Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]([CH2:11][CH3:12])=[C:9]2[C:5]([C:6]3[CH2:16][CH2:15][O:14][C:13]([CH2:19][C:20]([O:22]CC)=[O:21])([CH2:17][CH3:18])[C:7]=3[NH:8]2)=[CH:4][CH:3]=1.O.[OH-].[Li+].O>O1CCOCC1>[Br:1][C:2]1[C:10]([CH2:11][CH3:12])=[C:9]2[C:5]([C:6]3[CH2:16][CH2:15][O:14][C:13]([CH2:19][C:20]([OH:22])=[O:21])([CH2:17][CH3:18])[C:7]=3[NH:8]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC1(CC)OCCc2c1[nH]c1c(CC)c(Br)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCc1c(Br)ccc2c3c([nH]c12)C(CC)(CC(=O)O)OCC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
To a stirred solution of ethyl 2-(7-bromo-1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetate (2.8 g, 5 mmol) in dioxane (40 ml) was added lithium hydroxide monohydrate (2.8 g, 67 mmol) and water (30 ml). The mixture was stirred at room temperature overnight. It was concentrated under reduced pressure, neutralized with 5% HCl, extracted with CH2Cl2, dried over MgSO4, and concentrated. The crude product was recrystallized in dichloromethane/hexane (60 ml/20 ml) to give a white solid (980 mg, 53%). 1H NMR (300 MHz, CDCl3) δ 8.68 (br, NH)), 7.27 (d, 1H), 7.19 (d, 1H), 4.06 (m, 2H), 3.04 (qrt, 2H), 2.95 (qrt, 2H), 2.80 (m, 2H), 2.09 (m, 2H), 1.24 (t, 3H), 0.874 (t, 3H).
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([C:16]#[C:17][C:18]3[CH:19]=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=3)=[C:14]([CH2:25][CH3:26])[N:13]=[CH:12][N:11]=2)=[CH:6][CH:5]=1.[Li+].[OH-]>O.C1COCC1>[NH2:24][C:21]1[N:20]=[CH:19][C:18]([C:17]#[C:16][C:15]2[C:10]([C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:27])=[O:2])=[CH:9][CH:8]=3)=[N:11][CH:12]=[N:13][C:14]=2[CH2:25][CH3:26])=[CH:23][CH:22]=1
Reactant: CCc1ncnc(-c2ccc(C(=O)OC)cc2)c1C#Cc1ccc(N)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1ncnc(-c2ccc(C(=O)O)cc2)c1C#Cc1ccc(N)nc1
Temperature: 50 °C

Procedure:
The title compound is synthesized according to general procedure GP8 starting from 2.25 g (6.28 mmol) 4-[5-(6-amino-pyridin-3-ylethynyl)-6-ethyl-pyrimidin-4-yl]-benzoic acid methyl ester using 1.32 g (31.4 mmol.) LiOH in 5 mL water and 50 mL THF. The reaction mixture is stirred over night at 50° C. The solvent is removed under reduced pressure and the residue is taken up in water. Aqueous 1 M HCl is added until pH 5 is reached. The precipitated product is filtered off and taken up in water. After freeze drying 2.3 g of crude product are obtained which is used for the next step without further purification.
Reaction SMILES: Cl.C([O:4][C:5]([C:7]1[NH:18][C:17]2[C:12](=[CH:13][C:14]([Br:19])=[CH:15][CH:16]=2)[C:8]=1[CH2:9][CH2:10][NH2:11])=[O:6])C.C(O)C.[OH-].[Na+]>C(O)(=O)C>[Br:19][C:14]1[CH:13]=[C:12]2[C:17]([NH:18][C:7]([C:5]([OH:6])=[O:4])=[C:8]2[CH2:9][CH2:10][NH2:11])=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1[nH]c2ccc(Br)cc2c1CCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: NCCc1c(C(=O)O)[nH]c2ccc(Br)cc12
Yield: 91 %

