoethyl)imidazole and heated at reflux for 2 days. The solvent was removed under reduced pressure and the residue taken up in EtOAc and washed three times with H2O, then saturated NaHCO3 solution, and saturated NaCl solution. Drying over MgSO4 and removal of the solvent under reduced pressure left the crude product. This was recrystallized from EtOAc/hexane using charcoal to give 0.44 g (57.1% yield) of the product as pale yellow crystals, mp 168-170° C. The structure was confirmed by NMR and mass spectroscopy. (m+H)+ =338.
Reaction SMILES: CN(CCN(C)C)C.[Li]CCCC.[C:14]([O:18][C:19](=[O:28])[NH:20][C:21]1[CH:22]=[N:23][C:24]([Cl:27])=[CH:25][CH:26]=1)([CH3:17])([CH3:16])[CH3:15].[I:29]I>C1COCC1>[C:14]([O:18][C:19](=[O:28])[NH:20][C:21]1[CH:22]=[N:23][C:24]([Cl:27])=[CH:25][C:26]=1[I:29])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)nc1
Reactant: II
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1I
Reaction time: 0.5 h
Yield: 22.5 %

Procedure:
To a solution of TMEDA (25.4 g, 219.3 mmol) in dry THF (300 mL) was added dropwise n-BuLi (87.7 mL, 219.3 mmol) at −78° C., the mixture was stirred for 0.5 h at this temperature. A solution of (6-chloro-pyridin-3-yl)-carbamic acid tert-butyl ester (20 g, 87.7 mmol) in THF (170 mL) was added dropwise to the reaction mixture at −78° C. and the resulting mixture was continued to stir for 1 h at −78° C. Then a solution of I2 (26.7 g, 105.3 mmol) in dry THF (170 mL) was added dropwise at −78° C. After 1 h, the reaction was quenched with sat. aqueous NH4Cl (300 mL). The organic layer was separated and the aqueous phase was extracted with ethyl acetate (150 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (Petroleum ether/Ethyl acetate, 10/1) to give (6-chloro-4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester (7 g, 22.7%). 1H-NMR (CDCl3, 300 MHz) δ 8.95 (s, 1H), 7.73 (s, 1H), 6.64 (brs, 1H), 1.54 (s, 9H).
Reaction SMILES: [C:1]([C:4]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:5]=1[CH:6]=[C:7]1[S:11]C(=S)N[C:8]1=[O:13])([OH:3])=O.[OH-:20].[Na+].Cl>>[CH3:19][O:18][C:17]1[C:4]2[C:1](=[O:3])[S:11][C:7]([C:8]([OH:20])=[O:13])=[CH:6][C:5]=2[CH:14]=[CH:15][CH:16]=1
Reactant: COc1cccc(C=C2SC(=S)NC2=O)c1C(=O)O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: COc1cccc2cc(C(=O)O)sc(=O)c12

Procedure:
A solution of the benzylidenerhodanine of Example 10 in 46 ml. of 15% NaOH is refluxed for 0.75 hour, cooled, and poured into dilute HCl. The resulting tan precipitate is collected and air-dried. Two recrystallizations from methanol (charcoal) give 8-methoxy-1-oxo-1H-2-benzothiopyran-3-carboxylic acid as a pale yellow solid, m.p. 275° (dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[S:14][CH:15]=[CH:16][C:17]=3[Cl:18])[O:10][N:9]=2)=[CH:4][CH:3]=1.N([O-])=O.[Na+].[N-:23]=[N+:24]=[N-].[Na+]>C(O)(=O)C.O>[N:1]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[S:14][CH:15]=[CH:16][C:17]=3[Cl:18])[O:10][N:9]=2)=[CH:4][CH:3]=1)=[N+:23]=[N-:24]
Reactant: Nc1ccc(-c2noc(-c3sccc3Cl)n2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: [N-]=[N+]=Nc1ccc(-c2noc(-c3sccc3Cl)n2)cc1
Temperature: 2.5 °C
Reaction time: 0.33 h
Yield: 105.4 %

