Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([OH:8])=O)[CH3:2].[Li]CCCC.[CH2:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][CH:16]1C(Cl)=O.Cl>C1COCC1.CCOCC>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6](=[O:8])[CH:21]1[CH2:22][CH2:23][C:24]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20]1)[CH3:2]
Reactant: CCOC(=O)CC(=O)O
Reactant: O=C(Cl)C1CCc2ccccc2C1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)C1CCc2ccccc2C1
Temperature: -5 °C
Reaction time: 0.08 h
Yield: 93.5 %

Procedure:
A solution of malonic acid monoethyl ester (3.8 g, 29 mmol) in THF (80 ml) was cooled to −78° C. n-BuLi (36 ml, 58 mmol, 1.6 M in hexane) was added dropwise so that the temperature of the reaction mixture at the end the addition was −5° C. After 5 min. stirring at −5° C., reaction mixture was cooled to −65° C. and treated with a solution of (RS)-1,2,3,4-tetrahydro-naphthalene-2-carbonyl chloride (3.2 g, 16.5 mmol) in THF. Mixture was stirred for 10 min. at −65° C. and then added to a stirring mixture containing Et2O (200 ml) and 1N HCl (100 ml). Aqueous phase was extracted with Et2O (2×150 ml). Combined organic phases were washed successively with a saturated solution of NaHCO3 (100 ml) and NaCl (100 ml), dried over Na2SO4 and concentrated to provide (RS)-3-oxo-3-(1,2,3,4-tetrahydro-naphthalen-2-yl)-propionic acid ethyl ester (3.8 g, 93%) as a light brown oil, MS: m/e=246 (M+).
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[N:6][CH:5]=1)([O-:3])=[O:2].[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](O)=[O:25].C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([N:18]1[CH2:19][CH2:20][CH:15]([O:14][C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][N:6]=2)[CH2:16][CH2:17]1)=[O:25]
Reactant: O=[N+]([O-])c1cnc(OC2CCNCC2)c2ccccc12
Reactant: O=C(O)c1ccccc1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(c1ccccc1F)N1CCC(Oc2ncc([N+](=O)[O-])c3ccccc23)CC1
Yield: 92 %

Procedure:
Stir a reaction mixture of 4-(4-nitro-isoquinoline-1-yloxy)-piperidine (4.0 g, 14.6 mmol), 2-fluorobenzoic acid (2.45 g, 17.5 mmol), DCC (3.6 g, 17.5 mmol), and HOBt (2.37 g, 17.5 mmol) in THF (100 mL) at 22° C. overnight. Filter then concentrate. Subject residue to silica gel chromatography eluting with hexanes and ethyl acetate to provide (2-fluoro-phenyl)-[4-(4-nitro-isoquinoline-1-yloxy)-piperidin-1-yl]-methanone as a yellow solid (6.82 g, 92% yield, ES+ (m/z) 396.3 [M+H]).
Reaction SMILES: [Na].[C:2]([CH2:4][C:5]([NH2:7])=[O:6])#[N:3].[C:8]([C:16]1[CH:25]=[CH:24][C:19]([CH2:20][N:21]=[N+:22]=[N-:23])=[CH:18][C:17]=1[CH3:26])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(C1C=CC(C)=CC=1CN=[N+]=[N-])(=O)C1C=CC=CC=1>C(O)C>[NH2:3][C:2]1[N:21]([CH2:20][C:19]2[CH:24]=[CH:25][C:16]([C:8](=[O:15])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[C:17]([CH3:26])[CH:18]=2)[N:22]=[N:23][C:4]=1[C:5]([NH2:7])=[O:6]
Reactant: N#CCC(N)=O
Reactant: Cc1cc(CN=[N+]=[N-])ccc1C(=O)c1ccccc1
Agent: Cc1ccc(C(=O)c2ccccc2)c(CN=[N+]=[N-])c1
Agent: [Na]
Solvent: CCO
Product: Cc1cc(Cn2nnc(C(N)=O)c2N)ccc1C(=O)c1ccccc1
Reaction time: 0.08 h
Yield: 31 %