Procedure:
1.00 g. (2.87 mmoles) of ethyl-5-bromo-tryptamine-2-carboxylate hydrochloride are boiled for 2 hours in a mixture of 10 ml. of ethanol and 10 ml. of 4 n aqueous sodium hydroxide solution. The mixture is cooled with ice, acidified to pH 6 with glacial acetic acid, and the separated crystals are collected by filtration. 0.75 g. (91%) of 5-bromo-tryptamine-2-carboxylic acid are obtained; m.p.; 248°-249° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[C:8]([F:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:5]=2[NH2:14])[CH2:3][CH2:2]1.C([O-])(O)=O.[Na+].[CH3:20][CH:21]([CH3:25])[C:22](Cl)=[O:23]>ClCCl.O>[CH:1]1([C:4]2[CH:9]=[C:8]([F:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:5]=2[NH:14][C:22](=[O:23])[CH:21]([CH3:25])[CH3:20])[CH2:3][CH2:2]1
Reactant: CC(C)C(=O)Cl
Reactant: Nc1cc([N+](=O)[O-])c(F)cc1C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)C(=O)Nc1cc([N+](=O)[O-])c(F)cc1C1CC1
Reaction time: 8 h
Yield: 75.9 %

Procedure:
To a solution of 2-cyclopropyl-4-fluoro-5-nitrobenzenamine (as described in WO2011068898) (1.98 g, 10.09 mmol, 1 equiv) in dichloromethane (50 mL) at room temperature, was added NaHCO3 (7.65 g, 90.84 mmol, 9 equiv), followed by 2-methylpropanoyl chloride (6.34 mL, 60.56 mmol, 6 equiv). The reaction mixture was stirred overnight. The reaction mixture was taken in water, and the layers were separated. The organic layer was washed with ice-cold 1N NaOH 2×, brine 1×, dried over Na2SO4, and concentrated to dryness. The crude product was absorbed onto silica gel and purified by flash chromatography and eluted with hex:EtOAc=100:0 to 50%-70% EtOAc using 10% EtOAc increments to afford N-(2-cyclopropyl-4-fluoro-5-nitrophenyl)isobutyramide (2.04 g, 84%) as a light-brown solid.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[NH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1.C(O)(=O)C>C(OCC)(=O)C>[F:19][C:16]([F:17])([F:18])[C:12]1[CH:11]=[C:10]([NH:9][C:1]2[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH:2]=2)[CH:15]=[CH:14][N:13]=1
Reactant: Nc1ccnc(C(F)(F)F)c1
Reactant: O=C1CCCC(=O)C1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C1C=C(Nc2ccnc(C(F)(F)F)c2)CCC1
Temperature: 130 °C

Procedure:
A mixture of cyclohexane-1,3-dione (2.00 g, 17.8 mmol), 4-amino-2-trifluormethylpyridine (2.89 g, 17.8 mmol) and glacial acetic acid (10 mL) is heated at 130° C. for 4 h. The mixture cooled at room temperature, diluted with ethyl acetate and extracted three times with water. The phases are separated, and the aqueous layer is extracted with ethyl acetate. The combined organic layers are dried over Na2SO4 and concentreated under reduced pressure. The residue is purified by flash chromatography on silica (gradient dichloromethane/is methanol 95:5). Yield: 940 mg; ESI mass spectrum [M+H]+=257; Retention time HPLC: 0.80 min (V011_S01).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]2[C@H:10]([C:11]([C:16]3[CH:17]=[N:18][C:19](OC)=[CH:20][CH:21]=3)=[N:12][O:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON=C(Cl)C1C=NC([C:33]([F:36])([F:35])[F:34])=CC=1>>[C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]2[C@H:10]([C:11]([C:16]3[CH:17]=[N:18][C:19]([C:33]([F:36])([F:35])[F:34])=[CH:20][CH:21]=3)=[N:12][O:13]2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(C2=NO[C@H]3CN(C(=O)OC(C)(C)C)C[C@@H]23)cn1
Reactant: ON=C(Cl)c1ccc(C(F)(F)F)nc1
Product: CC(C)(C)OC(=O)N1C[C@@H]2ON=C(c3ccc(C(F)(F)F)nc3)[C@@H]2C1

Procedure:
The title compound was prepared in an analogous manner as the 4-methoxy-3-pyridyl cycloadduct 3c using chloro oxime 2d. 3d was isolated as a white solid after chromatography with 25% ethyl acetate/hexanes.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.C(N(CC)CC)C.[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>ClCCl>[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:1]2[CH2:5][CH2:4][CH2:3][C@H:2]2[CH2:6][N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: C1CN[C@H](CN2CCCC2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)cc1)N1CCC[C@H]1CN1CCCC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 83.3 %