Procedure:
To a mixture of 3-(4-aminophenyl)-5-(3-chloro-thiophen-2-yl)-[1,2,4]-oxadiazole (15.5 mg, 0.05 mmol) in acetic acid (2 mL) and conc. sulfinuric acid (0.3 mL) was added sodium nitrite (3.8 mg, 0.055 mmol) in water (0.5 mL). The mixture was stirred vigorously at 0-5° C. for 20 min, then sodium azide (3.6 mg, 0.055 mmol) in water (0.5 mL) was added. It was stirred at 0-5° C. for 3 h and then poured into ice water (30 mL). The resultant mixture was extracted with ethyl acetate (3×10 mL). The organic layer was washed with water, dried over anhydrous sodium sulfate, and evaporated. The crude residue was purified by flash chromatography to yield 16 mg (100%) of the title compound. 1H NMR (CDCl3): 8.18 (d, J=8.7 Hz, 2H), 7.63 (d, J=5.4 Hz, 1H), 7.18 (d, J=8.7 Hz, 1H), 7.16 (d, J=5.4 Hz, 2H).
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:16][C@H:17]([CH2:21][CH:22]2[CH2:24][CH2:23]2)[C:18]([NH2:20])=[O:19])=[N:7][C:8]=1[NH:9][C:10]1[S:14][N:13]=[C:12]([CH3:15])[CH:11]=1)#[N:2].[OH-].[Na+].OO.CC(O)=[O:31]>CCO.CS(C)=O>[NH2:20][C:18](=[O:19])[C@H:17]([NH:16][C:6]1[N:7]=[C:8]([NH:9][C:10]2[S:14][N:13]=[C:12]([CH3:15])[CH:11]=2)[C:3]([C:1]([NH2:2])=[O:31])=[N:4][CH:5]=1)[CH2:21][CH:22]1[CH2:23][CH2:24]1
Reactant: CC(=O)O
Reactant: Cc1cc(Nc2nc(N[C@H](CC3CC3)C(N)=O)cnc2C#N)sn1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: Cc1cc(Nc2nc(N[C@H](CC3CC3)C(N)=O)cnc2C(N)=O)sn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The compound (R)-2-(5-cyano-6-(3-methylisothiazol-5-ylamino)pyrazin-2-ylamino)-3-cyclopropylpropanamide (143 mg, 0.323 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (30%, 1.0 mL) were added. The mixture was stirred at room temperature for 15 min. HOAc (0.1 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (39 mg). MS found for C15H19N7O2S as (M+H)+ MS 362.2; UV 205.4, 275.6, 324.4 nm; t 0.418 min. 1H NMR: (CD3OD) δ 7.51 (s, 1H), 6.69 (s, 1H), 4.68-4.60 (m, 1H), 2.28 (s, 3H), 1.84-1.75 (m, 1H), 1.65-1.57 (m, 1H), 0.82-0.72 (m, 1H), 0.40-0.28 (m, 2H), 0.10-0.0 (m, 2H).
Reaction SMILES: [CH2:1]([C:8]1[C:13]([O:14]COC)=[CH:12][CH:11]=[C:10]([N:18]2[CH2:22][CH2:21][C@H:20]([OH:23])[C:19]2=[O:24])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][CH:26]([OH:28])C.O>CC(C)=O>[CH2:1]([C:8]1[C:13]([OH:14])=[CH:12][CH:11]=[C:10]([N:18]2[CH2:22][CH2:21][C:20]3([O:23][CH2:25][CH2:26][O:28]3)[C:19]2=[O:24])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCOc1ccc(N2CC[C@H](O)C2=O)nc1Cc1ccccc1
Reactant: CC(C)O
Solvent: O
Solvent: CC(C)=O
Product: O=C1N(c2ccc(O)c(Cc3ccccc3)n2)CCC12OCCO2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1.1 g of 2-benzyl-3-methoxymethyloxy-6-[(3S)-3-hydroxy-2-pyrrolidinone-1-yl]pyridine was dissolved in 20 ml of acetone, and 1 ml of a Jone's reagent was added thereto, followed by stirring at room temperature for 1.5 hours. 2-Propanol and water were added thereto, followed by extracting with ethyl acetate. The organic phase was further washed with brine, dried over anhydrous sodium sulfate and the solvent was removed. The resulting residue was dissolved in 20 ml of toluene. 1 ml of ethylene glycol and 198 mg of p-toluenesulfonic acid were added thereto, followed by heating under reflux for 2 hours while removing water by use of Dean Stark apparatus. After cooling as it was, water was added thereto and the mixture was extracted with ethyl acetate. The organic phase was further washed with brine, dried over anhydrous sodium sulfate and the solvent was removed. The residue was subjected to silica gel column chromatography using 30-40% ethyl acetate/hexane as an eluent for separation and purification, to give 398 mg of the target compound.
Reaction SMILES: [OH:1][C@H:2]([C@H:6]([CH3:10])[C:7]([OH:9])=[O:8])[C:3]([OH:5])=[O:4].CO[C:13](OC)([CH3:15])[CH3:14]>CC(C)=O.[Cu](Cl)Cl>[CH3:14][C:13]1([CH3:15])[O:1][C@H:2]([C@H:6]([CH3:10])[C:7]([OH:9])=[O:8])[C:3](=[O:5])[O:4]1
Reactant: COC(C)(C)OC
Reactant: C[C@H](C(=O)O)[C@@H](O)C(=O)O
Agent: Cl[Cu]Cl
Solvent: CC(C)=O
Product: C[C@H](C(=O)O)[C@H]1OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.5 %