Procedure:
A stirred solution of sodium (104 mg, 4.50 mmol) in absolute ethanol at 60° C. was treated with 2-cyanoacetamide (378 mg, 4.50 mmol), kept 5 min, and treated with a solution of 942 mg of a 4:1 mixture of 4-benzoyl-3-methyl-benzyl azide and 2-benzoyl-5-methylbenzyl azide in absolute ethanol (6 ml). The mixture was refluxed 1 hour, cooled to 0° , and filtered. The solid was washed twice with water, acidified with acetic acid, and dried. The ethanol filtrate was acidified with acetic acid and evaporated to dryness at 40° C. under vacuum. The residue from the filtrate was combined with the above solid and chromatographed on a column of silica gel (125 g) eluted in 17 ml fractions with 19:1 (v/v) dichloromethane-methanol. Fractions 19-25 were combined and evaporated to dryness, and the residue was triturated with diethyl ether (3×10 ml). The remaining solid was dried 18 hours at ambient temperature under vacuum to provide 330 mg (31%) 5-amino-1-(4-benzoyl-3-methylbenzyl)-1,2,3-triazole4-carboxamide, m.p. 181°-182° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13]1[N:21]=[C:20]([Cl:22])[N:19]=[C:18]2[C:14]=1[N:15]=[CH:16][N:17]2[CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>O>[Cl:22][C:20]1[N:19]=[C:18]2[C:14]([N:15]=[CH:16][N:17]2[CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:13]([NH:12][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH2:3][CH2:2][N:32]2[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]2)[N:21]=1
Reactant: CN1CCNCC1
Reactant: ClCCCOc1ccccc1Nc1nc(Cl)nc2c1ncn2C1CCCC1
Solvent: O
Product: CN1CCN(CCCOc2ccccc2Nc2nc(Cl)nc3c2ncn3C2CCCC2)CC1

Procedure:
[2-(3-Chloro-propoxy)-phenyl]-(2-chloro-9-cyclopentyl-purin-6-yl)-amine (0.4 mmol) are stirred at RT in N-methylpiperazine (0.3 ml) for 12 hours. The mixture is diluted with water and extracted 3 times with ethyl acetate. The combined organic phases are washed with brine and the extract is dried over sodium sulfate and evaporated. The residue is purified by flash chromatography on silica gel with (CH2Cl2/MeOH=9:1) as mobile phase. The product containing fractions are combined and evaporated. A pale oil with R=0.25 (CH2Cl2/MeOH=9:2) is obtained.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH:16]([C:18]([O:20][CH3:21])=[O:19])[CH2:15][CH2:14][NH:13]2)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.[C:31](Cl)(=[O:34])[O:32][CH3:33]>ClCCl>[C:2]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH:16]([C:18]([O:20][CH3:21])=[O:19])[CH2:15][CH2:14][N:13]2[C:31]([O:32][CH3:33])=[O:34])=[CH:8][CH:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(c2ccc(C(C)(C)C)cc2)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(c2ccc(C(C)(C)C)cc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 102.6 %

Procedure:
To a suspension of methyl 2-(4-tert-butylphenyl)piperidine-4-carboxylate hydrochloride (9.66 g, 30.98 mmol) in dichloromethane (100 mL) was added DIPEA (12 mL, 68.89 mmol). The reaction mixture was cooled in an ice-bath and methyl carbonochloridate (2.8 mL, 35.56 mmol) was added dropwise over 5 min. The reaction mixture was stirred for 18 h at room temperature and washed with 3.8 N HCl. The aqueous layer was extracted with DCM. The combined organic layers were dried over MgSO4 and evaporated. Dimethyl 2-(4-tert-butylphenyl)piperidine-1,4-dicarboxylate (10.6 g, quant.) was isolated as a dark brown oil. MS m/z 334 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[N:11][C:10]([C:13]([N:15]3[CH2:20][CH2:19][NH:18][C@@H:17]([CH3:21])[CH2:16]3)=[O:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[Br:22][C:23]1[CH:24]=[C:25]([C:29](O)=[O:30])[O:26][C:27]=1[Br:28].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:22][C:23]1[CH:24]=[C:25]([C:29]([N:18]2[CH2:19][CH2:20][N:15]([C:13]([C:10]3[N:11]=[CH:12][N:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)[N:9]=3)=[O:14])[CH2:16][C@@H:17]2[CH3:21])=[O:30])[O:26][C:27]=1[Br:28]
Reactant: C[C@H]1CN(C(=O)c2ncn(-c3cccc(F)c3)n2)CCN1
Reactant: O=C(O)c1cc(Br)c(Br)o1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H]1CN(C(=O)c2ncn(-c3cccc(F)c3)n2)CCN1C(=O)c1cc(Br)c(Br)o1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 87 mg (0.30 mmol) [1-(3-fluoro-phenyl)-1H-[1,2,4]triazol-3-yl]-((S)-3-methyl-piperazin-1-yl)-methanone, 84 mg (0.30 mmol) 4,5-dibromo-2-furoic acid, 0.11 g (0.33 mmol) TBTU and 80 μL (0.45 mmol) DIPEA in 5.0 mL DMF was stirred at RT for 12 h. The reaction mixture was purified by HPLC.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:10])=[N:4][CH:5]=[N:6][C:7]=1[O:8][CH3:9].Cl[C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:15]([C:21]([F:24])([F:23])[F:22])=[C:14]([Cl:25])[C:13]=1[N+:26]([O-:28])=[O:27].CC([O-])(C)C.[K+].C(O)(=O)C>CS(C)=O>[Cl:25][C:14]1[C:13]([N+:26]([O-:28])=[O:27])=[C:12]([N:6]2[C:7]([O:8][CH3:9])=[C:2]([NH2:1])[C:3]([Cl:10])=[N:4][CH2:5]2)[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:15]=1[C:21]([F:23])([F:24])[F:22]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Cl
Reactant: COc1ncnc(Cl)c1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: COC1=C(N)C(Cl)=NCN1c1c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]
Temperature: 0 °C
Yield: 103.2 %