Procedure:
(S)(+)-1-(2-Pyrrolidinylmethyl)pyrrolidine (1.07 g, 6.93 mmol) and triethylamine (763 mg, 7.56 mmol) are dissolved in dichloromethane (20 mL) and cooled to 0° C. 4-Fluorobenzoyl chloride (1.00 g, 6.3 mmol) in dichloromethane (2 mL) is added to the mixture at 0° C. and stirred at room temperature for 3 h. The reaction mixture is washed with brine, dried over Na2SO4, and evaporated. The residue is purified by silica-gel column chromatography (CH2Cl2:2M NH3 in MeOH=40:1) to give 1.45 g (83%) of the title compound. MS (APCI+) 277(M+1)+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[C:17]([NH:19][C:20]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=3)=[O:21])[N:16]=[C:15]([NH:29][C:30]([CH:32]([N:34]([CH3:42])[C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH3:33])=[O:31])[CH:14]=2)[C:5]2[N:10]([CH3:11])[N:9]=[C:8]([CH3:12])[C:6]=2[N:7]=1.[CH3:43][O-:44].[Na+].CO>O>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]([NH:19][C:17]2[N:16]=[C:15]([NH:29][C:30]([CH:32]([N:34]([CH3:42])[C:35](=[O:41])[O:36][C:37]([CH3:38])([CH3:39])[CH3:40])[CH3:33])=[O:31])[CH:14]=[C:13]([C:4]3[C:5]4[N:10]([CH3:11])[N:9]=[C:8]([CH3:12])[C:6]=4[N:7]=[C:2]([O:44][CH3:43])[N:3]=3)[CH:18]=2)=[O:21])=[N:23][CH:24]=1
Reactant: Cc1nn(C)c2c(-c3cc(NC(=O)c4ccc(Cl)cn4)nc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)c3)nc(Cl)nc12
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1nc(-c2cc(NC(=O)c3ccc(Cl)cn3)nc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)c2)c2c(n1)c(C)nn2C
Temperature: 50 °C
Reaction time: 1.17 h

Procedure:
A mixture of tert-butyl N-{1-[(4-{5-chloro-1,3-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl}-6-(5-chloropyridine-2-amido)pyridin-2-yl)carbamoyl]ethyl}-N-methylcarbamate K63a (54 mg, 88 μmol), sodium methoxide (24 mg, 439 μmol) and methanol (400 μl) is stirred at 50° C. for 70 minutes. At RT water (10 ml) is added and the mixture extracted with DCM. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 30 mg (56%). HPLC-MS: M+H=610; tR=1.12 min (METHOD—2).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[F:9][C:10]([F:18])([F:17])[C:11]([C:13]([F:16])([F:15])[F:14])=[O:12]>[Cl-].[Al+3].[Cl-].[Cl-].Cl>[F:9][C:10]([F:18])([F:17])[C:11]([C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[CH3:1])([OH:12])[C:13]([F:16])([F:15])[F:14]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: Cc1ccc(C)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc(C)c(C(O)(C(F)(F)F)C(F)(F)F)c1
Reaction time: 3 h
Yield: 88.2 %

Procedure:
A 1 L reactor was charged under nitrogen with 200.0 g (1.88 mol) of p-xylene and 12.5 g (0.094 mol/0.06 eq) of aluminum chloride, followed by adjusting the inside temperature to 18° C. Then, 327.7 g (1.97 mol/1.06 eq) of hexafluoroacetone was introduced in a temperature range of 18-25° C. After the introduction, stirring was conducted at room temperature for 3 hr. Then, 200 mL of 10% hydrochloric acid was added. The resulting aqueous layer was extracted two times with 50 mL of chloroform. The resulting organic layers were combined together, followed by removing water with anhydrous magnesium sulfate, filtration, concentration, and vacuum distillation, thereby obtaining 451.3 g of 2-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-1,4-dimethylbenzene represented by the following formula. Upon this, purity was 92%, and yield was 81%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:9]([NH2:11])[CH3:10])=[N:6][C:7]=1[CH3:8].Cl[C:13]1[N:18]=[C:17]([NH:19][C:20]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[NH:22][N:21]=2)[C:16]([Cl:28])=[CH:15][N:14]=1.CCN(C(C)C)C(C)C>CCCCO>[Cl:28][C:16]1[C:17]([NH:19][C:20]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[NH:22][N:21]=2)=[N:18][C:13]([NH:11][CH:9]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[C:7]([CH3:8])[N:6]=2)[CH3:10])=[N:14][CH:15]=1
Reactant: Cc1nc(C(C)N)ccc1F
Reactant: Clc1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1nc(C(C)Nc2ncc(Cl)c(Nc3cc(C4CC4)[nH]n3)n2)ccc1F
Temperature: 175 °C
Yield: 27.5 %