Procedure:
To a solution of (2R,3S)-2-hydroxy-3-methylsuccinic acid (2.48 g; 16.8 mmol; 1.0 eq.) in acetone (80.0 mL) was added 2,2-dimethoxypropane (4.13 g; 33.6 mmol; 2.0 eq.) and copper(II) chloride (226 mg; 1.68 mmol; 0.1 eq.). The resulting reaction mixture was stirred for 16 h at RT. The reaction mixture was evaporated and the residue taken up in CHCl3. Activated charcoal is added and the resulting mixture stirred for one hour. Filtration on a pad of celite gave the title product (mixture of diastereoisomers) as a greenish oil (1.85 g, 59%) used in the next step without further purification.
Reaction SMILES: CC(C)([O-])C.[K+].CO[C:9](=[O:23])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.C(OCC)(=O)[C:25]([O:27]CC)=[O:26]>>[C:17]1([C:14]2[CH:13]=[CH:12][C:11]([CH2:10][C:9](=[O:23])[C:25]([OH:27])=[O:26])=[CH:16][CH:15]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)Cc1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: O=C(O)C(=O)Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
40 g of Potassium t-butoxide was added to 150 ml of diethyl oxalate in small portions with stirring. After the initial exothermic reaction subsided, the reaction mixture was heated on a steam bath under nitrogen in order to dissolve solids. After cooling down to room temperature, 79 g of 4-biphenyl acetic acid methyl ester was added in one portion. The mixture was stirred at 60°-70° C. for 2 hours while low boiling material was removed under vaccum. On cooling to room temperature, the viscous residue was stirred with 200 ml of ether and 350 ml of water with cooling. The ether layer was separated and extracted once with 100 ml of water. The aqueous layers were combined, extracted once with ether, made acidic with concentrated HCl (cooling) and extracted with 2×300 ml of ether. Some solids did not dissolve in the ether layer and were filtered. The ether layer was then evaporated to dryness. and the semi solid residue was combined with the preceeding solids. A mixture of 160 ml of conc. HCl and 350 ml of acetic acid was added to the solids and heated under reflux for 21/2 hours. On cooling down to ca. 50° C. a solid preciptated, which was filtered and washed with 150 ml of water. The wet solid was stirred with 150 ml of acetonitrile for five minutes, then filtered and dried under high vaccum at room temperature for 3 hours. 42.2 g of the title compound m.p. 215°-218° C. were obtained.
Reaction SMILES: [CH2:1]([S:4][C:5]1[C:6]([S:14]([NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])=[O:15])=[C:7]([C:10]([O:12][CH3:13])=[O:11])[S:8][CH:9]=1)[CH2:2][CH3:3].ClC1C=C(C=CC=1)C(OO)=[O:27]>C(Cl)Cl>[CH2:1]([S:4]([C:5]1[C:6]([S:14]([NH:17][C:18]([CH3:20])([CH3:19])[CH3:21])(=[O:16])=[O:15])=[C:7]([C:10]([O:12][CH3:13])=[O:11])[S:8][CH:9]=1)=[O:27])[CH2:2][CH3:3]
Reactant: CCCSc1csc(C(=O)OC)c1S(=O)(=O)NC(C)(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCS(=O)c1csc(C(=O)OC)c1S(=O)(=O)NC(C)(C)C
Temperature: -80 °C
Reaction time: 0.33 h

Procedure:
A solution of 2.32 g 4-propylthio-3-(N-(1,1-dimethylethyl)aminosulfonyl)-2-thiophenecarboxylic acid, methyl ester in 75 mL methylene chloride was cooled to -80° C. and 1.39 g of 80-85% m-chloroperoxybenzoic acid was added in one portion. After stirring at -80° C. for 20 minutes and warming to 20° C. the solution was diluted with more methylene chloride and washed with aqueous sodium bicarbonate, sodium bisulfite, sodium bicarbonate and water, dried and concentrated to 2.2 g of colorless oil in sufficiently pure form for the purposes of this invention.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][N:7]=1)(=O)C.[OH-].[Na+].[Cl-].[Na+]>O>[OH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][N:7]=1
Reactant: CC(=O)OCc1ccc(C)cn1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(CO)nc1
Yield: 83.4 %