Procedure:
2.84 g (17.8 mmoles) of 5-amino-4-chloro-6-methoxypyrimidine are dissolved in 20 ml of dimethylsulfoxide. With stirring, a solution of 6.24 g (20.5 mmoles) of 1,3-dichloro-2,6-dinitro-4-trifluoromethylbenzene in 15 ml of dimethylsulfoxide and a solution of 2.30 g (20.5 mmoles) of potassium tert-butylate in 15 ml of dimethylsulfoxide are added simultaneously dropwise at 15° C. The dark red solution so obtained is stirred for 1 hour at 15°-20° C. and then poured into ice-water, neutralised with acetic acid and extracted three time with chloroform. The extracts are dried over sodium sulfate and the solvent is removed by rotary evaporation, affording 7.9 g of an oil. This crude product is purified by chromatography through a column of silica gel affording 3.19 g of a crystalline product. Recrystallisation from a mixture of 2 ml of toluene and 8 ml of cyclohexane yields 2.52 g of yellow crystals of m.p. 114°-116° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=1.CC(C)=[O:20].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH3:11][O:10][C:8]([C:6]1[S:7][C:3]([C:2]([OH:20])=[O:1])=[CH:4][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: CC(C)=O
Reactant: COC(=O)c1sc(CO)cc1-c1ccccc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: COC(=O)c1sc(C(=O)O)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
To a solution of 169 (1.20 g, 4.83 mmol) in 30 mL of acetone was added dropwise Jones reagent (5 mL, 1.3M, 6.5 mmol) and stirred at room temperature for 1 hour. The reaction mixture was quenched with 10 mL of IPA, stirred for 10 min, filtered over a pad of Celite®. The filtrate was concentrated under vacuum, diluted in ether, washed with brine, dried over sodium sulfate, filtered, concentrated under vacuum to yield compound 174 (1.156 g, 91%) as yellow solid.
Reaction SMILES: [F:1][C:2]1([F:11])[CH2:7][CH2:6][CH:5]([C:8](=[S:10])[NH2:9])[CH2:4][CH2:3]1.[CH3:12][O:13][C:14](=[O:22])[CH:15](Cl)[C:16](=O)[CH2:17][O:18][CH3:19]>C(O)C>[CH3:12][O:13][C:14]([C:15]1[S:10][C:8]([CH:5]2[CH2:6][CH2:7][C:2]([F:1])([F:11])[CH2:3][CH2:4]2)=[N:9][C:16]=1[CH2:17][O:18][CH3:19])=[O:22]
Reactant: COCC(=O)C(Cl)C(=O)OC
Reactant: NC(=S)C1CCC(F)(F)CC1
Solvent: CCO
Product: COCc1nc(C2CCC(F)(F)CC2)sc1C(=O)OC
Yield: 33.5 %