Procedure:
A microwave reaction vessel was charged with [1-(5-fluoro-6-methylpyridin-2-yl)ethyl]amine (Method 13; 159 mg, 1.03 mmol), 2,5-dichloro-4-(5-cyclopropyl-1H-pyrazole-3-ylamino)pyrimidine (Method 7; 335 mg, 1.24 mmol) and DIEA (0.35 ml, 2.0 mmol). Anhydrous n-BuOH (1.5 ml) was added, and the tube was sealed and heated in a microwave reactor at 175° C. for 10 hours. The resulting mixture was partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc, and the combined organics were washed with brine, dried, filtered, chromatography (Rf in 50:50 hexanes:EtOAc=0.25) to afford the title compound as a colourless solid (110 mg, 28%). 1H NMR (400 MHz, CDCl3) δ 0.65-0.75 (m, 2H), 0.85-0.95 (m, 2H), 1.47 (d, J=6.8 Hz, 3H), 1.82 (tt, J=8.5, 5.1 Hz, 1H), 2.46 (d, J=2.8 Hz, 3H), 4.99-5.09 (m, 1H), 6.01 (s, 1H), 6.26 (s, 1H), 7.05 (dd, J=8.3, 3.5 Hz, 1H), 7.15-7.23 (m, 1H), 7.38-7.48 (m, 1H), 7.84 (s, 1H). Calcd.: 387. Found [M+H+] 388.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH:12]([CH2:14][CH3:15])[CH3:13])[CH:6]=1.[OH-].[Na+]>CO>[CH:12]([O:11][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([OH:16])=[O:2])[CH:10]=[CH:9][CH:8]=1)([CH2:14][CH3:15])[CH3:13]
Reactant: CCC(C)Oc1cccc(CC(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(C)Oc1cccc(CC(=O)O)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
To 3-hydroxyphenyl acetic acid methyl ester (27.3 g, 165 mmol) in acetone (200 mL) was added 2-iodobutane (55 mL, 478 mmol) and potassium carbonate (83 g, 601 mmol). The mixture was heated at 65° C. for 48 hrs and filtered through a Celite® pad. The filtrate was concentrated in vacuo and the residue was diluted with dichloromethane and water. The aqueous phase was extracted with dichloromethane (3×100 mL). The combined extracts were washed with saturated sodium chloride (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford (3-sec-butoxy-phenyl)-acetic acid methyl ester. To a solution of (3-sec-butoxy-phenyl)-acetic acid methyl ester in methanol (200 mL) was added 10N sodium hydroxide solution (50 mL). The reaction mixture was stirred at 60° C. for 4 hrs. The solvent was evaporated and the mixture was acidified to pH=3 by addition of 6N hydrogen chloride solution. The aqueous phase was extracted with dichloromethane (3×100 m]L). The combined extracts were washed with saturated aqueous sodium chloride solution (80 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford (3-sec-butoxy-phenyl) acetic acid (25 g, 73% yield) as a light brown oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:23][CH2:22][C:21]3[C:16]([CH2:25][C:26]4[CH:31]=[CH:30][C:29](B5OC(C)(C)C(C)(C)O5)=[CH:28][CH:27]=4)([CH2:17][CH2:18][C:19](=[O:24])[CH:20]=3)[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CCN1[N:64]=[C:63]2[C:50]3C(SC4C2=CC=CC=4)=C(C)[CH:53]=[CH:54][C:49]1=3)CC>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]2[CH2:23][CH2:22][C:21]3[C:16]([CH2:25][C:26]4[CH:27]=[CH:28][C:29]([N:64]5[CH2:53][CH2:54][CH2:49][CH2:50][CH2:63]5)=[CH:30][CH:31]=4)([CH2:17][CH2:18][C:19](=[O:24])[CH:20]=3)[CH2:15]2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN(CC)CCn1nc2c3c(c(C)ccc31)Sc1ccccc1-2
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2CCC3=CC(=O)CCC3(Cc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)C2)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)N2CCC3=CC(=O)CCC3(Cc3ccc(N4CCCCC4)cc3)C2)cc1