Procedure:
14.0 g of 2-acetoxymethyl-5-methylpyridine were heated under reflux for 90 minutes in a solution of 4.5 g of sodium hydroxide in 150 ml of water. The cooled solution was saturated with sodium chloride and extracted with a total amount of 100 ml of chloroform. The organic phases were washed with saturated sodium chloride solution, dried over magnesium sulphate, and concentrated by evaporation at 40°/16 mm Hg. The oil obtained distilled at 12°/8 mm Hg. 8.7 g of 2-hydroxymethyl-5-methylpyridine were obtained.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:12]1[N:17]=[C:16]([Cl:18])[N:15]=[C:14]2[N:19]([CH3:22])[N:20]=[CH:21][C:13]=12>>[Cl:18][C:16]1[N:15]=[C:14]2[N:19]([CH3:22])[N:20]=[CH:21][C:13]2=[C:12]([N:8]2[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH2:7]2)[N:17]=1
Reactant: Cn1ncc2c(Cl)nc(Cl)nc21
Reactant: CS(=O)(=O)N1CCNCC1
Product: Cn1ncc2c(N3CCN(S(C)(=O)=O)CC3)nc(Cl)nc21

Procedure:
Reaction of 1-methanesulfonyl-piperazine with 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine 5 by General Procedure B gave 6-chloro-4-(4-methanesulfonyl-piperazin-1-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine.
Reaction SMILES: [CH:1]1([S:6][CH2:7][C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:13])=O>>[CH:1]1([S:6][CH2:7][C:8]([Cl:13])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CSC1CCCC1
Product: O=C(Cl)CSC1CCCC1
Temperature: 70 °C

Procedure:
The product from Example 143B (6.56 g) was combined with thionyl chloride (50 mL, 685 mmol) and the reaction mixture was heated at 70° C. for 2 hours. The reaction mixture was concentrated under vacuum, and the residue was dissolved in CHCl3 (50 mL) and concentrated again to remove excess thionyl chloride. The residue was distilled under vacuum (air bath 100-110° C./˜10 mm) to provide the title compound, used directly for the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14][C:5]2=1.[H-].[Na+].[CH3:24]I>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:24])[C:6]1[CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14][C:5]2=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCc2c([nH]c3ccc(Br)cc23)C1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1c2c(c3cc(Br)ccc31)CCN(C(=O)OC(C)(C)C)C2
Reaction time: 1 h
Yield: 62.1 %

Procedure:
tert-Butyl 6-bromo-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (1.15 g, 3.26 mmol) was dissolved in DMF (20 mL) and sodium hydride (60% weight dispersion in mineral oil, 196 mg, 4.89 mmol) was added. After 1 h, methyl iodide (0.30 mL, 4.9 mmol) was added and the reaction mixture was stirred for a further 30 min. The mixture was diluted with methylene chloride and washed with 5% lithium chloride solution (5×), dried over Na2SO4 and concentrated. Purification by flash column chromatography (silica gel, hexanes/ethyl acetate, 97:3 to 75:25) gave the title compound (740 mg, 36%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 7.58 (s, 1H), 7.24 (d overlapped by solvent, J=8.5, 1H), 7.14 (d, J=8.5, 1H), 4.67-4.53 (br m, 2H), 3.79-3.67 (br m, 2H), 3.60 (s, 3H), 2.78-2.66 (br m, 2H), 1.51 (s, 9H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][O:41]CC3C=CC=CC=3)=[CH:33][CH:32]=2)=[C:28]([CH:49]([CH3:51])[CH3:50])[NH:27][N:26]=1)(=[O:3])[CH3:2]>CO.O1CCCC1.[C].[Pd]>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][OH:41])=[CH:33][CH:32]=2)=[C:28]([CH:49]([CH3:51])[CH3:50])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCOCc3ccccc3)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCO)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.9 %