Procedure:
7.0 g 4,4-Difluoro-cyclohexanecarbothioic acid amide and 8.46 g 2-Chloro-4-methoxy-3-oxo-butyric acid methyl ester were dissolved in 70 ml ethanol and heated under reflux overnight. The cooled reaction mixture was evaporated under reduced pressure and the resulting residue was purified by silica chromatography with the eluent n-heptane:ethyl acetate=4:1=>2:1 to obtain 4.0 g 2-(4,4-Difluoro-cyclohexyl)-4-methoxymethyl-thiazole-5-carboxylic acid methyl ester as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl.[NH2:11][OH:12].C[O-].[Na+]>C(O)C>[OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4](=[N:11][OH:12])[NH2:5]
Reactant: NO
Reactant: N#Cc1ccccc1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: NC(=NO)c1ccccc1O

Procedure:
2-Hydroxybenzonitrile (10 grams), hydroxylamine HCl in 150 ml. ethanol, and sodium methoxide (9.0 grams) were refluxed for about 18 hours. The reaction mixture was then filtered and the ethanol evaporated. Next water was added and extracted into ethyl acetate. Drying and evaporation of the solvent left on oily product which solidified upon standing. The identity of the final product was confirmed by NMR and IR analysis.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[C:11]([O:18][CH3:19])=[N:12][C:13]([O:16][CH3:17])=[N:14][CH:15]=2)[N:7]([CH:20]([CH3:22])[CH3:21])[C:6]=1[CH:23]([C:25]1[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27]([F:33])[CH:26]=1)O)=[O:4].[NH2:34][C:35]1[CH:36]=[C:37]([Cl:43])[C:38](=[O:42])[N:39]([CH3:41])[CH:40]=1.C(OC(C1C=CN(C(C)C)C=1C(C1C=CC(C#N)=CC=1)O)=O)C.ClC1C=C(C=CC=1F)N>>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[C:11]([O:18][CH3:19])=[N:12][C:13]([O:16][CH3:17])=[N:14][CH:15]=2)[N:7]([CH:20]([CH3:22])[CH3:21])[C:6]=1[CH:23]([NH:34][C:35]1[CH:36]=[C:37]([Cl:43])[C:38](=[O:42])[N:39]([CH3:41])[CH:40]=1)[C:25]1[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27]([F:33])[CH:26]=1)=[O:4]
Reactant: COC(=O)c1cc(-c2cnc(OC)nc2OC)n(C(C)C)c1C(O)c1ccc(C#N)c(F)c1
Reactant: Cn1cc(N)cc(Cl)c1=O
Agent: CCOC(=O)c1ccn(C(C)C)c1C(O)c1ccc(C#N)cc1
Agent: Nc1ccc(F)c(Cl)c1
Product: COC(=O)c1cc(-c2cnc(OC)nc2OC)n(C(C)C)c1C(Nc1cc(Cl)c(=O)n(C)c1)c1ccc(C#N)c(F)c1

Procedure:
The title compound was prepared in analogy to the procedures described for Step H2 and Step H3 but 2-[(4-cyano-3-fluoro-phenyl)-hydroxy-methyl]-5-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-1H-pyrrole-3-carboxylic acid methyl ester (Step 195.2) and 5-amino-3-chloro-1-methyl-1H-pyridin-2-one (Step E5) were used instead of 2-[(4-cyano-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid ethyl ester and 3-chloro-4-fluoroaniline respectively. The title compound was obtained as a blue solid. tR: 1.10 min (HPLC 3); ESI-MS: tR=1.07 min, [M+H]+ 595/597 (LC-MS 1); TLC: Rf=0.29 (EtOAc).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11](=[O:24])[CH2:12][O:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[C:17]([CH3:23])[NH:18]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:25][CH:26](Br)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>CN(C=O)C.C(OCC)(=O)C>[CH2:3]([O:10][C:11](=[O:24])[CH2:12][O:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[C:17]([CH3:23])[N:18]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][Br:25])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCCCCCCCCCCC(Br)Br
Reactant: Cc1cc2c(OCC(=O)OCc3ccccc3)cccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc2c(OCC(=O)OCc3ccccc3)cccc2n1CCCCCCCCCCCCBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 0.093 g, 6.45 mmole) in DMF (10 mL), (2-methyl-1H-indol-4-yloxy)-acetic acid benzyl ester (2) (0.845 g, 2.3 mmole) was added. The mixture was stirred at room temperature for 1 h. To the mixture, dibromododecane (0.765 g, 2.3 mmole) was added and the reaction mixture was stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate and washed with water. The organic layer was separated, dried with sodium sulphate and concentrated. The residue was purified by column chromatography (10:1, hexane: EtOAc) to afford intermediate 3. Yield: 0.708 g, 45%.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1.[Cl:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:13]=1[C:14](Cl)=[O:15]>C1C(Cl)=CC=C(Cl)C=1>[Cl:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:13]=1[C:14]([NH:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1)=[O:15]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: Nc1nc(C(Cl)(Cl)Cl)ns1
Solvent: Clc1ccc(Cl)cc1
Product: O=C(Nc1nc(C(Cl)(Cl)Cl)ns1)c1c(Cl)cccc1Cl
Yield: 22 %