Procedure:
The following compounds were similarly prepared from 2-(4-t-Butylbenzenesulfonyl)-8a-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzyl]-1,3,4,7,8,8a-hexahydro-2H-isoquinolin-6-one (IA-5: Y=4-(B(OC(CH3)2C(CH3)2O)):
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10](O)[C:9]2[CH2:8][CH2:7][CH2:6][C:5]([CH3:19])([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[N:3]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:10]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5]([CH3:19])([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[N:3]=[C:2]([CH3:1])[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc(O)c2c(n1)C(C)(c1ccccc1)CCC2
Product: Cc1nc(Cl)c2c(n1)C(C)(c1ccccc1)CCC2

Procedure:
A mixture of 2,8-dimethyl-8-phenyl-5,6,7,8-tetrahydro-quinazolin-4-ol (4 g, 16 mmol) and 25 mL of phosphorous oxychloride was heated under reflux for 2 hours, concentrated under reduced pressure and ice, water and dichloromethane were added. The mixture was basified with aqueous sodium carbonate and the organic layer was dried (sodium sulfate) and evaporated to afford 4.4 g of 4-chloro-2,8-dimethyl-8-phenyl-5,6,7,8-tetrahydroquinazoline as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=3[F:42])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[C:23]=3[CH3:33])=[CH:16][CH:15]=2)=[CH:9][C:3]=1[O:4][CH2:5][C:6](O)=[O:7].Cl.C([O:46][C:47](=[O:51])[CH2:48][CH2:49][NH2:50])C>>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=3[F:42])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][S:29]([CH3:32])(=[O:30])=[O:31])[C:23]=3[CH3:33])=[CH:16][CH:15]=2)=[CH:9][C:3]=1[O:4][CH2:5][C:6]([NH:50][CH2:49][CH2:48][C:47]([OH:51])=[O:46])=[O:7]
Reactant: CCOC(=O)CCN
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccc(Oc2ccc(Cl)c(OCC(=O)O)c2)cc1)Cc1ccc(F)cc1F
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccc(Oc2ccc(Cl)c(OCC(=O)NCCC(=O)O)c2)cc1)Cc1ccc(F)cc1F

Procedure:
The product from Example 91I and β-alanine ethyl ester hydrochloride was processed as described in Example 104B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ8.97 (s, 1 H), 7.94 (t, 1 H), 7.40 (d, 1 H), 6.87-7.35 (m, 10 H), 6.76 (d, 1 H), 6.50 (dd, 1 H), 4.56 (s, 2 H), 4.08 (s, 2 H), 4.06 (s, 2 H), 3.32 (q, 2 H), 2.90 (s, 3 H), 2.39 (t, 3 H), 2.33 (s, 3 H); MS (ESI) m/z 688 (M+H+).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:7]1)=[O:5])C.C(O)C.[OH-].[Na+].[ClH:36]>ClCCl>[ClH:36].[C:25]1([N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCCCCCN(c2ccccc2)c2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: O=C(O)[C@@H]1CCCN(CCCCCCN(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The ester prepared in Example 3 (3.4 g, 8.3 mmol) was dissolved into ethanol (10 ml) and a 12 N sodium hydroxide solution (1.5 ml) was added. The reaction mixture was stirred at room temperature for 6 h. A concentrated hydrochloric acid solution (2.3 ml) was added with cooling of the reaction vessel in an ice-bath and dichloromethane (300 ml) was added. The resulting emulsion was dried over sodium sulphate and the solvent evaporated in vacuo to give a residue which was crystallised from ethyl acetate. This afforded 2.8 g (81% of the title compound.
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]N)=[CH:33][C:32]=2[CH3:42])=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=[O:3])[CH3:2].[CH2:46]([O:53][C:54]([NH:56][C:57]([N:59]1C=CC=N1)=[NH:58])=[O:55])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>O1CCCC1>[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][N:56]([C:54]([O:53][CH2:46][C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)=[O:55])[C:57]([NH2:59])=[NH:58])=[CH:33][C:32]=2[CH3:42])=[C:28]([CH:43]([CH3:44])[CH3:45])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: N=C(NC(=O)OCc1ccccc1)n1cccn1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCN)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCN(C(=N)N)C(=O)OCc3ccccc3)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 60 °C
Reaction time: 20 h
Yield: 55.9 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)-2-methylphenyl]-methyl}-5-isopropyl-1H-pyrazole (70 mg) in tetrahydrofuran (3 mL) was added N-(benzyloxycarbonyl)-1H-pyrazole-1-carboxamidine (0.27 g), and the mixture was stirred at 60° C. for 20 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1-ethyl acetate-ethyl acetate/ethanol=10/1) to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[3-(N-benzyloxycarbonylguanidino)propoxy]-2-methylphenyl}-methyl)-5-isopropyl-1H-pyrazole (50 mg). This material was dissolved in methanol (1 mL). To the solution was added sodium methoxide (28% methanol solution, 0.01 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give 4-({4-[3-(N′-benzyloxycarbonylguanidino)propoxy]-2-methylphenyl}methyl)-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole (35 mg). This material was dissolved in methanol (2 mL). To the solution was added 10% palladium-carbon powder (15 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give the title compound (27 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22](=[O:24])[CH3:23])=[C:18]([CH3:25])[CH:17]=2)=[C:12]([CH:26]([CH3:28])[CH3:27])[N:11]=[N:10]1.[CH3:29][Mg]Br>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([OH:24])([CH3:29])[CH3:23])=[C:18]([CH3:25])[CH:17]=2)=[C:12]([CH:26]([CH3:28])[CH3:27])[N:11]=[N:10]1
Reactant: C[Mg]Br
Reactant: CC(=O)c1ccc(OCc2c(C(C)C)nnn2-c2c(Cl)cccc2Cl)cc1C
Solvent: C1CCOC1
Product: Cc1cc(OCc2c(C(C)C)nnn2-c2c(Cl)cccc2Cl)ccc1C(C)(C)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.1 %