Procedure:
3-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-benzyloxypropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole (2.75 g) was dissolved in a mixed solvent of methanol (20 mL) and tetrahydrofuran (9 mL). To the solution was added 10% palladium-carbon powder (550 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours. The insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give the title compound (2.4 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]([OH:12])=O)=[CH:7][C:6]=2[CH:13]=1.[ClH:14].Cl.[NH2:16][C@@H:17]1[CH:22]2[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]2)[CH2:18]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[ClH:14].[N:19]12[CH2:24][CH2:23][CH:22]([CH2:21][CH2:20]1)[C@@H:17]([NH:16][C:10]([C:8]1[S:9][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:13][C:6]=3[CH:7]=1)=[O:12])[CH2:18]2
Reactant: O=C(O)c1cc2cc(Br)ccc2s1
Reactant: N[C@H]1CN2CCC1CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cc(Br)ccc2s1

Procedure:
133.7 mg (0.52 mmol) of 5-bromo-1-benzothiophene-2-carboxylic acid (Example 13A), 155.4 mg (0.78 mmol) of (R)-3-aminoquinuclidine dihydrochloride, 296.7 mg (0.78 mmol) of HATU, 369.8 mg (2.86 mmol) of N,N-diisopropylethylamine and 1.5 ml of DMF are reacted by general method C. The reaction mixture is purified by preparative HPLC. The product is dissolved in acetonitrile, and an excess of 1N hydrochloric acid is added. Finally, the solvent is removed. 175 mg (84% of theory) of the title compound are isolated.
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][C:8]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:9]=1[C:10]([NH:12][CH:13]([CH:15]1[CH2:17][CH2:16]1)[CH3:14])=[O:11].[Br:23][C:24]1[CH:28]=[C:27]([C:29](OC2C=CC=CC=2)=[O:30])[N:26]([C:38]2[C:43]([Cl:44])=[CH:42][CH:41]=[CH:40][N:39]=2)[N:25]=1.Cl>CS(C)=O>[Br:23][C:24]1[CH:28]=[C:27]([C:29]([NH:7][C:8]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:9]=2[C:10](=[O:11])[NH:12][CH:13]([CH:15]2[CH2:17][CH2:16]2)[CH3:14])=[O:30])[N:26]([C:38]2[C:43]([Cl:44])=[CH:42][CH:41]=[CH:40][N:39]=2)[N:25]=1
Reactant: O=C(Oc1ccccc1)c1cc(Br)nn1-c1ncccc1Cl
Reactant: CC(NC(=O)c1cc(Cl)ccc1N)C1CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: CC(NC(=O)c1cc(Cl)ccc1NC(=O)c1cc(Br)nn1-c1ncccc1Cl)C1CC1
Yield: 38.6 %

Procedure:
0.18 g of potassium tert-butoxide was added to a mixed solution comprising 0.23 g of 2-amino-5-chloro-N-(1-cyclopropylethyl)benzamide, 0.30 g of phenyl 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylate and 5 ml of dimethyl sulfoxide, followed by reaction at room temperature for 1 hour. The reaction liquid was slowly added to diluted hydrochloric acid, the mixed liquid was subjected to extraction with ethyl acetate, and the organic layer was washed with a saturated sodium hydrogen carbonate aqueous solution and with a sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=8/2 to 7.5/2.5) to obtain 0.16 g of the desired product.
Reaction SMILES: [N:1]([CH2:4][C:5]1[NH:6][C:7](=[O:15])[C:8]2[CH2:14][O:13][CH2:12][CH2:11][C:9]=2[N:10]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][CH2:4][C:5]1[NH:6][C:7](=[O:15])[C:8]2[CH2:14][O:13][CH2:12][CH2:11][C:9]=2[N:10]=1
Reactant: [N-]=[N+]=NCc1nc2c(c(=O)[nH]1)COCC2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCc1nc2c(c(=O)[nH]1)COCC2
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 94.9 %

Procedure:
To a solution of 2-(azidomethyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one (19 g, 92 mmol) in THF (945 mL) at 35° C. was added triphenylphosphine (26.5 g, 101 mmol). Gas evolution was noted immediately and after approximately 40 minutes a fine precipitate formed. The reaction was allowed to stir for 1.5 h then 18.17 mL water was added. After an addition 2 h the reaction mixture was cooled to room temperature, filtered twice, concentrated to approximately ⅓ of the original volume and filtered once more. The solid material was washed with THF to yield a total of 15.82 g of the title compound. 1H NMR (400 MHz, MeOD) δ ppm 2.66 (t, J=5.56 Hz, 2H) 3.76 (s, 2H) 3.94 (t, J=5.56 Hz, 2H) 4.49 (s, 2H)