Procedure:
A solution of 22.0 g (0.1 mole) 5-amino-3-trichloromethyl-1,2,4-thiadiazole and 20.1 g (0.1 mole) 2,6-dichlorobenzoyl chloride was refluxed for 8 hours in 200 ml dichlorobenzene. After filtration, the crude product precipitated from the filtrate upon standing. Recrystallization from toluene gave 8.6 g (22% yield) of pure product; m.p. 209° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[O:7][C:6](=[O:8])[C:5](=[CH:9][NH:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([OH:21])[CH:12]=2)[C:4](=[O:22])[O:3]1.[H-].[Na+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O.O>[CH2:26]([O:21][C:13]1[CH:12]=[C:11]([NH:10][CH:9]=[C:5]2[C:4](=[O:22])[O:3][C:2]([CH3:23])([CH3:1])[O:7][C:6]2=[O:8])[CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(NC=C2C(=O)OC(C)(C)OC2=O)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC=C2C(=O)OC(C)(C)OC2=O)cc1OCc1ccccc1
Reaction time: 1.5 h
Yield: 86.4 %

Procedure:
After suspending methyl 4-(((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methyl)amino)-2-hydroxybenzoate (13.975 g, 43.5 mmol) in dimethylformamide (140 ml) at room temperature under a nitrogen atmosphere, sodium hydride (1.87 g, 46.8 mmol) was gradually added. After 1.5 hours, benzyl bromide 5.7 ml, 47.9 mmol) was added dropwise and the mixture was stirred for 2 days. The reaction solution was diluted with water (700 ml) and stirred overnight, and the precipitated crystals were filtered, washed with diethyl ether and dried at 70° C. to obtain the title compound (15.477 g, 37.6 mmol, 86.5%) as white crystals.
Reaction SMILES: [CH3:1][N:2]([C:4]([NH:6][C:7]([NH2:9])=[NH:8])=[NH:5])[CH3:3].CC(C)=O.O.[C:15]([OH:23])(=[O:22])[CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20]>CC(C)=O.O>[CH3:1][N:2]([C:4]([NH:6][C:7]([NH2:9])=[NH:8])=[NH:5])[CH3:3].[C:15]([O-:23])(=[O:22])[CH2:16][CH2:17][CH2:18][C:19]([O-:21])=[O:20]
Reactant: O=C(O)CCCC(=O)O
Agent: CN(C)C(=N)NC(=N)N
Solvent: O
Solvent: CC(C)=O
Product: O=C([O-])CCCC(=O)[O-]
Temperature: 10 °C
Yield: 143.9 %

Procedure:
9.75 g (2.5 molar equivalents) of the metformin free-base was stirred in a mixed solution of 112.5 ml of acetone and 5 ml of water at 40° C., and a solution of 3.98 g (1 molar equivalent) of glutaric acid in acetone-water was added dropwise thereto and stirred at 10° C. The produced crystal was filtered and dried in hot air, thus obtaining 11.24 g (yield: 95.3%) of metformin glutarate.
Reaction SMILES: [N:1]1([C@@H:6]2[CH2:11][CH2:10][C@H:9]([NH:12]C(=O)OC(C)(C)C)[CH2:8][CH2:7]2)[CH:5]=[N:4][CH:3]=[N:2]1.[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23]>C(Cl)Cl>[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23].[N:1]1([C@@H:6]2[CH2:7][CH2:8][C@H:9]([NH2:12])[CH2:10][CH2:11]2)[CH:5]=[N:4][CH:3]=[N:2]1.[C:22]([OH:24])([C:21]([F:26])([F:25])[F:20])=[O:23]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](n2cncn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1CC[C@@H](n2cncn2)CC1