Procedure:
To a −78° C. solution of 1-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-ethanone (500 mg, 1.19 mmol) in THF (12 mL) is added methylmagnesium bromide (2.0 mL, 5.98 mmol, 3.0 M in THF) dropwise. The reaction mixture is warmed to room temperature. After 4 h, the reaction is cooled to 0° C., quenched with NH4Cl, and warmed to room temperature. The reaction mixture is concentrated and the residue is partitioned between Et2O and 1N HCl. The aqueous layer is extracted with Et2O and the combined organic layers are washed with brine, dried (MgSO4), filtered, concentrated and chromatographed eluting with 0% to 30% EtOAC/Hexane to yield the title compound (414 mg, 80%). 1H NMR (400 MHz, CDCl3) δ 7.49-7.46 (m, 2H), 7.43-7.38 (m, 1H), 7.23-7.19 (m, 2H), 6.70 (d, 1H, J=8.8 Hz), 4.89 (s, 2H), 3.20 (sept, 1H, J=6.6 Hz), 2.04 (s, 3H), 1.53 (s, 6H), 1.45 (d, 6H, J=6.6 Hz).
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.F[C:12]1[C:17]([S:18][CH2:19][CH2:20][CH3:21])=[CH:16][CH:15]=[CH:14][N:13]=1>O>[C:4]1([CH2:3][S:10][C:12]2[C:17]([S:18][CH2:19][CH2:20][CH3:21])=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCCSc1cccnc1F
Reactant: SCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCCSc1cccnc1SCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.2 %

Procedure:
To a stirred suspension of 0.62 g (0.013 mol) of 50% sodium hydride (in mineral oil), which had been washed with hexanes, in 20 mls dry dimethylformamide cooled to -5° under nitrogen was added dropwise 1.6 g (0.013 mol) benzyl mercaptan such that the temperature was maintained below 5°. The suspension was stirred at room temperature for 1 hour, cooled to 0°, and a solution of 2.0 g (0.012 mol) of the product from Example 1 was added dropwise while maintaining the temperature between 0° and 5°. After warming to room temperature, the solution was poured into water and extracted with ether. The combined organic layers were washed with water and with brine, dried over magnesium sulfate, and evaporated to an oil which was purified by flash chromatography to afford 0.9 g (27%) oil: NMR (CDCl3, 200 MHz), 1.02 (3H, t, J=7 Hz), 1.6 (2H, m), 2.9 (2H, t, J=7 Hz), 4.45 (2H, s), 6.9-7.6 (7H, m), 8.3 (1H, m); IR (neat) 1560, 1370 cm-1.