Procedure:
Sodium hydride (60%, 0.034 g, 0.86 mmol) was added portionwise to a solution of 1H-1,2,4-triazole (0.064 g, 0.92 mmol) in N,N-dimethylformamide (2 mL). After stirred for 5 min, trans-4-[(tert-butoxycarbonyl)amino]cyclohexyl methanesulfonate (0.18 g, 0.61 mmol) was added. The resulting mixture was stirred at 65° C. over weekend. The cooled mixture was poured into ice-cold water, extracted with EtOAc. The organic layers were concentrated and purified on silica gel (eluting with 0 to 5% MeOH in EtOAc) to give tert-butyl [cis-4-(1H-1,2,4-triazol-1-yl)cyclohexyl]carbamate (0.14 g, 86%). LCMS calculated for C13H23N4O2 (M+H)+: m/z=267.2. Found: 267.1. This carbamate intermediate was treated with trifluoroacetic acid (0.28 mL, 3.7 mmol) in methylene chloride (1 mL) at room temperature for 1 h and then concentrated to give the desired product as TFA salt. LCMS calculated for C8H15N4 (M+H)+: m/z=167.1. Found: 167.2.
Reaction SMILES: BrCC1CC1(F)F.[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:16][C:17]1[N:18]=[C:19]([N:27]2[CH2:31][CH2:30][NH:29][C:28]2=[O:32])[S:20][C:21]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[CH2:8]([N:29]1[CH2:30][CH2:31][N:27]([C:19]2[S:20][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:17]([CH3:16])[N:18]=2)[C:28]1=[O:32])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: BrCc1ccccc1
Agent: FC1(F)CC1CBr
Product: CCOC(=O)c1sc(N2CCN(Cc3ccccc3)C2=O)nc1C
Yield: 93 %

Procedure:
Following the procedure as described in Preparation 13, making variations as required to replace bromomethyl-2,2-difluorocyclopropane with benzyl bromide to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 93% yield: mp 122-124° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.35-7.26 (m, 5H), 4.40 (s, 2H), 4.19 (q, J=7.2 Hz, 2H), 3.97 (t, J=7.5 Hz, 2H), 3.42 (t, J=7.5 Hz, 2H), 2.48 (s, 3H), 1.23 (t, J=7.2 Hz, 3H); MS (ES+) m/z 346.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[N:10]=[C:9](I)[S:8][C:6]=2[N:7]=1.[C:18]([NH:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)(=[O:20])[CH3:19]>>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[N:10]=[C:9]([C:26]3[CH:27]=[C:22]([NH:21][C:18](=[O:20])[CH3:19])[CH:23]=[CH:24][CH:25]=3)[S:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2nc(I)sc2n1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Product: CC(=O)Nc1cccc(-c2nc3c(N4CCOCC4)nc(Cl)nc3s2)c1

Procedure:
4-(5-Chloro-2-iodothiazolo[5,4-d]pyrimidin-7-yl)morpholine 18 was reacted with (3-acetylaminophenyl)boronic acid via General Procedure A to give crude N-(3-(5-chloro-7-morpholinothiazolo[5,4-d]pyrimidin-2-yl)phenyl)acetamide, which was then reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine via General Procedure A again to give 124. MS (Q1) 449 (M+)
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6]2=[N:8][CH:9]=[CH:10][C:5]2=[C:4](Cl)[N:3]=1.C([Sn](CCCC)(CCCC)[C:17]1[O:18][CH:19]=[CH:20][CH:21]=1)CCC>CN(C=O)C.C(OCC)C.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>[Cl:1][C:2]1[NH:7][C:6]2=[N:8][CH:9]=[CH:10][C:5]2=[C:4]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: Clc1nc(Cl)c2ccnc-2[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Clc1nc(-c2ccco2)c2ccnc-2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.4 %

Procedure:
A solution of 2,4-dichloro-1H-pyrrolo[2,3-d]pyrimidine (4.1 g, 21.8 mmol) in DMF (20 mL) was treated with PdCl2(PPh3)2 (772 mg, 0.17 mmol) and 2-(tributylstannyl)-furan (6.9 mL, 21.8 mmol), stirred at room temperature for 16 h, diluted with diethyl ether and filtered to give the title compound (2.94 g, 61%) as a pale orange solid.